US20030021781A1 - Therapeutic application of chimeric and radiolabelled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma - Google Patents
Therapeutic application of chimeric and radiolabelled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma Download PDFInfo
- Publication number
- US20030021781A1 US20030021781A1 US09/905,928 US90592801A US2003021781A1 US 20030021781 A1 US20030021781 A1 US 20030021781A1 US 90592801 A US90592801 A US 90592801A US 2003021781 A1 US2003021781 A1 US 2003021781A1
- Authority
- US
- United States
- Prior art keywords
- antibody
- human
- cells
- antibodies
- cell
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1027—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2799/00—Uses of viruses
- C12N2799/02—Uses of viruses as vector
- C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
- C12N2799/028—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a herpesvirus
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
- Y10S424/80—Antibody or fragment thereof whose amino acid sequence is disclosed in whole or in part
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
- Y10S424/801—Drug, bio-affecting and body treating compositions involving antibody or fragment thereof produced by recombinant dna technology
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/808—Materials and products related to genetic engineering or hybrid or fused cell technology, e.g. hybridoma, monoclonal products
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/808—Materials and products related to genetic engineering or hybrid or fused cell technology, e.g. hybridoma, monoclonal products
- Y10S530/809—Fused cells, e.g. hybridoma
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/867—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof involving immunoglobulin or antibody produced via recombinant dna technology
Definitions
- the present invention is directed to the treatment of B cell lymphoma using chimeric and radiolabeled antibodies to the B cell surface antigen Bp35 (“CD20”).
- CD20 B cell surface antigen Bp35
- the immune system of vertebrates (for example, primates, which include humans, apes, monkeys, etc.) consists of a number of organs and cell types which have evolved to: accurately and specifically recognize foreign microorganisms (“antigen”) which invade the vertebrate-host; specifically bind to such foreign microorganisms; and, eliminate/destroy such foreign microorganisms.
- Lymphocytes amongst others, are critical to the immune system. Lymphocytes are produced in the thymus, spleen and bone marrow (adult) and represent about 30% of the total white blood cells present in the circulatory system of humans (adult). There are two major sub-populations of lymphocytes: T cells and B cells.
- T cells are responsible for cell mediated immunity, while B cells are responsible for antibody production (humoral immunity).
- T cells and B cells can be considered as interdependent—in a typical immune response, T cells are activated when the T cell receptor binds to fragments of an antigen that are bound to major histocompatability complex (“MHC”) glycoproteins on the surface of an antigen presenting cell; such activation causes release of biological mediators (“interleukins”) which, in essence, stimulate B cells to differentiate and produce antibody (“immunoglobulins”) against the antigen.
- MHC major histocompatability complex
- each B cell within the host expresses a different antibody on it surface one B cell will express antibody specific for one antigen, while another B cell will express antibody specific for a different antigen. Accordingly, B cells are quite diverse, and this diversity is critical to the immune system. In humans, each B cell can produce an enormous number of antibody molecules (ie about 10 7 to 10 8 ). Such antibody production most typically ceases (or substantially decreases) when the foreign antigen has been neutralized. Occasionally, however, proliferation of a particular B cell will continue unabated; such proliferation can result in a cancer referred to as “B cell lymphoma.”
- T cells and B cells both comprise cell surface proteins which can be utilized as “markers” for differentiation and identification.
- One such human B cell marker is the human B lymphocyte-restricted differentiation antigen Bp35, referred to as “CD20.”
- CD20 is expressed during early pre-B cell development and remains until plasma cell differentiation. Specifically, the CD20 molecule may regulate a step in the activation process which is required for cell cycle initiation and differentiation and is usually expressed at very high levels on neoplastic (“tumor”) B cells.
- CD20 by definition, is present on both “normal” B cells as well as “malignant” B cells, ie those B cells whose unabated proliferation can lead to B cell lymphoma.
- the CD20 surface antigen has the potential of serving as a candidate for “targeting” of B cell lymphomas.
- such targeting can be generalized as follows: antibodies specific to the CD20 surface antigen of B cells are, eg injected into a patient. These anti-CD20 antibodies specifically bind to the CD20 cell surface antigen of (ostensibly) both normal and malignant B cells; the anti-CD20 antibody bound to the CD20 surface antigen may lead to the destruction and depletion of neoplastie B cells. Additionally, chemical agents or radioactive labels having the potential to destroy the tumor can be conjugated to the anti-CD20 antibody such that the agent is specifically “delivered” to, eg, the neoplastic B cells. Irrespective of the approach, a primary goal is to destroy the tumor: the specific approach can be determined by the particular anti-CD20 antibody which is utilized and, thus, the available approaches to targeting the CD20 antigen can vary considerably.
- Murine (mouse) monoclonal antibody 1F5 an anti-CD20 antibody
- IF5 an anti-CD20 antibody
- IF5 Extremely high levels (>2 grams) of IF5 were reportedly required to deplete circulating tumor cells, and the results were described as being “transient.” Press et al., “Monoclonal Antibody 1F5 (Anti-CD20) Serotherapy of Human B-Cell Lymphomas.” Blood 69/2:584-591 (1987).
- non-human monoclonal antibodies typically lack human effector functionality, ie they are unable to, inter alia, mediate complement dependent lysis or lyse human target cells through antibody dependent cellular toxicity or Fc-receptor mediated phagocytosis.
- non-human monoclonal antibodies can be recognized by the human host as a foreign protein; therefore, repeated injections of such foreign antibodies can lead to the induction of immune responses leading to harmful hypersensitivity reactions.
- HAMA Human Anti-Mouse Antibody response
- these “foreign” antibodies can be attacked by the immune system of the host such that they are, in effect, neutralized before they reach their target site.
- Lymphocytes and lymphoma cells are inherently sensitive to radiotherapy for several reasons: the local emission of ionizing radiation of radiolabeled antibodies may kill cells with or without the target antigen (eg, CD20) in close proximity to antibody bound to the antigen; penetrating radiation may obviate the problem of limited access to the antibody in bulky or poorly vascularized tumors; and, the total amount of antibody required may be reduced.
- the radionuclide emits radioactive particles which can damage cellular DNA to the point where the cellular repair mechanisms are unable to allow the cell to continue living; therefore, if the target cells are tumors, the radioactive label beneficially kills the tumor cells.
- Radiolabeled antibodies include the use of a radioactive substance which may require the need for precautions for both the patient (ie possible bone marrow transplantation) as well as the health care provider (ie the need to exercise a high degree of caution when working with the radioactivity).
- an approach at improving the ability of murine monoclonal antibodies to be effective in the treatment of B-cell disorders has been to conjugate a radioactive label or toxin to the antibody such that the label or toxin is localized at the tumor site.
- the above-referenced IF5 antibody has been “labeled” with iodine-131 (“ 131 I”) and was reportedly evaluated for biodistribution in two patients. See Eary, J. F. et al., “Imaging and Treatment of B-Cell Lymphoma” J. Nuc. Med. 31/8:1257-1268 (1990); see also, Press, O. W.
- Toxins ie chemotherapeutic agents such as doxorubicin or mitomycin C have also been conjugated to antibodies. See, for example, PCT published application WO 92/07466 (published May 14, 1992).
- “Chimeric” antibodies ie antibodies which comprise portions from two or more different species (eg, mouse and human) have been developed as an alternative to “conjugated” antibodies.
- Liu, A. Y. et al. “Production of a Mouse-Human Chimeric Monoclonal Antibody to CD20 with Potent Fc-Dependent Biologic Activity” J. Immun. 139/10:3521-3526 (1987), describes a mouse/human chimeric antibody directed against the CD20 antigen. See also, PCT Publication No. WO 88/04936.
- no information is provided as to the ability, efficacy or practicality of using such chimeric antibodies for the treatment of B cell disorders in the reference.
- B cell lymphomas Disclosed herein are therapeutic methods designed for the treatment of B cell disorders, and in particular, B cell lymphomas. These protocols are based upon the administration of immunologically active chimeric anti-CD20 antibodies for the depletion of peripheral blood B cells, including B cells associated with lymphoma; administration of radiolabeled anti-CD20 antibodies for targeting localized and peripheral B cell associated tumors; and administration of chimeric anti-CD20 antibodies and radiolabeled anti-CD20 antibodies in a cooperative therapeutic strategy.
- FIG. 1 is a diagrammatic representation of a tandem chimeric antibody expression vector useful in the production of immunologically active chimeric anti-CD20 antibodies (“TCAE 8”);
- FIGS. 2A through 2E are the nucleic acid sequence of the vector of FIG. 1;
- FIGS. 3A through 3F are the nucleic acid sequence of the vector of FIG. 1 further comprising murine light and heavy chain variable regions (“anti-CD20 in TCAE 8”);
- FIG. 4 is the nucleic acid and amino acid sequences (including CDR and framework regions) of murine variable region light chain derived from murine anti-CD20 monoclonal antibody 2B8;
- FIG. 5 is the nucleic acid and amino acid sequences (including CDR and framework regions) of murine variable region heavy chain derived from murine anti-CD20 monoclonal antibody 2B8;
- FIG. 6 are flow cytometry results evidencing binding of fluorescent-labeled human C1q to chimeric anti-CD20 antibody, including, as controls labeled C1q; labeled C1q and murine anti-CD20 monoclonal antibody 2B8; and labeled C1q and human IgG1,k;
- FIG. 7 represents the results of complement related lysis comparing chimeric anti-CD20 antibody and murine anti-CD20 monoclonal antibody 2B8;
- FIG. 8 represents the results of antibody mediated cellular cytotoxicity with in vivo human effector cells comparing chimeric anti-CD20 antibody and 2B8;
- FIGS. 9A, 9B and 9 C provide the results of non-human primate peripheral blood B lymphocyte depletion after infusion of 0.4 mg/kg (A); 1.6 mg/kg (B); and 6.4 mg/kg (C) of immunologically active chimeric anti-CD20 antibody;
- FIG. 10 provides the results of, inter alia, non-human primate peripheral blood B lymphocyte depletion after infusion of 0.01 mg/kg of immunologically active chimeric anti-CD20 antibody;
- FIG. 11 provides results of the tumoricidal impact of Y2B8 in a mouse xenographic model utilizing a B cell lymphoblastic tumor
- FIG. 12 provides results of the tumoricidal impact of C2B8 in a mouse xenographic model utilizing a B cell lymphoblastic tumor
- FIG. 13 provides results of the tumoricidal impact of a combination of Y2B8 and C2B8 in a mouse xenographic model utilizing a B cell lymphoblastic tumor
- FIGS. 14A and 14B provide results from a Phase I/II clinical analysis of C2B8 evidencing B-cell population depletion over time for patients evidencing a partial remission of the disease ( 14 A) and a minor remission of the disease ( 14 B).
- antibodies are composed of two light chains and two heavy chain molecules; these chains form a general “Y” shape, with both light and heavy chains forming the arms of the Y and the heavy chains forming the base of the Y.
- Light and heavy chains are divided into domains of structural and functional homology.
- the variable domains of both the light (“V L ”) and the heavy (“V H ”) chains determine recognition and specificity.
- the constant region domains of light (“C L ”) and heavy (“C H ”) chains confer important biological properties, eg antibody chain association, secretion, transplacental mobility, Fc receptor binding complement binding, etc.
- the series of events leading to immunoglobulin gene expression in the antibody producing cells are complex.
- variable domain region gene sequences are located in separate germ line gene segments referred to as “V H ,” “D,” and “J H ,” or “V L ” and “J L .” These gene segments are joined by DNA rearrangements to form the complete V regions expressed in heavy and light chains, respectively. The rearranged, joined V segments (V L -J L and V H -D-J H ) then encode the complete variable regions or antigen binding domains of light and heavy chains, respectively.
- anti-CD20 antibody is an antibody which specifically recognizes a cell surface non-glycosylated phosphoprotein of 35,000 Daltons, typically designated as the human B lymphocyte restricted differentiation antigen Bp35, commonly referred to as CD20.
- the term “chimeric” when used in reference to anti-CD20 antibodies encompasses antibodies which are most preferably derived using recombinant deoxyribonucleic acid techniques and which comprise both human (including immunologically “related” species, eg, chimpanzee) and non-human components: the constant region of the chimeric antibody is most preferably substantially identical to the constant region of a natural human antibody; the variable region of the chimeric antibody is most preferably derived from a non-human source and has the desired antigenic and specificity to the CD20 cell surface antigen.
- the non-human source can be any vertebrate source which can be used to generate antibodies to a human CD20 cell surface antigen or material comprising a human CD20 cell surface antigen.
- non-human source includes, but is not limited to, rodents (eg, rabbit, rat, mouse, etc.) and non-human primates (eg, Old World Monkey, Ape, etc.).
- rodents eg, rabbit, rat, mouse, etc.
- non-human primates eg, Old World Monkey, Ape, etc.
- the non-human component is derived from a murine source.
- the phrase “immunologically active” when used in reference to chimeric anti-CD20 antibodies means a chimeric antibody which binds human C1q, mediates complement dependent lysis (“CDC”) of human B lymphoid cell lines, and lyses human target cells through antibody dependent cellular cytotoxicity (“ADCC”).
- CDC mediates complement dependent lysis
- ADCC antibody dependent cellular cytotoxicity
- the phrases “indirect labeling” and “indirect labeling approach” both mean that a chelating agent is covalently attached to an antibody and at least one radionuclide is inserted into the chelating agent.
- Preferred chelating agents and radionuclides are set forth in Srivagtava, S. C. and Mease, R. C.,“Progress in Research on Ligands, Nuclides and Techniques for Labeling Monoclonal Antibodies,” Nucl. Med. Bio. 18/6: 589-603 (1991) (“Srivagtava”) which is incorporated herein by reference.
- a particularly preferred chelating agent is 1-isothiocycmatobenzyl-3-methyldiothelene triaminepent acetic acid (“MX-DTPA”); particularly preferred radionuclides for indirect labeling include indium [111] and yttrium [90].
- MX-DTPA 1-isothiocycmatobenzyl-3-methyldiothelene triaminepent acetic acid
- radionuclides for indirect labeling include indium [111] and yttrium [90].
- the phrases “direct labeling” and “direct labeling approach” both mean that a radionuclide is covalently attached directly to an antibody (typically via an amino acid residue).
- Preferred radionuclides are provided in Srivagtava; a particularly preferred radionuclide for direct labeling is iodine [131] covalently attached via tyrosine residues.
- the indirect labeling approach is particularly preferred.
- the therapeutic approaches disclosed herein are based upon the ability of the immune system of primates to rapidly recover, or rejuvenate, peripheral blood B cells. Additionally, because the principal immune response of primates is occasioned by T cells, when the immune system has a peripheral blood B cell deficiency, the need for “extraordinary” precautions (ie patient isolation, etc.) is not necessary. As a result of these and other nuances of the immune systems of primates, our therapeutic approach to B cell disorders allows for the purging of peripheral blood B cells using immunologically active chimeric anti-CD20 antibodies.
- the route of administration of the immunologically active chimeric anti-CD20 antibodies and radioalabeled anti-CD20 antibodies is preferably parenteral; as used herein, the term “parenteral” includes intravenous, intramuscular, subcutaneous, rectal, vaginal or intraperitoneal administration. Of these, intravenous administration is most preferred.
- the immunologically active chimeric anti-CD20 antibodies and radiolabeled anti-CD20 antibodies will typically be provided by standard technique within a pharmaceutically acceptable buffer, for example, sterile saline, sterile buffered water, propylene glycol, combinations of the foregoing, etc.
- a pharmaceutically acceptable buffer for example, sterile saline, sterile buffered water, propylene glycol, combinations of the foregoing, etc.
- Methods for preparing parenteraly administerable agents are described in Pharmaceutical Carriers & Formulations, Martin, Remington's Pharmaceutical Sciences, 15th Ed. (Mack Pub. Co., Easton, Pa. 1975), which is incorporated herein by reference.
- the specific, therapeutically effective amount of immunologically active chimeric anti-CD20 antibodies useful to produce a unique therapeutic effect in any given patient can be determined by standard techniques well known to those of ordinary skill in the art.
- Effective dosages ie therapeutically effective amounts of the immunologically active chimeric anti-CD20 antibodies range from about 0.001 to about 30 mg/kg body weight, more preferably from about 0.01 to about 25 mg/kg body weight, and most preferably from about 0.4 to about 20.0 mg/kg body weight.
- Other dosages are viable; factors influencing dosage include, but are not limited to, the severity of the disease; previous treatment approaches; overall health of the patient; other diseases present, etc. The skilled artisan is readily credited with assessing a particular patient and determining a suitable dosage that falls within the ranges, or if necessary, outside of the ranges.
- Introduction of the immunologically active chimeric anti-CD20 antibodies in these dose ranges can be carried out as a single treatment or over a series of treatments. With respect to chimeric antibodies, it is preferred that such introduction be carried out over a series of treatments; this preferred approach is predicated upon the treatment methodology associated with this disease. While not wishing to be bound by any particular theory, because the immunologically active chimeric anti-CD20 antibodies are both immunologically active and bind to CD20, upon initial introduction of the immunologically active chimeric anti-CD20 antibodies to the individual, peripheral blood B cell depletion will begin; we have observed a nearly complete depletion within about 24 hours post treatment infusion.
- the first “event” then, can be viewed as principally directed to substantially depleting the patient's peripheral blood B cells; the subsequent “events” can be viewed as either principally directed to simultaneously or serially clearing remaining B cells from the system clearing lymph node B cells, or clearing other tissue B cells.
- a preferred treatment course can occur over several stages; most preferably, between about 0.4 and about 20 mg/kg body weight of the immunologically active chimeric anti-CD 20 antibodies is introduced to the patient once a week for between about 2 to 10 weeks, most preferably for about 4 weeks.
- radiolabeled anti-CD20 antibodies With reference to the use of radiolabeled anti-CD20 antibodies, a preference is that the antibody is non-chimeric; this preference is predicted upon the significantly longer circulating half-life of chimeric antibodies vis-a-vis murine antibodies (ie with a longer circulating half-life, the radionuclide is present in the patient for extended periods).
- radiolabeled chimeric antibodies can be beneficially utilized with lower milli-Curries (“mCi”) dosages used in conjunction with the chimeric antibody relative to the murine antibody. This scenario allows for a decrease in bone marrow toxicity to an acceptable level, while maintaining therapeutic utility.
- mCi milli-Curries
- iodine [131] is a well known radionuclide used for targeted immunotherapy.
- the clinical usefulness of iodine [131] can be limited by several factors including: eight-day physical half-life; dehalogenation of iodinated antibody both in the blood and at tumor sites; and emission characteristics (eg large gamma component) which can be suboptimal for localized dose deposition in tumor.
- Yttrium [90] provides several benefits for utilization in radioimmunotherapeutic applications: the 64 hour half-life of yttrium [90] is long enough to allow antibody accumulation by tumor and, unlike eg iodine [131], yttrium [90] is a pure beta emitter of high energy with no accompanying gamma irradiation in its decay, with a range in tissue of 100 to 1000 cell diameters. Furthermore, the minimal amount of penetrating radiation allows for outpatient administration of yttrium [90]-labeled antibodies. Furthermore, interalization of labeled antibody is not required for cell killing, and the local emission of ionizing radiation should be lethal for adjacent tumor cells lacking the target antigen.
- a diagnostic “imaging” radionuclide such as indium [111] can be utilized for determining the location and relative size of a tumor prior to the administration of therapeutic does of yttrium [90]-labeled anti-CD20.
- Indium [111] is particularly preferred as the diagnostic radionuclide because: between about 1 to about 10 mCi can be safely administered without detectable toxicity; and the imaging data is generally predictive of subsequent yttrium [90]-labeled antibody distribution.
- Effective single treatment dosages ie therapeutically effective amounts of yttrium [90] labeled anti-CD20 antibodies range from between about 5 and about 75 mCi, more preferably between about 10 and about 40 mCi.
- Effective single treatment non-marrow ablative dosages of iodine [131] labeled anti-CD20 antibodies range from between about 5 and about 70 mCi, more preferably between about 5 and about 40 mCi.
- Effective single treatment ablative dosages ie may require autologous bone marrow transplantation) of iodine [131] labeled anti-CD20 antibodies range from between about 30 and about 600 mCi, more preferably between about 50 and less than about 500 mCi.
- an effective single treatment non-marrow ablative dosages of iodine [131] labeled chimeric anti-CD20 antibodies range from between about 5 and about 40 mCi, more preferably less than about 30 mCi. Imaging criteria for, eg the indium [111] label, are typically less than about 5 mCi.
- radiolabeled anti-CD20 antibodies therapy therewith can also occur using a single therapy treatment or using multiple treatments. Because of the radionuclide component, it is preferred that prior to treatment, peripheral stem cells (“PSC”) or bone marrow (“BM”) be “harvested” for patients experiencing potentially fatal bone marrow toxicity resulting from radiation. BM and/or PSC are harvested using standard techniques, and then purged and frozen for possible reinfusion.
- PSC peripheral stem cells
- BM bone marrow
- a diagnostic dosimetry study using a diagnostic labeled antibody be conducted on the patient, a purpose of which is to ensure that the therapeutically labeled antibody (eg using yttrium [90]) will not become unnecessarily “concentrated” in any normal organ or tissue.
- the light and heavy chains can be expressed separately, using, for example, immunoglobulin light chain and immunoglobulin heavy chains in separate plasmids. These can then be purified and assembled in vitro into complete antibodies; methodologies for accomplishing such assembly have been described. See, for example, Scharff, M., Harvey Lectures 69:125 (1974). In vitro reaction parameters for the formation of IgG antibodies from reduced isolated light and heavy chains have also been described. See, for example, Beychok, S., Cells of Immunoglobulin Synthesis, Academic Press, New York, p. 69, 1979. Co-expression of light and heavy chains in the same cells to achieve intracellular association and linkage of heavy and light chains into complete H 2 L 2 IgG antibodies is also possible. Such co-expression can be accomplished using either the same or different plasmids in the same host cell.
- Another approach and one which is our most preferred approach for developing a chimeric non-human/human anti-CD20 antibody, is based upon utilization of an expression vector which includes, ab initio, DNA encoding heavy and light chain constant regions from a human source.
- a vector allows for inserting DNA encoding non-human variable region such that a variety of non-human anti-CD20 antibodies can be generated, screened and analyzed for various characteristics (eg type of binding specificity, epitope binding regions, etc.); thereafter, cDNA encoding the light and heavy chain variable regions from a preferred or desired anti-CD20 antibody can be incorporated into the vector.
- TCAE Tandem Chimeric Antibody Expression
- TCAE 8 is a derivative of a vector owned by the assignee of this patent document, referred to as TCAE 5.2 the difference being that in TCAE 5.2, the translation initiation start site of the dominant selectable marker (neomycin phosphostransferase, “NEO”) is a consensus Kozak sequence, while for TCAE 8, this region is a partially impaired consensus Kozak sequence.
- the initiation start site of the dominant selectable marker of the TCAE vectors also referred to as “ANEX vector” vis-a-vis protein expression are disclosed in detail in the co-pending application filed herewith.
- TCAE 8 comprises four (4) transcriptional cassettes, and these are in tandem order, ie a human immunoglobulin light chain absent a variable region; a human immunoglobulin heavy chain absent a variable region; DHFR; and NEO.
- Each transcriptional cassette contains its own eukaryotic promoter and polyadenylation region (reference is made to FIG. 1 which is a diagrammatic representation of the TCAE 8 vector). Specifically:
- the CMV promoter/enhancer in front of the immunoglobulin heavy chain is a truncated version of the promoter/enhancer in front of the light chain, from the Nhe I site at -350 to the Sst I site at ⁇ 16 (see, 41 Cell 521, 1985).
- a human immunoglobulin light chain constant region was derived via amplification of cDNA by a PCR reaction.
- the light chain was isolated from normal human blood (IDEC Pharmaceuticals Corporation, La Jolla, Calif.); RNA therefrom was used to synthesize cDNA which was then amplified using PCR techniques (primers were derived vis-a-vis the consensus from Kabat).
- the heavy chain was isolated (using PCR techniques) from cDNA prepared from RNA which was in turn derived from cells transfected with a human IgG1 vector (see, 3 Prot. Eng. 531, 1990; vector pN ⁇ 1 62).
- amino acids 225 was changed from valine to alanine (GTT to GCA), and amino acid 287 was changed from methionine to lysine (ATG to AAG);
- the human immunoglobulin light and heavy chain cassettes contain synthetic signal sequences for secretion of the immunoglobulin chains;
- the human immunoglobulin light and heavy chain cassettes contain specific DNA restriction sites which allow for insertion of light and heavy immunoglobulin variable regions which maintain the transitional reading frame and do not alter the amino acids normally found in immunoglobulin chains;
- the DHFR cassette contained its own eukaryotic promoter (mouse beta globin major promoter, “BETA”) and polyadenylation region (bovine growth hormone polyadenylation, “BGH”); and
- the NEO cassette contained its own eukaryotic promoter (BETA) and polyadenylation region (SV40 early polyadenylation, “SV”).
- BETA eukaryotic promoter
- the Kozak region was a partially impaired consensus Kozak sequence (which included an upstream Cla I site): ClaI ⁇ 3 +1 GGGAGCTTGG ATCGAT ccTct ATG Gtt
- the TCAE vectors beneficially allow for substantially reducing the time in generating the immunologically active chimeric anti-CD20 antibodies.
- the sequence of the variable region of a non-human anti-CD20 antibody can be obtained, followed by oligonucleotide synthesis of portions of the sequence or, if appropriate, the entire sequence; thereafter, the portions or the entire synthetic sequence can be inserted into the appropriate locations within the vector.
- TCAE 8 or an equivalent vector
- the host cell line utilized for protein expression is most preferably of mammalian origin; those skilled in the art are credited with ability to preferentially determine particular host cell lines which are best suited for the desired gene product to be expressed therein.
- Exemplary host cell lines include, but are not limited to, DG44 and DUXB11 (Chinese Hamster Ovary lines, DHFR minus), HELA (human cervical carcinoma), CVI (monkey kidney line), COS (a derivative of CVI with SV40 T antigen), R1610 (Chinese hamster fibroblast) BALBC/3T3 (mouse fibroblast), HAK (hamster kidney line), SP210 (mouse myeloma), P3x63-Ag3.653 (mouse myeloma), BFA-1c1BPT (bovine endothelial cells), RAJI (human lymphocyte) and 293 (human kidney). Host cell lines are typically available from commercial services, the American Tissue Culture Collection or from published literature.
- the host cell line is either DG44 (“CHO”) or SP2/0. See Urland, G. et al., “Effect of gamma rays and the dihydrofolate reductase locus: deletions and inversions.” Som. Cell & Mol. Gen. 12/6:555-566 (1986), and Shulman, M. et al., “A better cell line for making hybridomas secreting specific antibodies.” Nature 276:269 (1978), respectively. Most preferably, the host cell line is DG44. Transfection of the plasmid into the host cell can be accomplished by any technique available to those in the art.
- transfection including electrophoresis and electroporation
- cell fusion with enveloped DNA
- microinjection and infection with intact virus.
- transfection including electrophoresis and electroporation
- cell fusion with enveloped DNA
- microinjection and infection with intact virus.
- plasmid introduction into the host is via electroporation.
- mice were repeatedly immunized with the human lymphoblastoid cell line SB (see, Adams, R. A. et al., “Direct implantation and serial transplantation of human acute lymphoblastic leukemia in hamsters, SB-2.′′ Can Res 28:1121-1125 (1968); this cell line is available from the American Tissue Culture Collection, Rockville, Md., under ATCC accession number ATCC CCL 120), with weekly injections over a period of 3-4 months. Mice evidencing high serum titers of anti-CD20 antibodies, as determined by inhibition of known. CD20-specific antibodies (anti-CD20 antibodies utilized were Leu 16, Beckton Dickinson, San Jose, Calif., Cat. No.
- Assays for CD20 specificity were accomplished by radioimmunoassay. Briefly, purified anti-CD20 B1 was radiolabeled with I 125 by the iodobead method as described in Valentine, M. A. et al., (1989) J. Biol. Chem. 264:11282. (I 125 Sodium Iodide, ICN, Irvine, Calif., Cat. No. 28665H).
- Hybridomas were screened by co-incubation of 0.05 ml of media from each of the fusion wells together with 0.05 ml of I 125 labeled anti-CD20 B1 (10 ng) in 1% BSA, PBS (pH 7.4), and 0.5 ml of the same buffer containing 100,000 SB cells. After incubation for 1 hr at room temperature, the cells were harvested by transferring to 96 well titer plates (V&P Scientific, San Diego, Calif.), and washed thoroughly. Duplicate wells containing unlabeled anti-CD20 B1 and wells containing no inhibiting antibody were used as positive and negative controls, respectively. Wells containing greater than 50% inhibition were expanded and cloned. The antibody demonstrating the highest inhibition was derived from the cloned cell line designated herein as “2B8.“
- Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (“carbon-14 labeled MX-DTPA”) was used as a chelating agent for conjugation of radiolabel to 2B8.
- Manipulations of MX-DTPA were conducted to maintain metal-free conditions, ie metal-free reagents were utilized and, when possible, polypropylene plastic containers (flasks, beakers, graduated cylinders, pipette tips) washed with Alconox and rinsed with Milli-Q water, were similarly utilized.
- MX-DTPA was obtained as a dry solid from Dr.
- Purified 2B8 was prepared for conjugation with MX-DTPA by transferring the antibody into metal-free 50 mM bicine-NaOff, pH 8.6, containing 150 mM NaCl, using repetitive buffer exchange with CENTRICON 30TM spin filters (30,000D, MWCO; Amicon). Generally, 50-200 ⁇ L of protein (10 mg/nl) was added to the filter unit, followed by 2 mL of bicine buffer. The filter was centrifuged at 4° C. in a Sorval SS-34 rotor (6,000 rpm, 45 min.). Retentate volume was approximately 50-100 ⁇ L; this process was repeated twice using the same filter.
- Retentate was transferred to a polypropylene 1.5 mL screw cap tube, assayed for protein, diluted to 10.0 mg/mL and stored at 4° C. until utilized; protein was similarly transferred into 50 mM sodium citrate, pH 5.5, containing 150 mM NaCl and 0.05% sodium azide, using the foregoing protocol.
- Conjugation of 2B8 with MX-DTPA was performed in polypropylene tubes at ambient temperature. Frozen MX-DTPA stock solutions were thawed immediately prior to use. 50-200 mL of protein at 10 mg/mL were reacted with MX-DTPA at a molar ratio of MX-DTPA-to-2B8 of 4:1. Reactions were initiated by adding the MX-DTPA stock solution and gently mixing; the conjugation was allowed to proceed overnight (14 to 20 hr), at ambient temperature.
- Unreacted MX-DTPA was removed from the conjugate by dialysis or repetitive ultrafiltration, as described above in Example I.B.ii, into metal-free normal saline (0.9% w/v) containing 0.05% sodium azide.
- the protein concentration was adjusted to 10 mg/mL and stored at 4° C. in a polypropylene tube until radiolabeled.
- MX-DTPA incorporation was determined by scintillation counting and comparing the value obtained with the purified conjugate to the specific activity of the carbon-[14]-labeled MX-DTPA.
- MX-DTPA incorporation was assessed by incubating the conjugate with an excess of a radioactive carrier solution of yttrium-[90] of known concentration and specific activity.
- a stock solution of yttrium chloride of known concentration was prepared in metal-free 0.05 N HCl to which carrier-free yttrium-[90] (chloride salt) was added. An aliquot of this solution was analyzed by liquid scintillation counting to determine an accurate specific activity for this reagent.
- a volume of the yttrium chloride reagent equal to 3-times the number of mols of chelate expected to be attached to the antibody, (typically 2 mol/mol antibody), was added to a polypropylene tube, and the pH adjusted to 4.0-4.5 with 2 M sodium acetate. Conjugated antibody was subsequently added and the mixture incubated 15-30 min. at ambient temperature. The reaction was quenched by adding 20 mM EDTA to a final concentration of 1 mM and the pH of the solution adjusted to approximately pH 6 with 2M sodium acetate.
- Samples for assay were diluted in 1 ⁇ PBS/1% BSA, applied to plates and serially diluted (1:2) into the same buffer. After incubating plates for 1 h. at ambient temperature, the plates were washed three times with 1 ⁇ PBS. Secondary antibody (goat anti-mouse IgG1-specific HRP conjugate 50 ⁇ L) was added to wells (1:1500 dilution in 1 ⁇ PBS/1% BSA) and incubated 1 h. at ambient temperature. Plates were washed four times with 1 ⁇ PBS followed by the addition of ABTS substrate solution (50 mM sodium citrate, pH 4.5 containing 0.01% ATBS and 0.001% H 2 O 2 ). Plates were read at 405 nm after 15-30 min.
- ABTS substrate solution 50 mM sodium citrate, pH 4.5 containing 0.01% ATBS and 0.001% H 2 O 2 .
- Conjugates were radiolabeled with carrier-free indium-[111]. An aliquot of isotope (0.1-2 mCi/mg antibody) in 0.05 M HCl was transferred to a polypropylene tube and approximately one-tenth volume of metal-free 2 M HCl added. After incubation for 5 min., metal-free 2 M sodium acetate was added to adjust the solution to pH 4.0-4.4. Approximately 0.5 mg of 2B8-MX-DTPA was added from a stock solution of 10.0 mg/mL DTPA in normal saline, or 50 mM sodium citrate/150 mM NaCl containing 0.05% sodium azide, and the solution gently mixed immediately.
- the pH solution was checked with pH paper to verify a value of 4.0-4.5 and the mixture incubated at ambient temperature for 15-30 min. Subsequently, the reaction was quenched by adding 20 mM EDTA to a final concentration of 1 mM and the reaction mixture was adjusted to approximately pH 6.0 using 2 M sodium acetate.
- the HPLC unit consisted of Waters Model 6000 or TosoHaas Model TSK-6110 solvent delivery system fitted, respectively, with a Waters U6K or Rheodyne 700 injection valve. Chromatographic separations were performed using a gel permeation column (BioRad SEC-250; 7.5 ⁇ 300 mm or comparable TosoHaas column) and a SEC-250 guard column (7.5 ⁇ 100 mm). The system was equipped with a fraction collector (Pharmacia Frac200) and a UV monitor fitted with a 280 nm filter (Pharmacia model UV-1).
- the radioincorporation was calculated by summing the radioactivity associated with the eluted protein peak and dividing this number by the total radioactivity eluted from the column; this value was then expressed as a percentage (data not shown). In some cases, the radioincorporation was determined using instant thin-layer chromatography (“ITLC”). Radiolabeled conjugate was diluted 1:10 or 1:20 in 1 ⁇ PBS containing or 1 ⁇ PBS/1 mM DTPA, then 1 ⁇ L was spotted 1.5 cm from one end of a 1 ⁇ 5 cm strip of ITLC SG paper. The paper was developed by ascending chromatography using 10% ammonium acetate in methanol:water (1:1;v/v).
- ITLC instant thin-layer chromatography
- the strip was dried, cut in half crosswise, and the radioactivity associated with each section determined by gamma counting.
- the radioactivity associated with the bottom half of the strip was expressed as a percentage of the total radioactivity, determined by summing the values for both top and bottom halves (data not shown).
- 2B8-MX-DTPA was radiolabeled with indium ([111] following a protocol similar to the one described above but without purification by HPLC; this was referred to as the “mix-and-shoot” protocol.
- I2B8 was evaluated for tissue biodistribution in six-to-eight week old BALB/c mice.
- the radiolabeled conjugate was prepared using clinical-grade 2B8-MX-DTPA following the “mix and shoot” protocol described above.
- the specific activity of the conjugate was 2.3 mCi/mg and the conjugate was formulated in PBS, pH 7.4 containing 50mg/mL HSA.
- Mice were injected intravenously with 100 82 L of 12B8 (approximately 21 ⁇ Ci) and groups of three mice were sacrificed by cervical dislocation at 0, 24, 48, and 72 hours.
- 2B8-MX-DTPA was radiolabeled with indium-([11] to a specific activity of 2.3 mCi/mg and approximately 1.1 ⁇ Ci was injected into each of 20 BALB/c mice. Subsequently, groups of five mice each were sacrificed at 1, 24, 48 and 72 hours and their organs removed and prepared for analysis. In addition, portions of the skin, muscle and bone were removed and processed for analysis; the urine and feces were also collected and analyzed for the 24-72 hour time points.
- 2B8-MX-DTPA was also radiolabeled with yttrium-[90] and its biological distribution evaluated in BALB/c mice over a 72-hour time period.
- four groups of five mice each were injected intravenously with approximately 1 ⁇ Ci of clinically-formulated conjugate (specific activity:12.2 mCi/mg); groups were subsequently sacrificed at 1, 24, 48 and 72 hours and their organs and tissues analyzed as described above. Radioactivity associated with each tissue specimen was determined by measuring bremstrahlung energy with a gamma scintillation counter. Activity values were subsequently expressed as percent injected dose per gram tissue or percent injected dose per organ. While organs and other tissues were rinsed repeatedly to remove superficial blood, the organs were not perfused. Thus, organ activity values were not discounted for the activity contribution represented by internally associated blood.
- conjugated 2B8 was radiolabeled with indium-[111] to a specific activity of 2.3 mCi/mg and roughly 1.1 ⁇ Ci was injected into each of twenty BALB/c mice to determine biodistribution of the radiolabeled material. Subsequentially, groups of five mice each were sacrificed at 1, 24, 48 and 72 hours and their organs and a portion of the skin, muscle and bone were removed and processed for analysis. In addition, the urine and feces were collected and analyzed for the 24-72 hour time-points.
- the level of radioactivity in the blood dropped from 40.3% of the injected dose per gram at 1 hour to 18.9% at 72 hours (data not shown). Values for the heart, kidney, muscle and spleen remained in the range of 0.7-9.8% throughout the experiment. Levels of radioactivity found in the lungs decreased from 14.2% at 1 hour to 7.6% at 72 hours; similarly the respective liver injected-dose per gram values were 10.3% and 9.9%. These data were used in determining radiation absorbed dose estimates I2B8 described below.
- 2B8-MX-DTPA was prepared and radiolabeled with 111 Indium to a specific activity of 2.7 mCi/mg.
- One hundred microliters of labeled conjugate (approximately 24 ⁇ Ci) were subsequently injected into each of 12 athymic mice bearing Ramos B cell tumors. Tumors ranged in weight from 0.1 to 1.0 grams.
- 50 ⁇ L of blood was removed by retro-orbital puncture, the mice sacrificed by-cervical dislocation, and the tail, heart, lungs, liver, kidney, spleen, muscle, femur, and tumor removed.
- the radioactivity associated with each tissue specimen was determined using a gamma counter and the values expressed as percent injected dose per gram.
- tissue reactivity of murine monoclonal antibody 2B8 was evaluated using a panel of 32 different human tissues fixed with acetone.
- Antibody 2B8 reacts with the anti-CD20 antigen which had a very restricted pattern of tissue distribution, being observed only in a subset of cells in lymphoid tissues including those of hematopoietic origin.
- lymph node immunoreactivity was observed in a population of mature cortical B-lymphocytes as well as proliferating cells in the germinal centers. Positive reactivity was also observed in the peripheral blood, B-cell areas of the tonsils, white pulp of the spleen, and with 40-70% of the medullary lymphocytes found in the thymus. Positive reactivity was also seen in the follicles of the lamina limbal (Peyer's Patches) of the large intestines.
- aggregates or scattered lymphoid cells in the stroma of various organs including the bladder, breast, cervix, esophagus, lung, parotid, prostate, small intestine, and stomach, were also positive with antibody 2B8 (data not shown).
- the tissue reactivity of the 2B8-MX-DTPA conjugate was evaluated using a panel of sixteen human tissues which had been fixed with acetone. As previously demonstrated with the native antibody (data not shown), the 2B8-MX-DTPA conjugate recognized the CD20 antigen which exhibited a highly restricted pattern of distribution, being found only on a subset of cells of lymphoid origin. In the lymph node, immunoreactivity was observed in the B cell population. Strong reactivity was seen in the white pulp of the spleen and in the medullary lymphocytes of the thymus.
- Immunoreactivity was also observed in scattered lymphocytes in the bladder, heart, large intestines, liver, lung, and uterus, and was attributed to the presence of inflammatory cells present in these tissues. As with the native antibody, no reactivity was observed with neuroectodermal cells or with mesenchymal elements (data not shown).
- PSC Peripheral Stem Cell
- BM Bone Marrow
- Dose Levels of Y2B8 are as follows: Dose Level Dose (mCi) 1. 20 2. 30 3. 40
- MTD Maximum Tolerated Dose
- Imaging (Dosimetry) Studies are conducted as follows: each patient is involved in two in vivo biodistribution studies using I2B8. In the first study, 2 mg of 12B8 (5 mCi), is administered as an intravenous (i.v.) infusion over one hour; one week later 2B8 (ie unconjugated antibody) is administered by i.v. at a rate not to exceed 250 mg/hr followed immediately by 2 mg of I2B8 (5 mCi) administered by i.v. over one hour.
- Whole body average retention times for the indium [111] label are determined; such determinations are also made for recognizable organs or tumor lesions (“regions of interest”).
- the regions of interest are compared to the whole body concentrations of the label; based upon this comparison, an estimate of the localization and concentration of Y2B8 can be determined using standard protocols. If the estimated cumulative dose of Y2B8 is greater than eight (8) times the estimated whole body dose, or if the estimated cumulative dose for the liver exceeds 1500 cGy, no treatment with Y2B8 should occur.
- Dose Levels of Y2B8 are as follows: Dose Level Dose (mCi) 1. 10 2. 15 3. 20
- Optimal imaging will be defined by: (1) best effective imaging with the slowest disappearance of antibody; (2) best distribution minimizing compartmentalization in a single organ; and (3) best subjective resolution of the lesion (tumor/background comparison).
- the first therapeutic dose of Y2B8 will begin 14 days after the last dose of 12B8; for subsequent patients, the first therapeutic dose of Y2B8 will begin between two to seven days after the I2B8.
- RNA was isolated from the 2B8 mouse hybridoma cell (as described in Chomczynki, P. et al., “Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.” Anal. Biochem. 162:156-159 (1987)). and cDNA was prepared therefrom.
- the mouse immunoglobulin light chain variable region DNA was isolated from the cDNA by polymerase chain reaction using a set of DNA primers with homology to mouse light chain signal sequences at the 5′ end and mouse light chain J region at the 3′ end. Primer sequences were as follows: 1. V L Sense (SEQ. ID. NO.
- FIGS. 1 and 2 for the corresponding Bg1 II and Bsi WI sites in TCAE 8
- FIG. 3 for the corresponding sites in anti-CD20 in TCAE 8.
- FIG. 4 SEQ. ID. NO. 5
- FIG. 4 further provides the amino acid sequence from this murine variable region, and the CDR and framework regions.
- the mouse light chain variable region from 2B8 is in the mouse kappa VI family. See, Kabat, supra.
- V H Sense SEQ. ID. NO. 6
- V H Antisense SEQ. ID. NO. 7
- FIGS. 1 and 2 for corresponding Mlu I and Nhe I sites in TCAE 8
- FIG. 3 for corresponding sites in anti-CD20 in TCAE 8.
- FIG. 5 The sequence for this mouse heavy chain is set forth in FIG. 5 (SEQ. ID. NO. 8); see also FIG. 3, nucleotide 2401 through 2820.
- FIG. 5 also provides the amino acid sequence from this murine variable region, and the CDR and framework regions.
- the mouse heavy chain variable region from 2B8 is in the mouse VH 2B family. See, Kabat, supra.
- CHO cells DG44 were grown in SSFM II minus hypoxanthine and thymidine media (Gibco, Grand Island, N.Y., Form No. 91-0456PK); SP2/0 mouse myeloma cells were grown in Dulbecco's Modified Eagles Medium media (“DMEM”) (Irvine Scientific, Santa Ana, Calif., Cat. No. 9024) with 5% fetal bovine serum and 20 ml/L glutamine added.
- DMEM Dulbecco's Modified Eagles Medium media
- chimeric anti-CD20 was analyzed by electrophoresis in polyacrylamide gels and estimated to be greater than about 95% pure. Affinity and specificity of the chimeric antibody was determined based upon 2B8. Chimeric anti-CD20 antibody tested in direct and competitive binding assays, when compared to murine anti-CD20 monoclonal antibody 2B8, evidenced comparable affinity and specificity on a number of CD20 positive B cells lines (data not presented).
- the apparent affinity constant (“Kap”) of the chimeric antibody was determined by direct binding of I 125 radiolabeled chimeric anti-CD20 and compared to radiolabeled 2B8 by Scatchard plot; estimated Kap for CHO produced chimeric anti-CD20 was 5.2 ⁇ 10 ⁇ 9 M and for SP2/0 produced antibody, 7.4 ⁇ 10 ⁇ 9 M. The estimated Kap for 2B8 was 3.5 ⁇ 10 ⁇ 9 M. Direct competition by radioimmunoassay was utilized to confirm both the specificity and retention of immunoreactivity of the chimeric antibody by comparing its ability to effectively compete with 2B8.
- Example II.B The results of Example II.B indicate, inter alia, that chimeric anti-CD20 antibodies were generated from CHO and SP2/0 transfectomas using the TCAE 8 vectors, and these chimeric antibodies had substantially the same specificity and binding capability as murine anti-CD20 monoclonal antibody 2B8.
- C1q was obtained from Quidel, Mira Mesa, Calif., Prod. No. A400 and FITC label from Sigma, St. Louis Mo., Prod. No. F-7250; FITC. Labeling of C1q was accomplished in accordance with the protocol described in Selected Methods In Cellular Immunology, Michell & Shiigi, Ed. (W. H. Freeman & Co., San Francisco, Calif., 1980, p. 292).
- Chimeric anti-CD20 antibodies were analyzed for their ability to lyse lymphoma cell lines in the presence of human serum (complement source).
- CD20 positive SB cells were labeled with 51 Cr by admixing 100 ⁇ Ci of 51 Cr with 1 ⁇ 10 6 SB cells for 1 hr at 37° C.; labeled SB cells were then incubated in the presence of equivalent amounts of human complement and equivalent amounts (0-50 ⁇ g/ml) of either chimeric anti-CD20 antibodies or 2B8 for 4 hrsat 37° C.
- equivalent amounts of human complement and equivalent amounts (0-50 ⁇ g/ml) of either chimeric anti-CD20 antibodies or 2B8 for 4 hrsat 37° C.
- CD20 positive cells SB
- CD20 negative cells T cell leukemia line HSB; see, Adams, Richard, “Formal Discussion,” Can. Res. 27:2479-2482 (1967); ATCC deposit no. ATCC CCL 120.1) were utilized; both were labeled with 51 Cr. Analysis was conducted following the protocol described in Brunner, K. T.
- Example II The results of Example II indicate, inter alia, that the chimeric ant4-CD20 antibodies of Example I were immunologically active.
- lymph node biopsies were taken at days 7, 14 and 28 following the last injection, and a single cell preparation stained for quantitation of lymphocyte populations by flow cytometry.
- HBSS Hanks Balanced Salt Solution
- fetal bovine serum heat inactivated at 56° C. for 30 min.
- a 0.1 ml volume of the cell preparation was distributed to each of six (6), 15 ml conical centrifuge tubes
- Fluorescein labeled monoclonal antibodies with specificity for the human lymphocyte surface markers CD2 (AMAC, Westbrook, Me.), CD20 (Becton Dickinson) and human IgM (Binding Site, San Diego, Calif.) were added to 3 of the tubes for identifying T and B lymphocyte populations.
- Chimeric anti-CD20 antibody bound to monkey B cell surface CD20 was measured in the fourth tube using polyclonal goat anti-human IgG coupled with phycoerythrin (AMAC). This reagent was pre-adsorbed on a monkey Ig-sepharose column to prevent cross-reactivity to monkey Ig, thus allowing specific detection and quantitation of chimeric anti-CD20 antibody bound to cells.
- AMAC phycoerythrin
- Lymphocyte populations were initially identified by forward versus right angle light scatter in a dot-plot bitmap with unlabeled leucocytes. The total lymphocyte population was then isolated by gating out all other events. Subsequent fluorescence measurements reflected only gated lymphocyte specific events.
- FIGS. 9A, B and C provide the results derived from the chimeric anti-CD20:CHO & SP2/0 study, with FIG. 9A directed to the 0.4 mg/kg dose level; FIG. 9B directed to the 1.6 mg/kg dose level; and FIG. 9C directed to the 6.4 mg/kg dose level.
- Table I summarizes the results of single and multiple doses of immunologically active chimeric anti-CD20 antibody on the peripheral blood populations; single dose condition was 6.4 mg/kg; multiple dose condition was 0.4 mg/kg over four (4) consecutive days (these results were derived from the monkeys described above).
- Table II summarizes the effect of immunologically active, chimeric anti-CD20 antibodies on cell populations of lymph nodes using the treatment regimen of Table I (4 daily doses of 0.4 mg/kg; 1 dose of 6.4 mg(kg); comparative values for normal lymph nodes (control monkey, axillary and inguinal) and normal bone marrow (two monkeys) are also provided.
- Table II evidence effective depletion of B lymphocytes for both treatment regimens.
- Table II further indicates that for the non-human primates, complete saturation of the B cells in the lymphatic tissue with immunologically active, chimeric anti-CD20 antibody was not achieved; additionally, antibody coated cells were observed seven (7) days after treatment, followed by a marked depletion of lymph node B cells, observed on day 14.
- Example III.A The results of Example III.A indicate, inter alia, that low doses of immunologically active, chimeric anti-CD20 leads to long-term peripheral blood B cell depletion in primates.
- the data also indicates that significant depletion of B cell populations was achieved in peripheral lymph nodes and bone marrow when repetitive high doses of the antibody were administered.
- Continued follow-up on the test animals has indicated that even with such severe depletion of peripheral B lymphocytes during the first week of treatment, no adverse health effects have been observed.
- a conclusion to be drawn is that the pluripotent stem cells of these primates were not adversely affected by the treatment.
- Toxicity ranged from “none”, to “fever” to “moderate” (two patients) to “severe” (one patient); all patients completed the therapy treatment.
- Peripheral Blood Lymphocytes were analyzed to determine, inter alia, the impact of C2B8 on T-cells and B-cells. Consistently for all patients, Peripheral Blood B Lymphocytes were depleted after infusion with C2B8 and such depletion was maintained for in excess of two weeks.
- One patient (receiving 100 mg/ 2 of C2B8) evidenced a Partial Response to the C2B8 treatment (reduction of greater than 50% in the sum of the products of the perpendicular diameters of all measurable indicator lesions lasting greater than four weeks, during which no new lesions may appear and no existing lesions may enlarge); at least one other patient (receiving 500 mg/m 2 ) evidenced a Minor Response to the C2B8 treatment (reduction of less than 50% but at least 25% in the sum of the products of the two longest perpendicular diameters of all measurable indicator lesions).
- results of the PBLs are set forth in FIG. 14; data for the patient evidencing a PR is set forth in FIG.
- FIG. 14A for the patient evidencing an MR, data is set forth in FIG. 14B.
- the B cell markers CD20 and CD19, Kappa and Lambda were depleted for a period in excess of two weeks; while there was a slight, initial reduction in T-cell counts, these returned to an approximate base-line level in a relatively rapid time-frame.
- Phase I consisting of a dose escalation to characterize dose limiting toxicities and determination of biologically active tolerated dose level
- groups of three patients will receive weekly i.v. infusions of C2B8 for a total of four (4) separate infusions.
- Cumulative dose at each of the three levels will be as follows: 500 mg/m 2 (125 mg/m 2 /infusion); 1000 mg/m 2 (250 mg/m 2 /infusion); 1500 mg/m 2 (375 mg/m 2 /infusion.
- a biologically active tolerated dose is defined, and will be determined, as the lowest dose with both tolerable toxicity and adequate activity); in Phase II, additional patients will receive the biologically active tolerated dose with an emphasis on determining the activity of the four doses of C2B8.
- a combination therapeutic approach using C2B8 and Y2B8 was investigated in a mouse xenographic model (nu/nu mice, female, approximately 10 weeks old) utilizing a B cell lymphoblastic tumor (Ramos tumor cells). For comparative purposes, additional mice were also treated with C2B8 and Y2B8.
- Ramos tumor cells (ATCC, CRL 1596) were maintained in culture using RPMI-1640 supplemented with 10% fetal calf serum and glutamine at 37° C. and 5% C0 2 . Tumors were initiated in nine female nude mice approximately 7-10 weeks old by subcutaneous injection of 1.7 ⁇ 10 6 Ramos cells in a volume of 0.10 ml (HBSS) using a 1 cc syringe fitted with 25 g needle. All animals were manipulated in a laminar flow hood and all cages, bedding, food and water were autoclaved.
- HBSS 0.10 ml
- Tumor cells were passaged by excising tumors and passing these through a 40 mesh screen; cells were washed twice with 1 ⁇ HBSS (50 ml) by centrifugation (1300RPM), resuspended in 1 ⁇ HBSS to 10 ⁇ 10 6 cells/ml, and frozen at ⁇ 70° C. until used.
- mice were thawed, pelleted by centrifugation (1300RPM) and washed twice with 1 ⁇ HBSS. Cells were then resuspended to approximately 2.0 ⁇ 10 6 cells/ml. Approximately 9 to 12 mice were injected with 0.10 ml of the cell suspension (s.c.) using a 1 cc syringe fitted with a 25 g needle; injections were made on the animal's left side, approximately mid-region. Tumors developed in approximately two weeks. Tumors were excised and processed as described above. Study mice were injected as described above with 1.67 ⁇ 10 6 cells in 0.10 ml HBSS.
- mice were injected with the tumor cells. Approximately ten days later, 24 mice were assigned to four study groups (six mice/group) while attempting to maintain a comparable tumor size distribution in each group (average tumor size, expressed as a product of length x width of the tumor, was approximately 80 mm 2 ). The following groups were treated as indicated via tail-vain injections using a 100 ⁇ l Hamilton syringe fitted with a 25 g needle: A. Normal Saline B. Y2B8 (100 ⁇ Ci) C. C2B8 (200 ⁇ g); and D. Y2B8 (100 ⁇ Ci) + C2B8 (200 ⁇ g)
- Yttrium-[90] chloride (6 mCi) was transformed to a polypropylene tube and adjusted to pH 4.1-4.4 using metal free 2M sodium acetate.
- 2B8-MX-DTPA (0.3 mg in normal saline; see above for preparation of 2B8-MX-DTPA) was added and gently mixed by vortexing. After 15 min. incubation, the reaction was quenched by adding 0.05 ⁇ volume 20 mM EDTA and 0.05 ⁇ volume 2M sodium acetate.
- Radioactivity concentration was determined by diluting 5.0 ⁇ l of the reaction mixture in 2.5 ml 1 ⁇ PBS containing 75 mg/ml HSA and 1 mM DTPA (“formulation buffer”); counting was accomplished by adding 10.0 ⁇ l to 20 ml of EcolumeTM scintillation cocktail. The remainder of the reactive mixture was added to 3.0 ml formulation buffer, sterile filtered and stored at 2-8° C. until used. Specific activity (14 mCi/mg at time of injection) was calculated using the radioactivity concentration and the calculated protein concentration based upon the amount of antibody added to the reaction mixture..Protein-associated radioactivity was determined using instant thin-layer chromatography. Radioincorporation was 95%. Y2B8 was diluted in formulation buffer immediately before use and sterile-filtered (final radioactivity concentration was 1.0 mCi/ml).
- C2B8 was prepared as described above. C2B8 was provided as a sterile reagent in normal saline at 5.0 mg/ml. Prior to injection, the C2B8 was diluted in normal saline to 2.0 mg/ml and sterile filtered.
- tumor size was expressed as a product of length and width, and measurements were taken on the days indicated in FIG. 11 (Y2B8 vs. Saline); FIG. 12 (C2B8 vs. Saline); and FIG. 13 (Y2B8+C2B8 vs. Saline). Standard error was also determined.
- Radiolabeled C2B8 such a strategy allows for utilization of the benefits of the immunologically active portion of C2B8 plus those benefits associated with a radiolabel.
- Preferred radiolabels include yttrium-90 given the larger circulating half-life of C2B8 versus the murine antibody 2B8.
- a preferred alternative strategy is to treat the patient with C2B8 (either with a single dose or multiple doses) such that most, if not all, peripheral B cells have been depleted. This would then be followed with the use of radiolabeled 2B8; because of the depletion of peripheral B cells, the radiolabeled 2B8 stands an increased chance of targeting tumor cells.
- Iodine [131] labeled 2B8 is preferably utilized, given the types of results reported in the literature with this label (see Kaminski).
- An alternative preference involves the use of a radiolabeled 2B8 (or C2B8) first in an effort to increase the permeability of a tumor, followed by single or multiple treatments with C2B8; the intent of this strategy is to increase the chances of the C2B8 in getting both outside and inside the tumor mass.
- a further strategy involved the use of chemotherapeutic agenst in combination with C2B8. These strategies include so-called “staggered” treatments, ie, treatment with chemotherapeutic agent, followed by treatment with C2B8, followed by a repetition of this protocol. Alternatively, initial treatment with a single or multiple doses of C2B8, thereafter followed with chemotherapeutic treatement, is viable.
- chemotherapeutic agents include, but are not limited to: cyclophlsphamide; doxorubicin; vincristine; and prednisone, See Armitage, J. O. et al., Cancer 50:1695 (1982), incorporated herein by reference.
- Anti-CD20 in TCAE 8 was deposited with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Md., 20852, under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure (“Budapest Treaty”). The microorganism was tested by the ATCC on Nov. 9, 1992, and determined to be viable on that date. The ATCC has assigned this microorganism for the following ATCC deposit number: ATCC 69119 (anti-CD20 in TCAE 8). Hybridoma 2B8 was deposited with the ATCC on Jun. 22, 1993 under the provisions of the Budapest Treaty. The viability of the culture was determined on June 25, 1993 and the ATCC has assigned this hybridoma the following ATCC deposit number: HB 11388.
Abstract
Disclosed herein are therapeutic treatment protocols designed for the treatment of B cell lymphoma. These protocols are based upon therapeutic strategies which include the use of administration of immunologically active mouse/human chimeric anti-CD20 antibodies, radiolabeled anti-CD20 antibodies, and cooperative strategies comprising the use of chimeric anti-CD20 antibodies and radiolabeled anti-CD20 antibodies.
Description
- The references to be discussed throughout this document are set forth merely for the information described therein prior to the filing dates of this documents and nothing herein is to be construed as an admission, either express or implied, that the references are “prior art” or that the inventors are not entitled to antedate such descriptions by virtue of prior inventions or priority based on earlier filed applications.
- The present invention is directed to the treatment of B cell lymphoma using chimeric and radiolabeled antibodies to the B cell surface antigen Bp35 (“CD20”).
- The immune system of vertebrates (for example, primates, which include humans, apes, monkeys, etc.) consists of a number of organs and cell types which have evolved to: accurately and specifically recognize foreign microorganisms (“antigen”) which invade the vertebrate-host; specifically bind to such foreign microorganisms; and, eliminate/destroy such foreign microorganisms. Lymphocytes, amongst others, are critical to the immune system. Lymphocytes are produced in the thymus, spleen and bone marrow (adult) and represent about 30% of the total white blood cells present in the circulatory system of humans (adult). There are two major sub-populations of lymphocytes: T cells and B cells. T cells are responsible for cell mediated immunity, while B cells are responsible for antibody production (humoral immunity). However, T cells and B cells can be considered as interdependent—in a typical immune response, T cells are activated when the T cell receptor binds to fragments of an antigen that are bound to major histocompatability complex (“MHC”) glycoproteins on the surface of an antigen presenting cell; such activation causes release of biological mediators (“interleukins”) which, in essence, stimulate B cells to differentiate and produce antibody (“immunoglobulins”) against the antigen.
- Each B cell within the host expresses a different antibody on it surface one B cell will express antibody specific for one antigen, while another B cell will express antibody specific for a different antigen. Accordingly, B cells are quite diverse, and this diversity is critical to the immune system. In humans, each B cell can produce an enormous number of antibody molecules (ie about 107 to 108). Such antibody production most typically ceases (or substantially decreases) when the foreign antigen has been neutralized. Occasionally, however, proliferation of a particular B cell will continue unabated; such proliferation can result in a cancer referred to as “B cell lymphoma.”
- T cells and B cells both comprise cell surface proteins which can be utilized as “markers” for differentiation and identification. One such human B cell marker is the human B lymphocyte-restricted differentiation antigen Bp35, referred to as “CD20.” CD20 is expressed during early pre-B cell development and remains until plasma cell differentiation. Specifically, the CD20 molecule may regulate a step in the activation process which is required for cell cycle initiation and differentiation and is usually expressed at very high levels on neoplastic (“tumor”) B cells. CD20, by definition, is present on both “normal” B cells as well as “malignant” B cells, ie those B cells whose unabated proliferation can lead to B cell lymphoma. Thus, the CD20 surface antigen has the potential of serving as a candidate for “targeting” of B cell lymphomas.
- In essence, such targeting can be generalized as follows: antibodies specific to the CD20 surface antigen of B cells are, eg injected into a patient. These anti-CD20 antibodies specifically bind to the CD20 cell surface antigen of (ostensibly) both normal and malignant B cells; the anti-CD20 antibody bound to the CD20 surface antigen may lead to the destruction and depletion of neoplastie B cells. Additionally, chemical agents or radioactive labels having the potential to destroy the tumor can be conjugated to the anti-CD20 antibody such that the agent is specifically “delivered” to, eg, the neoplastic B cells. Irrespective of the approach, a primary goal is to destroy the tumor: the specific approach can be determined by the particular anti-CD20 antibody which is utilized and, thus, the available approaches to targeting the CD20 antigen can vary considerably.
- For example, attempts at such targeting of CD20 surface antigen have been reported. Murine (mouse) monoclonal antibody 1F5 (an anti-CD20 antibody) was reportedly administered by continuous intravenous infusion to B cell lymphoma patients. Extremely high levels (>2 grams) of IF5 were reportedly required to deplete circulating tumor cells, and the results were described as being “transient.” Press et al., “Monoclonal Antibody 1F5 (Anti-CD20) Serotherapy of Human B-Cell Lymphomas.”Blood 69/2:584-591 (1987). A potential problem with this approach is that non-human monoclonal antibodies (eg, murine monoclonal antibodies) typically lack human effector functionality, ie they are unable to, inter alia, mediate complement dependent lysis or lyse human target cells through antibody dependent cellular toxicity or Fc-receptor mediated phagocytosis. Furthermore, non-human monoclonal antibodies can be recognized by the human host as a foreign protein; therefore, repeated injections of such foreign antibodies can lead to the induction of immune responses leading to harmful hypersensitivity reactions. For murine-based monoclonal antibodies, this is often referred to as a Human Anti-Mouse Antibody response, or “HAMA” response. Additionally, these “foreign” antibodies can be attacked by the immune system of the host such that they are, in effect, neutralized before they reach their target site.
- Lymphocytes and lymphoma cells are inherently sensitive to radiotherapy for several reasons: the local emission of ionizing radiation of radiolabeled antibodies may kill cells with or without the target antigen (eg, CD20) in close proximity to antibody bound to the antigen; penetrating radiation may obviate the problem of limited access to the antibody in bulky or poorly vascularized tumors; and, the total amount of antibody required may be reduced. The radionuclide emits radioactive particles which can damage cellular DNA to the point where the cellular repair mechanisms are unable to allow the cell to continue living; therefore, if the target cells are tumors, the radioactive label beneficially kills the tumor cells. Radiolabeled antibodies, by definition, include the use of a radioactive substance which may require the need for precautions for both the patient (ie possible bone marrow transplantation) as well as the health care provider (ie the need to exercise a high degree of caution when working with the radioactivity).
- Therefore, an approach at improving the ability of murine monoclonal antibodies to be effective in the treatment of B-cell disorders has been to conjugate a radioactive label or toxin to the antibody such that the label or toxin is localized at the tumor site. For example, the above-referenced IF5 antibody has been “labeled” with iodine-131 (“131I”) and was reportedly evaluated for biodistribution in two patients. See Eary, J. F. et al., “Imaging and Treatment of B-Cell Lymphoma” J. Nuc. Med. 31/8:1257-1268 (1990); see also, Press, O. W. et al., “Treatment of Refractory Non-Hodgkin's Lymphoma with Radiolabeled MB-1 (Anti-CD37) Antibody” J. Clin. Onc. 7/8:1027-1038 (1989) (indication that one patient treated with 131I-labeled IF-5 achieved a “partial response”); Goldenberg, D. M. et al., “Targeting, Dosimetry and Radioimmunotherapy of B-Cell Lymphomas with Iodine-131-Labeled LL2 Monoclonal Antibody” J. Clin. Onc. 9/4:548-564 (1991) (three of eight patients receiving multiple injections reported to have developed a HAMA response); Appelbaum, F. R. “Radiolabeled Monoclonal Antibodies in the Treatment of Non-Hodgkin's Lymphoma Hem./Onc. Clinics of N.A. 5/5:1013-1025 (1991) (review article); Press, O. W. et al “Radiolabeled-Antibody Therapy of B-Cell Lymphoma with Autologous Bone Marrow Support.” New England Journal of Medicine 329/17: 1219-12223 (1993) (iodine-131 labeled anti-CD20 antibody IF5 and B1); and Kaminski, M. G. et al “Radioimmunotherapy of B-Cell Lymphoma with [131I] Anti-B1 (Anti-CD20) Antibody”. NEJM 329/7 (1993) (iodine-131 labeled anti-CD20 antibody B1; hereinafter “Kaminski”).
- Toxins (ie chemotherapeutic agents such as doxorubicin or mitomycin C) have also been conjugated to antibodies. See, for example, PCT published application WO 92/07466 (published May 14, 1992).
- “Chimeric” antibodies, ie antibodies which comprise portions from two or more different species (eg, mouse and human) have been developed as an alternative to “conjugated” antibodies. For example, Liu, A. Y. et al., “Production of a Mouse-Human Chimeric Monoclonal Antibody to CD20 with Potent Fc-Dependent Biologic Activity”J. Immun. 139/10:3521-3526 (1987), describes a mouse/human chimeric antibody directed against the CD20 antigen. See also, PCT Publication No. WO 88/04936. However, no information is provided as to the ability, efficacy or practicality of using such chimeric antibodies for the treatment of B cell disorders in the reference. It is noted that in vitro functional assays (eg complement dependent lysis (“CDC”); antibody dependent cellular cytotoxicity (“ADCC”), etc.) cannot inherently predict the in vivo capability of a chimeric antibody to destroy or deplete target cells expressing the specific antigen. See, for example, Robinson, R. D. et al., “Chimeric mouse-human anti-carcinoma antibodies that mediate different anti-tumor cell biological activities,” Hum. Antibod. Hybridomas 2:84-93 (1991) (chimeric mouse-human antibody having undetectable ADCC activity). Therefore, the potential therapeutic efficacy of chimeric antibody can only truly be assessed by in vivo experimentation.
- What is needed, and what would be a great advance in the art, are therapeutic approaches targeting the CD20 antigen for the treatment of B cell lymphomas in primates, including, but not limited to, humans.
- Disclosed herein are therapeutic methods designed for the treatment of B cell disorders, and in particular, B cell lymphomas. These protocols are based upon the administration of immunologically active chimeric anti-CD20 antibodies for the depletion of peripheral blood B cells, including B cells associated with lymphoma; administration of radiolabeled anti-CD20 antibodies for targeting localized and peripheral B cell associated tumors; and administration of chimeric anti-CD20 antibodies and radiolabeled anti-CD20 antibodies in a cooperative therapeutic strategy.
- FIG. 1 is a diagrammatic representation of a tandem chimeric antibody expression vector useful in the production of immunologically active chimeric anti-CD20 antibodies (“
TCAE 8”); - FIGS. 2A through 2E are the nucleic acid sequence of the vector of FIG. 1;
- FIGS. 3A through 3F are the nucleic acid sequence of the vector of FIG. 1 further comprising murine light and heavy chain variable regions (“anti-CD20 in
TCAE 8”); - FIG. 4 is the nucleic acid and amino acid sequences (including CDR and framework regions) of murine variable region light chain derived from murine anti-CD20 monoclonal antibody 2B8;
- FIG. 5 is the nucleic acid and amino acid sequences (including CDR and framework regions) of murine variable region heavy chain derived from murine anti-CD20 monoclonal antibody 2B8;
- FIG. 6 are flow cytometry results evidencing binding of fluorescent-labeled human C1q to chimeric anti-CD20 antibody, including, as controls labeled C1q; labeled C1q and murine anti-CD20 monoclonal antibody 2B8; and labeled C1q and human IgG1,k;
- FIG. 7 represents the results of complement related lysis comparing chimeric anti-CD20 antibody and murine anti-CD20 monoclonal antibody 2B8;
- FIG. 8 represents the results of antibody mediated cellular cytotoxicity with in vivo human effector cells comparing chimeric anti-CD20 antibody and 2B8;
- FIGS. 9A, 9B and9C provide the results of non-human primate peripheral blood B lymphocyte depletion after infusion of 0.4 mg/kg (A); 1.6 mg/kg (B); and 6.4 mg/kg (C) of immunologically active chimeric anti-CD20 antibody;
- FIG. 10 provides the results of, inter alia, non-human primate peripheral blood B lymphocyte depletion after infusion of 0.01 mg/kg of immunologically active chimeric anti-CD20 antibody;
- FIG. 11 provides results of the tumoricidal impact of Y2B8 in a mouse xenographic model utilizing a B cell lymphoblastic tumor;
- FIG. 12 provides results of the tumoricidal impact of C2B8 in a mouse xenographic model utilizing a B cell lymphoblastic tumor;
- FIG. 13 provides results of the tumoricidal impact of a combination of Y2B8 and C2B8 in a mouse xenographic model utilizing a B cell lymphoblastic tumor; and
- FIGS. 14A and 14B provide results from a Phase I/II clinical analysis of C2B8 evidencing B-cell population depletion over time for patients evidencing a partial remission of the disease (14A) and a minor remission of the disease (14B).
- Generally, antibodies are composed of two light chains and two heavy chain molecules; these chains form a general “Y” shape, with both light and heavy chains forming the arms of the Y and the heavy chains forming the base of the Y. Light and heavy chains are divided into domains of structural and functional homology. The variable domains of both the light (“VL”) and the heavy (“VH”) chains determine recognition and specificity. The constant region domains of light (“CL”) and heavy (“CH”) chains confer important biological properties, eg antibody chain association, secretion, transplacental mobility, Fc receptor binding complement binding, etc. The series of events leading to immunoglobulin gene expression in the antibody producing cells are complex. The variable domain region gene sequences are located in separate germ line gene segments referred to as “VH,” “D,” and “JH,” or “VL” and “JL.” These gene segments are joined by DNA rearrangements to form the complete V regions expressed in heavy and light chains, respectively. The rearranged, joined V segments (VL-JL and VH-D-JH) then encode the complete variable regions or antigen binding domains of light and heavy chains, respectively.
- Serotherapy of human B cell lymphomas using an anti-CD20 murine monoclonal antibody (1F5) has been described by Press et al., (69Blood 584, 1987, supra); the reported therapeutic responses, unfortunately, were transient. Additionally, 25% of the tested patients reportedly developed a human anti-mouse antibody (HAMA) response to the serotherapy. Press et al., suggest that these antibodies, conjugated to toxins or radioisotopes, might afford a more lasting clinical benefit than the unconjugated antibody.
- Owing to the debilitating effects of B cell lymphoma and the very real need to provide viable treatment approaches to this disease, we have embarked upon different approaches having a particular antibody, 2B8, as the common link between the approaches. One such approach advantageously exploits the ability of mammalian systems to readily and efficiently recover peripheral blood B cells; using this approach, we seek to, in essence, purge or deplete B cells in peripheral blood and lymphatic tissue as a means of also removing B cell lymphomas. We accomplish this by utilization of, inter alia, immunologically active, chimeric anti-CD20 antibodies. In another approach, we seek to target tumor cells for destruction with radioactive labels.
- As used herein, the term “anti-CD20 antibody” is an antibody which specifically recognizes a cell surface non-glycosylated phosphoprotein of 35,000 Daltons, typically designated as the human B lymphocyte restricted differentiation antigen Bp35, commonly referred to as CD20. As used herein, the term “chimeric” when used in reference to anti-CD20 antibodies, encompasses antibodies which are most preferably derived using recombinant deoxyribonucleic acid techniques and which comprise both human (including immunologically “related” species, eg, chimpanzee) and non-human components: the constant region of the chimeric antibody is most preferably substantially identical to the constant region of a natural human antibody; the variable region of the chimeric antibody is most preferably derived from a non-human source and has the desired antigenic and specificity to the CD20 cell surface antigen. The non-human source can be any vertebrate source which can be used to generate antibodies to a human CD20 cell surface antigen or material comprising a human CD20 cell surface antigen. Such non-human source includes, but is not limited to, rodents (eg, rabbit, rat, mouse, etc.) and non-human primates (eg, Old World Monkey, Ape, etc.). Most preferably, the non-human component (variable region) is derived from a murine source. As used herein, the phrase “immunologically active” when used in reference to chimeric anti-CD20 antibodies, means a chimeric antibody which binds human C1q, mediates complement dependent lysis (“CDC”) of human B lymphoid cell lines, and lyses human target cells through antibody dependent cellular cytotoxicity (“ADCC”). As used herein, the phrases “indirect labeling” and “indirect labeling approach” both mean that a chelating agent is covalently attached to an antibody and at least one radionuclide is inserted into the chelating agent. Preferred chelating agents and radionuclides are set forth in Srivagtava, S. C. and Mease, R. C.,“Progress in Research on Ligands, Nuclides and Techniques for Labeling Monoclonal Antibodies,”Nucl. Med. Bio. 18/6: 589-603 (1991) (“Srivagtava”) which is incorporated herein by reference. A particularly preferred chelating agent is 1-isothiocycmatobenzyl-3-methyldiothelene triaminepent acetic acid (“MX-DTPA”); particularly preferred radionuclides for indirect labeling include indium [111] and yttrium [90]. As used herein, the phrases “direct labeling” and “direct labeling approach” both mean that a radionuclide is covalently attached directly to an antibody (typically via an amino acid residue). Preferred radionuclides are provided in Srivagtava; a particularly preferred radionuclide for direct labeling is iodine [131] covalently attached via tyrosine residues. The indirect labeling approach is particularly preferred.
- The therapeutic approaches disclosed herein are based upon the ability of the immune system of primates to rapidly recover, or rejuvenate, peripheral blood B cells. Additionally, because the principal immune response of primates is occasioned by T cells, when the immune system has a peripheral blood B cell deficiency, the need for “extraordinary” precautions (ie patient isolation, etc.) is not necessary. As a result of these and other nuances of the immune systems of primates, our therapeutic approach to B cell disorders allows for the purging of peripheral blood B cells using immunologically active chimeric anti-CD20 antibodies.
- Because peripheral blood B cell disorders, by definition, can indicate a necessity for access to the blood for treatment, the route of administration of the immunologically active chimeric anti-CD20 antibodies and radioalabeled anti-CD20 antibodies is preferably parenteral; as used herein, the term “parenteral” includes intravenous, intramuscular, subcutaneous, rectal, vaginal or intraperitoneal administration. Of these, intravenous administration is most preferred.
- The immunologically active chimeric anti-CD20 antibodies and radiolabeled anti-CD20 antibodies will typically be provided by standard technique within a pharmaceutically acceptable buffer, for example, sterile saline, sterile buffered water, propylene glycol, combinations of the foregoing, etc. Methods for preparing parenteraly administerable agents are described inPharmaceutical Carriers & Formulations, Martin, Remington's Pharmaceutical Sciences, 15th Ed. (Mack Pub. Co., Easton, Pa. 1975), which is incorporated herein by reference.
- The specific, therapeutically effective amount of immunologically active chimeric anti-CD20 antibodies useful to produce a unique therapeutic effect in any given patient can be determined by standard techniques well known to those of ordinary skill in the art.
- Effective dosages (ie therapeutically effective amounts) of the immunologically active chimeric anti-CD20 antibodies range from about 0.001 to about 30 mg/kg body weight, more preferably from about 0.01 to about 25 mg/kg body weight, and most preferably from about 0.4 to about 20.0 mg/kg body weight. Other dosages are viable; factors influencing dosage include, but are not limited to, the severity of the disease; previous treatment approaches; overall health of the patient; other diseases present, etc. The skilled artisan is readily credited with assessing a particular patient and determining a suitable dosage that falls within the ranges, or if necessary, outside of the ranges.
- Introduction of the immunologically active chimeric anti-CD20 antibodies in these dose ranges can be carried out as a single treatment or over a series of treatments. With respect to chimeric antibodies, it is preferred that such introduction be carried out over a series of treatments; this preferred approach is predicated upon the treatment methodology associated with this disease. While not wishing to be bound by any particular theory, because the immunologically active chimeric anti-CD20 antibodies are both immunologically active and bind to CD20, upon initial introduction of the immunologically active chimeric anti-CD20 antibodies to the individual, peripheral blood B cell depletion will begin; we have observed a nearly complete depletion within about 24 hours post treatment infusion. Because of this, subsequent introduction(s) of the immunologically active chimeric anti-CD20 antibodies (or radiolabeled anti-CD20 antibodies) to the patient is presumed to: a) clear remaining peripheral blood B cells; b) begin B cell depletion from lymph nodes; c) begin B cell depletion from other tissue sources, eg, bone marrow, tumor, etc. Stated again, by using repeated introductions of the immunologically active chimeric anti-CD20 antibodies, a series of events take place, each event being viewed by us as important to effective treatment of the disease. The first “event” then, can be viewed as principally directed to substantially depleting the patient's peripheral blood B cells; the subsequent “events” can be viewed as either principally directed to simultaneously or serially clearing remaining B cells from the system clearing lymph node B cells, or clearing other tissue B cells.
- In effect, while a single dosage provides benefits and can be effectively utilized for disease treatment/management, a preferred treatment course can occur over several stages; most preferably, between about 0.4 and about 20 mg/kg body weight of the immunologically active chimeric anti-CD 20 antibodies is introduced to the patient once a week for between about 2 to 10 weeks, most preferably for about 4 weeks.
- With reference to the use of radiolabeled anti-CD20 antibodies, a preference is that the antibody is non-chimeric; this preference is predicted upon the significantly longer circulating half-life of chimeric antibodies vis-a-vis murine antibodies (ie with a longer circulating half-life, the radionuclide is present in the patient for extended periods). However, radiolabeled chimeric antibodies can be beneficially utilized with lower milli-Curries (“mCi”) dosages used in conjunction with the chimeric antibody relative to the murine antibody. This scenario allows for a decrease in bone marrow toxicity to an acceptable level, while maintaining therapeutic utility.
- A variety of radionuclides are applicable to the present invention and those skilled in the art are credited with the ability to readily determine which radionuclide is most appropriate under a variety of circumstances. For example, iodine [131] is a well known radionuclide used for targeted immunotherapy. However, the clinical usefulness of iodine [131] can be limited by several factors including: eight-day physical half-life; dehalogenation of iodinated antibody both in the blood and at tumor sites; and emission characteristics (eg large gamma component) which can be suboptimal for localized dose deposition in tumor. With the advent of superior chelating agents, the opportunity for attaching metal chelating groups to proteins has increased the opportunities to utilize other radionuclides such as indium [131] and yttrium [90]. Yttrium [90] provides several benefits for utilization in radioimmunotherapeutic applications: the 64 hour half-life of yttrium [90] is long enough to allow antibody accumulation by tumor and, unlike eg iodine [131], yttrium [90] is a pure beta emitter of high energy with no accompanying gamma irradiation in its decay, with a range in tissue of 100 to 1000 cell diameters. Furthermore, the minimal amount of penetrating radiation allows for outpatient administration of yttrium [90]-labeled antibodies. Furthermore, interalization of labeled antibody is not required for cell killing, and the local emission of ionizing radiation should be lethal for adjacent tumor cells lacking the target antigen.
- One non-therapeutic limitation to yttrium [90] is based upon the absence-of significant gamma radiation making imaging therewith difficult. To avoid this problem, a diagnostic “imaging” radionuclide, such as indium [111], can be utilized for determining the location and relative size of a tumor prior to the administration of therapeutic does of yttrium [90]-labeled anti-CD20. Indium [111] is particularly preferred as the diagnostic radionuclide because: between about 1 to about 10 mCi can be safely administered without detectable toxicity; and the imaging data is generally predictive of subsequent yttrium [90]-labeled antibody distribution. Most imaging studies utilize 5mCi indium [111]-labeled antibody because this dose is both safe and has increased imaging efficiency compared with lower doses, with optimal imaging occurring at three to six days after antibody administration. See, for example, Murray J. L. , 26J. Nuc. Med. 3328 (1985) and Carraguillo, J. A. et al , 26 J. Nuc. Med. 67 (1985).
- Effective single treatment dosages (ie therapeutically effective amounts) of yttrium [90] labeled anti-CD20 antibodies range from between about 5 and about 75 mCi, more preferably between about 10 and about 40 mCi. Effective single treatment non-marrow ablative dosages of iodine [131] labeled anti-CD20 antibodies range from between about 5 and about 70 mCi, more preferably between about 5 and about 40 mCi. Effective single treatment ablative dosages (ie may require autologous bone marrow transplantation) of iodine [131] labeled anti-CD20 antibodies range from between about 30 and about 600 mCi, more preferably between about 50 and less than about 500 mCi. In conjunction with a chimeric anti-CD20 antibody, owing to the longer circulating half life vis-a-vis murine antibodies, an effective single treatment non-marrow ablative dosages of iodine [131] labeled chimeric anti-CD20 antibodies range from between about 5 and about 40 mCi, more preferably less than about 30 mCi. Imaging criteria for, eg the indium [111] label, are typically less than about 5 mCi.
- With respect to radiolabeled anti-CD20 antibodies, therapy therewith can also occur using a single therapy treatment or using multiple treatments. Because of the radionuclide component, it is preferred that prior to treatment, peripheral stem cells (“PSC”) or bone marrow (“BM”) be “harvested” for patients experiencing potentially fatal bone marrow toxicity resulting from radiation. BM and/or PSC are harvested using standard techniques, and then purged and frozen for possible reinfusion. Additionally, it is most preferred that prior to treatment a diagnostic dosimetry study using a diagnostic labeled antibody (eg using indium [111]) be conducted on the patient, a purpose of which is to ensure that the therapeutically labeled antibody (eg using yttrium [90]) will not become unnecessarily “concentrated” in any normal organ or tissue.
- Chimeric mouse/human antibodies have been described. See, for example, Morrison, S. L. et al.,PNAS I1:6851-6854 (November 1984); European Patent Publication No, 173494; Boulienne, G. L. et al., Nature 312:642 (December 1984); Neubeiger, M. S. et al., Nature 314:268 (March 1985); European Patent Publication No. 125023; Tan et al., J. Immunol. 135:8564 (November 1985); Sun, L. K et al.,
Hybridoma 5/1:517 (1986); Sahagan et al., J. Immunol. 137:1066-1074 (1986). See generally, Muron, Nature 312:597 (December 1984); Dickson,Genetic Engineering News 5/3 (March 1985); Marx, Science 229 455 (August 1985); and Morrison Science 229:1202-1207 (September 1985). Robinson et al., in PCT Publication Number WO 88/04936 describe a chimeric antibody with human constant region and murine variable region, having specificity to an epitope of CD20; the murine portion of the chimeric antibody of the Robinson references is derived from the 2H7 mouse monoclonal antibody (gamma 2b, kappa). While the reference notes that the described chimeric antibody is a “prime candidate” for the treatment of B cell disorders, this statement can be viewed as no more than a suggestion to those in the art to determine whether or not this suggestion is accurate for this particular antibody, particularly because the reference lacks any data to support an assertion of therapeutic effectiveness, and importantly, data using higher order mammals such as primates or humans. - Methodologies for generating chimeric antibodies are available to those in the art. For example, the light and heavy chains can be expressed separately, using, for example, immunoglobulin light chain and immunoglobulin heavy chains in separate plasmids. These can then be purified and assembled in vitro into complete antibodies; methodologies for accomplishing such assembly have been described. See, for example, Scharff, M.,Harvey Lectures 69:125 (1974). In vitro reaction parameters for the formation of IgG antibodies from reduced isolated light and heavy chains have also been described. See, for example, Beychok, S., Cells of Immunoglobulin Synthesis, Academic Press, New York, p. 69, 1979. Co-expression of light and heavy chains in the same cells to achieve intracellular association and linkage of heavy and light chains into complete H2L2 IgG antibodies is also possible. Such co-expression can be accomplished using either the same or different plasmids in the same host cell.
- Another approach, and one which is our most preferred approach for developing a chimeric non-human/human anti-CD20 antibody, is based upon utilization of an expression vector which includes, ab initio, DNA encoding heavy and light chain constant regions from a human source. Such a vector allows for inserting DNA encoding non-human variable region such that a variety of non-human anti-CD20 antibodies can be generated, screened and analyzed for various characteristics (eg type of binding specificity, epitope binding regions, etc.); thereafter, cDNA encoding the light and heavy chain variable regions from a preferred or desired anti-CD20 antibody can be incorporated into the vector. We refer to these types of vectors as Tandem Chimeric Antibody Expression (“TCAE”) vectors. A most preferred TCAE vector which was used to generate immunologically active chimeric anti-CD20 antibodies for therapeutic treatment of lymphomas is
TCAE 8.TCAE 8 is a derivative of a vector owned by the assignee of this patent document, referred to as TCAE 5.2 the difference being that in TCAE 5.2, the translation initiation start site of the dominant selectable marker (neomycin phosphostransferase, “NEO”) is a consensus Kozak sequence, while forTCAE 8, this region is a partially impaired consensus Kozak sequence. Details regarding the impact of the initiation start site of the dominant selectable marker of the TCAE vectors (also referred to as “ANEX vector”) vis-a-vis protein expression are disclosed in detail in the co-pending application filed herewith. -
TCAE 8 comprises four (4) transcriptional cassettes, and these are in tandem order, ie a human immunoglobulin light chain absent a variable region; a human immunoglobulin heavy chain absent a variable region; DHFR; and NEO. Each transcriptional cassette contains its own eukaryotic promoter and polyadenylation region (reference is made to FIG. 1 which is a diagrammatic representation of theTCAE 8 vector). Specifically: - 1) the CMV promoter/enhancer in front of the immunoglobulin heavy chain is a truncated version of the promoter/enhancer in front of the light chain, from the Nhe I site at -350 to the Sst I site at −16 (see, 41Cell 521, 1985).
- 2) a human immunoglobulin light chain constant region was derived via amplification of cDNA by a PCR reaction. In
TCAE 8, this was the human immunoglobulin light chain kappa constant region (Kabat numbering, amino acids 108-214,allotype Km 3, (see, Kabat, E. A. “Sequences of proteins of immunological interest,” NIH Publication, Fifth Ed. No. 91-3242, 1991)), and the human immunoglobulinheavy chain gamma 1 constant region (Kabat numbering amino acids 114-478, allotype Gmla, Gmlz). The light chain was isolated from normal human blood (IDEC Pharmaceuticals Corporation, La Jolla, Calif.); RNA therefrom was used to synthesize cDNA which was then amplified using PCR techniques (primers were derived vis-a-vis the consensus from Kabat). The heavy chain was isolated (using PCR techniques) from cDNA prepared from RNA which was in turn derived from cells transfected with a human IgG1 vector (see, 3 Prot. Eng. 531, 1990; vector pNγ162). Two amino acids were changed in the isolated human IgG1 to match the consensus amino acid sequence from Kabat, to wit: amino acid 225 was changed from valine to alanine (GTT to GCA), and amino acid 287 was changed from methionine to lysine (ATG to AAG); - 3) The human immunoglobulin light and heavy chain cassettes contain synthetic signal sequences for secretion of the immunoglobulin chains;
- 4) The human immunoglobulin light and heavy chain cassettes contain specific DNA restriction sites which allow for insertion of light and heavy immunoglobulin variable regions which maintain the transitional reading frame and do not alter the amino acids normally found in immunoglobulin chains;
- 5) The DHFR cassette contained its own eukaryotic promoter (mouse beta globin major promoter, “BETA”) and polyadenylation region (bovine growth hormone polyadenylation, “BGH”); and
- 6) The NEO cassette contained its own eukaryotic promoter (BETA) and polyadenylation region (SV40 early polyadenylation, “SV”).
- With respect to the
TCAE 8 vector and the NEO cassette, the Kozak region was a partially impaired consensus Kozak sequence (which included an upstream Cla I site):ClaI −3 +1 GGGAGCTTGG ATCGAT ccTct ATG Gtt - (In the TCAE 5.2 vector, the change is between the ClaI and ATG regions, to wit: ccAcc.)
- The complete sequence listing of TCAE 8 (including the specific components of the four transcriptional cassettes) is set forth in FIG. 2 (SEQ. ID. NO. 1).
- As will be appreciated by those in the art, the TCAE vectors beneficially allow for substantially reducing the time in generating the immunologically active chimeric anti-CD20 antibodies. Generation and isolation of non-human light and heavy chain variable regions, followed by incorporation thereof within the human light chain constant transcriptional cassette and human heavy chain constant transcriptional cassette, allows for production of immunologically active chimeric anti-CD20 antibodies.
- We have derived a most preferred non-human variable region with specificity to the CD20 antigen using a murine source and hybridoma technology. Using polymerase chain reaction (“PCR”) techniques, the murine light and heavy variable regions were cloned directly into the
TCAE 8 vector—this is the most preferred route for incorporation of the non-human variable region into the TCAE vector. This preference is principally predicated upon the efficiency of the PCR reaction and the accuracy of insertion. However, other equivalent procedures for accomplishing this task are available. For example, using TCAE 8 (or an equivalent vector), the sequence of the variable region of a non-human anti-CD20 antibody can be obtained, followed by oligonucleotide synthesis of portions of the sequence or, if appropriate, the entire sequence; thereafter, the portions or the entire synthetic sequence can be inserted into the appropriate locations within the vector. Those skilled in the art are credited with the ability to accomplish this task. - Our most preferred immunologically active chimeric anti-CD20 antibodies were derived from utilization of
TCAE 8 vector which included murine variable regions derived from monoclonal antibody to CD20; this antibody (to be discussed in detail. infra), is referred to as “2B8.” The complete sequence of the variable regions obtained from 2B8 in TCAE 8 (“anti-CD20 inTCAE 8”) is set forth in FIG. 3 (SEQ. ID. NO. 2). - The host cell line utilized for protein expression is most preferably of mammalian origin; those skilled in the art are credited with ability to preferentially determine particular host cell lines which are best suited for the desired gene product to be expressed therein. Exemplary host cell lines include, but are not limited to, DG44 and DUXB11 (Chinese Hamster Ovary lines, DHFR minus), HELA (human cervical carcinoma), CVI (monkey kidney line), COS (a derivative of CVI with SV40 T antigen), R1610 (Chinese hamster fibroblast) BALBC/3T3 (mouse fibroblast), HAK (hamster kidney line), SP210 (mouse myeloma), P3x63-Ag3.653 (mouse myeloma), BFA-1c1BPT (bovine endothelial cells), RAJI (human lymphocyte) and 293 (human kidney). Host cell lines are typically available from commercial services, the American Tissue Culture Collection or from published literature.
- Preferably the host cell line is either DG44 (“CHO”) or SP2/0. See Urland, G. et al., “Effect of gamma rays and the dihydrofolate reductase locus: deletions and inversions.”Som. Cell & Mol. Gen. 12/6:555-566 (1986), and Shulman, M. et al., “A better cell line for making hybridomas secreting specific antibodies.” Nature 276:269 (1978), respectively. Most preferably, the host cell line is DG44. Transfection of the plasmid into the host cell can be accomplished by any technique available to those in the art. These include, but are not limited to, transfection (including electrophoresis and electroporation), cell fusion with enveloped DNA, microinjection, and infection with intact virus. See, Ridgway, A. A. G. “Mammalian Expression Vectors.” Chapter 24.2, pp. 470-472 Vectors, Rodriguez and Denhardt, Eds. (Butterworths, Boston, Mass. 1988). Most preferably, plasmid introduction into the host is via electroporation.
- The following examples are not intended, nor are they to be construed, as limiting the invention. The examples are intended to evidence; dose-imaging using a radiolabeled anti-CD20 antibody (“I2B8“); radiolabeled anti-CD20 antibody (“Y2B8“); and immunologically active, chimeric anti-CD20 antibody (“C2B8“) derived utilizing a specific vector (“
TCAE 8“) and variable regions derived from murine anti-CD20 monoclonal antibody (“2B8“). - A Anti-CD20 Monoclonal Antibody (Murine) Production (“2B8“)
- BALB/C mice were repeatedly immunized with the human lymphoblastoid cell line SB (see, Adams, R. A. et al., “Direct implantation and serial transplantation of human acute lymphoblastic leukemia in hamsters, SB-2.″Can Res 28:1121-1125 (1968); this cell line is available from the American Tissue Culture Collection, Rockville, Md., under ATCC accession number ATCC CCL 120), with weekly injections over a period of 3-4 months. Mice evidencing high serum titers of anti-CD20 antibodies, as determined by inhibition of known. CD20-specific antibodies (anti-CD20 antibodies utilized were Leu 16, Beckton Dickinson, San Jose, Calif., Cat. No. 7670; and B1, Coulter Corp., Hialeah, Fla., Cat. No. 6602201) were identified; the spleens of such mice were then removed. Spleen cells were fused with the mouse myeloma SP2/0 in accordance with the protocol described in Einfeld, D. A. et al., (1988) EMBO 7:711 (SP2/0 has ATCC accession no. ATCC CRL 8006).
- Assays for CD20 specificity were accomplished by radioimmunoassay. Briefly, purified anti-CD20 B1 was radiolabeled with I125 by the iodobead method as described in Valentine, M. A. et al., (1989) J. Biol. Chem. 264:11282. (I125 Sodium Iodide, ICN, Irvine, Calif., Cat. No. 28665H). Hybridomas were screened by co-incubation of 0.05 ml of media from each of the fusion wells together with 0.05 ml of I125 labeled anti-CD20 B1 (10 ng) in 1% BSA, PBS (pH 7.4), and 0.5 ml of the same buffer containing 100,000 SB cells. After incubation for 1 hr at room temperature, the cells were harvested by transferring to 96 well titer plates (V&P Scientific, San Diego, Calif.), and washed thoroughly. Duplicate wells containing unlabeled anti-CD20 B1 and wells containing no inhibiting antibody were used as positive and negative controls, respectively. Wells containing greater than 50% inhibition were expanded and cloned. The antibody demonstrating the highest inhibition was derived from the cloned cell line designated herein as “2B8.“
- B. Preparation of 2B8-MX-DTPA Conjugate
- i. MX-DTPA
- Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (“carbon-14 labeled MX-DTPA”) was used as a chelating agent for conjugation of radiolabel to 2B8. Manipulations of MX-DTPA were conducted to maintain metal-free conditions, ie metal-free reagents were utilized and, when possible, polypropylene plastic containers (flasks, beakers, graduated cylinders, pipette tips) washed with Alconox and rinsed with Milli-Q water, were similarly utilized. MX-DTPA was obtained as a dry solid from Dr. Otto Gansow (National Institute of Health, Bethesda, Md.) and stored desiccated at 4° C. (protected from light), with stock solutions being prepared in Milli-Q water at a concentration of 2-5 mM, with storage at −70° C. MX-DTPA was also obtained from Coulter Immunology (Hialeah, Fla.) as the disodium salt in water and stored at −70° C.
- ii. Preparation of 2B8
- Purified 2B8 was prepared for conjugation with MX-DTPA by transferring the antibody into metal-free 50 mM bicine-NaOff, pH 8.6, containing 150 mM NaCl, using repetitive buffer exchange with
CENTRICON 30™ spin filters (30,000D, MWCO; Amicon). Generally, 50-200 μL of protein (10 mg/nl) was added to the filter unit, followed by 2 mL of bicine buffer. The filter was centrifuged at 4° C. in a Sorval SS-34 rotor (6,000 rpm, 45 min.). Retentate volume was approximately 50-100 μL; this process was repeated twice using the same filter. Retentate was transferred to a polypropylene 1.5 mL screw cap tube, assayed for protein, diluted to 10.0 mg/mL and stored at 4° C. until utilized; protein was similarly transferred into 50 mM sodium citrate, pH 5.5, containing 150 mM NaCl and 0.05% sodium azide, using the foregoing protocol. - iii. Conjugation of 2B8 with MX-DTPA
- Conjugation of 2B8 with MX-DTPA was performed in polypropylene tubes at ambient temperature. Frozen MX-DTPA stock solutions were thawed immediately prior to use. 50-200 mL of protein at 10 mg/mL were reacted with MX-DTPA at a molar ratio of MX-DTPA-to-2B8 of 4:1. Reactions were initiated by adding the MX-DTPA stock solution and gently mixing; the conjugation was allowed to proceed overnight (14 to 20 hr), at ambient temperature. Unreacted MX-DTPA was removed from the conjugate by dialysis or repetitive ultrafiltration, as described above in Example I.B.ii, into metal-free normal saline (0.9% w/v) containing 0.05% sodium azide. The protein concentration was adjusted to 10 mg/mL and stored at 4° C. in a polypropylene tube until radiolabeled.
- iv. Determination of MX-DTPA Incorporation
- MX-DTPA incorporation was determined by scintillation counting and comparing the value obtained with the purified conjugate to the specific activity of the carbon-[14]-labeled MX-DTPA. For certain studies, in which non-radioactive MX-DTPA (Coulter Immunology) was utilized, MX-DTPA incorporation was assessed by incubating the conjugate with an excess of a radioactive carrier solution of yttrium-[90] of known concentration and specific activity.
- A stock solution of yttrium chloride of known concentration was prepared in metal-free 0.05 N HCl to which carrier-free yttrium-[90] (chloride salt) was added. An aliquot of this solution was analyzed by liquid scintillation counting to determine an accurate specific activity for this reagent. A volume of the yttrium chloride reagent equal to 3-times the number of mols of chelate expected to be attached to the antibody, (typically 2 mol/mol antibody), was added to a polypropylene tube, and the pH adjusted to 4.0-4.5 with 2 M sodium acetate. Conjugated antibody was subsequently added and the mixture incubated 15-30 min. at ambient temperature. The reaction was quenched by adding 20 mM EDTA to a final concentration of 1 mM and the pH of the solution adjusted to approximately
pH 6 with 2M sodium acetate. - After a 5 min. incubation, the entire volume was purified by high-performance, size-exclusion chromatography (described infra). The eluted protein-containing fractions were combined, the protein concentration determined, and an aliquot assayed for radioactivity. The chelate incorporation was calculated using the specific activity of the yttrium-[90] chloride preparation and the protein concentration.
- v. Immunoreactivity of 2B8-MX-DTPA
- The immunoreactivity of conjugated 2B8 was assessed using whole-cell ELISA. Mid-log phase SB cells were harvested from culture by centrifugation and washed two times with 1× HBSS. Cells were diluted to 1-2×106 cells/mL in HBSS and aliquoted into 96-well polystyrene microtiter plates at 50,000-100,000 cells/well. The plates were dried under vacuum for 2 h. at 40-45° C. to fix the cells to the plastic; plates were stored dry at −20° C. until utilized. For assay, the plates were warmed to ambient temperature immediately before use, then blocked with 1× PBS, pH 7.2-7.4 containing 1% BSA (2 h). Samples for assay were diluted in 1× PBS/1% BSA, applied to plates and serially diluted (1:2) into the same buffer. After incubating plates for 1 h. at ambient temperature, the plates were washed three times with 1× PBS. Secondary antibody (goat anti-mouse IgG1-
specific HRP conjugate 50 μL) was added to wells (1:1500 dilution in 1× PBS/1% BSA) and incubated 1 h. at ambient temperature. Plates were washed four times with 1× PBS followed by the addition of ABTS substrate solution (50 mM sodium citrate, pH 4.5 containing 0.01% ATBS and 0.001% H2O2). Plates were read at 405 nm after 15-30 min. incubation. Antigen-negative HSB cells were included in assays to monitor non-specific binding. Immunoreactivity of the conjugate was calculated by plotting the absorbance values vs. the respective dilution factor and comparing these to values obtained using native antibody (representing 100% immunoreactivity) tested on the same plate; several values on the linear portion of the titration profile were compared and a mean value determined (data not shown). - vi. Preparation of Indium-[111]-Labeled 2B8-MX-DTPA (“I2B8“)
- Conjugates were radiolabeled with carrier-free indium-[111]. An aliquot of isotope (0.1-2 mCi/mg antibody) in 0.05 M HCl was transferred to a polypropylene tube and approximately one-tenth volume of metal-free 2 M HCl added. After incubation for 5 min., metal-free 2 M sodium acetate was added to adjust the solution to pH 4.0-4.4. Approximately 0.5 mg of 2B8-MX-DTPA was added from a stock solution of 10.0 mg/mL DTPA in normal saline, or 50 mM sodium citrate/150 mM NaCl containing 0.05% sodium azide, and the solution gently mixed immediately. The pH solution was checked with pH paper to verify a value of 4.0-4.5 and the mixture incubated at ambient temperature for 15-30 min. Subsequently, the reaction was quenched by adding 20 mM EDTA to a final concentration of 1 mM and the reaction mixture was adjusted to approximately pH 6.0 using 2 M sodium acetate.
- After a 5-10 min. incubation, uncomplexed radioisotope was removed by size-exclusion chromatography. The HPLC unit consisted of Waters Model 6000 or TosoHaas Model TSK-6110 solvent delivery system fitted, respectively, with a Waters U6K or
Rheodyne 700 injection valve. Chromatographic separations were performed using a gel permeation column (BioRad SEC-250; 7.5×300 mm or comparable TosoHaas column) and a SEC-250 guard column (7.5×100 mm). The system was equipped with a fraction collector (Pharmacia Frac200) and a UV monitor fitted with a 280 nm filter (Pharmacia model UV-1). Samples were applied and eluted isocratically using 1× PBS, pH 7.4, at 1.0 mL/min flow rate. One-half milliliter fractions were collected in glass tubes and aliquots of these counted in a gamma counter. The lower and upper windows were set to 100 and 500 KeV respectively. - The radioincorporation was calculated by summing the radioactivity associated with the eluted protein peak and dividing this number by the total radioactivity eluted from the column; this value was then expressed as a percentage (data not shown). In some cases, the radioincorporation was determined using instant thin-layer chromatography (“ITLC”). Radiolabeled conjugate was diluted 1:10 or 1:20 in 1× PBS containing or 1× PBS/1 mM DTPA, then 1 μL was spotted 1.5 cm from one end of a 1×5 cm strip of ITLC SG paper. The paper was developed by ascending chromatography using 10% ammonium acetate in methanol:water (1:1;v/v). The strip was dried, cut in half crosswise, and the radioactivity associated with each section determined by gamma counting. The radioactivity associated with the bottom half of the strip (protein-associated radioactivity) was expressed as a percentage of the total radioactivity, determined by summing the values for both top and bottom halves (data not shown).
- Specific activities were determined by measuring the radioactivity of an appropriate aliquot of the radiolabeled conjugate. This value was corrected for the counter efficiency (typically 75%) and related to the protein concentration of the conjugate, previously determined by absorbance at 280 nm, and the resulting value expressed as mCi/mg protein.
- For some experiments, 2B8-MX-DTPA was radiolabeled with indium ([111] following a protocol similar to the one described above but without purification by HPLC; this was referred to as the “mix-and-shoot” protocol.
- vii. Preparation of Yttrium-[90]-Labeled 2B8-MX-DTPA (“Y2B8“)
- The same protocol described for the preparation of I2B8 was followed for the preparation of the yttrium-[90]-labeled 2B8-MX-DTPA (Y2B8“) conjugate except that 2 ng HCl was not utilized; all preparations of yttrium-labeled conjugates were purified by size-exclusion chromatography as described above.
- C. Non-Human Animal Studies
- i. Biodistribution of Radiolabeled 2B8-MX-DTPA
- I2B8 was evaluated for tissue biodistribution in six-to-eight week old BALB/c mice. The radiolabeled conjugate was prepared using clinical-grade 2B8-MX-DTPA following the “mix and shoot” protocol described above. The specific activity of the conjugate was 2.3 mCi/mg and the conjugate was formulated in PBS, pH 7.4 containing 50mg/mL HSA. Mice were injected intravenously with 10082 L of 12B8 (approximately 21 μCi) and groups of three mice were sacrificed by cervical dislocation at 0, 24, 48, and 72 hours. After sacrifice, the tail, heart, lungs, liver, kidney, spleen, muscle, and femur were removed, washed and weighed; a sample of blood was also removed for analysis. Radioactivity associated with each specimen was determined by gamma counting and the perfect injected dose per gram tissue subsequently determined. No attempt was made to discount the activity contribution represented by the blood associated with individual organs.
- In a separate protocol, aliquots of 2B8-MX-DTPA incubated at 4° C. and 30° C. for 10 weeks were radiolabeled with indium-[111] to a specific activity of 2.1 mCi/mg for both preparations. These conjugates were then used in biodistribution studies in mice as described above.
- For dosimetry determinations, 2B8-MX-DTPA was radiolabeled with indium-([11] to a specific activity of 2.3 mCi/mg and approximately 1.1 μCi was injected into each of 20 BALB/c mice. Subsequently, groups of five mice each were sacrificed at 1, 24, 48 and 72 hours and their organs removed and prepared for analysis. In addition, portions of the skin, muscle and bone were removed and processed for analysis; the urine and feces were also collected and analyzed for the 24-72 hour time points.
- Using a similar approach, 2B8-MX-DTPA was also radiolabeled with yttrium-[90] and its biological distribution evaluated in BALB/c mice over a 72-hour time period. Following purification by HPLC size exclusion chromatography, four groups of five mice each were injected intravenously with approximately 1 μCi of clinically-formulated conjugate (specific activity:12.2 mCi/mg); groups were subsequently sacrificed at 1, 24, 48 and 72 hours and their organs and tissues analyzed as described above. Radioactivity associated with each tissue specimen was determined by measuring bremstrahlung energy with a gamma scintillation counter. Activity values were subsequently expressed as percent injected dose per gram tissue or percent injected dose per organ. While organs and other tissues were rinsed repeatedly to remove superficial blood, the organs were not perfused. Thus, organ activity values were not discounted for the activity contribution represented by internally associated blood.
- ii. Tumor Localization of 12B8
- The localization of radiolabeled 2B8-Na-DTPA was determined in athymic mice bearing Ramos B cell tumors. Six-to-eight week old athymic mice were injected subcutaneously (left-rear flank) with 0.1 mL of RPMI-1640 containing 1.2×107 Ramos tumor cells which had been previously adapted for growth in athymic mice. Tumors arose within two weeks and ranged in weight from 0.07 to 1.1 grams. Mice were injected intravenously with 100 μL of indium-([11]-labeled 2B8-MX-DTPA (16.7 μCi) and groups of three mice were sacrificed by cervical dislocation at 0, 24, 48, and 72 hours. After sacrifice the tail, heart, lungs, liver, kidney, spleen, muscle, femur, and tumor were removed, washed, weighed; a sample of blood was also removed for analysis. Radioactivity associated with each specimen was determined by gamma counting and the percent injected dose per gram tissue determined.
- iii. Biodistribution and Tumor Localization Studies with Radiolabeled 2B8-MX-DTPA
- Following the preliminary biodistribution experiment described above (Example I.B.viii.a.), conjugated 2B8 was radiolabeled with indium-[111] to a specific activity of 2.3 mCi/mg and roughly 1.1 μCi was injected into each of twenty BALB/c mice to determine biodistribution of the radiolabeled material. Subsequentially, groups of five mice each were sacrificed at 1, 24, 48 and 72 hours and their organs and a portion of the skin, muscle and bone were removed and processed for analysis. In addition, the urine and feces were collected and analyzed for the 24-72 hour time-points. The level of radioactivity in the blood dropped from 40.3% of the injected dose per gram at 1 hour to 18.9% at 72 hours (data not shown). Values for the heart, kidney, muscle and spleen remained in the range of 0.7-9.8% throughout the experiment. Levels of radioactivity found in the lungs decreased from 14.2% at 1 hour to 7.6% at 72 hours; similarly the respective liver injected-dose per gram values were 10.3% and 9.9%. These data were used in determining radiation absorbed dose estimates I2B8 described below.
- The biodistribution of yttrium-[90]-labeled conjugate, having a specific activity of 12.2 mCi/mg antibody, was evaluated in BALB/c mice. Radioincorporations of >90% were obtained and the radiolabeled antibody was purified by HPLC. Tissue deposition of radioactivity was evaluated in the major organs, and the skin, muscle, bone, and urine and feces over 72 hours and expressed as percent injected dose/g tissue. Results (not shown) evidenced that while the levels of radioactivity associated with the blood dropped from approximately 39.2% injected dose per gram at 1 hour to roughly 15.4% after 72 hours the levels of radioactivity associated with tail, heart, kidney, muscle and spleen remained fairly constant at 10.2% or less throughout the course of the experiment. Importantly, the radioactivity associated with the bone ranged from 4.4% of the injected dose per gram bone at 1 hour to 3.2% at 72 hours. Taken together, these results suggest that little free yttrium was associated with the conjugate and that little free radiometal was released during the course of the study. These data were used in determining radiation absorbed dose estimates for Y2B8 described below.
- For tumor localization studies, 2B8-MX-DTPA was prepared and radiolabeled with111Indium to a specific activity of 2.7 mCi/mg. One hundred microliters of labeled conjugate (approximately 24 μCi) were subsequently injected into each of 12 athymic mice bearing Ramos B cell tumors. Tumors ranged in weight from 0.1 to 1.0 grams. At time points of 0, 24, 48, and 72 hours following injection, 50 μL of blood was removed by retro-orbital puncture, the mice sacrificed by-cervical dislocation, and the tail, heart, lungs, liver, kidney, spleen, muscle, femur, and tumor removed. After processing and weighing the tissues, the radioactivity associated with each tissue specimen was determined using a gamma counter and the values expressed as percent injected dose per gram.
- The results (not shown) evidenced that the tumor concentrations of the111In-2B8-MX-DTPA increased steadily throughout the course of the experiment. Thirteen percent of the injected dose was accumulated in the tumor after 72 hours. The blood levels, by contrast, dropped during the experiment from over 30% at time zero to 13% at 72 hours. All other tissues (except muscle) contained between 1.3 and 6.0% of the injected dose per gram tissue by the end of the experiment; muscle tissue contained approximately 13% of the injected dose per gram.
- D. Human Studies
- i. 2B8 and 2B8-MX-DTPA: Immunohistology Studies with Human Tissues
- The tissue reactivity of murine monoclonal antibody 2B8 was evaluated using a panel of 32 different human tissues fixed with acetone. Antibody 2B8 reacts with the anti-CD20 antigen which had a very restricted pattern of tissue distribution, being observed only in a subset of cells in lymphoid tissues including those of hematopoietic origin.
- In the lymph node, immunoreactivity was observed in a population of mature cortical B-lymphocytes as well as proliferating cells in the germinal centers. Positive reactivity was also observed in the peripheral blood, B-cell areas of the tonsils, white pulp of the spleen, and with 40-70% of the medullary lymphocytes found in the thymus. Positive reactivity was also seen in the follicles of the lamina propria (Peyer's Patches) of the large intestines. Finally, aggregates or scattered lymphoid cells in the stroma of various organs, including the bladder, breast, cervix, esophagus, lung, parotid, prostate, small intestine, and stomach, were also positive with antibody 2B8 (data not shown).
- All simple epithelial cells, as well as the stratified epithelia and epithelia of different organs, were found to be unreactive. Similarly, no reactivity was seen with neuroectodermal cells, including those in the brain, spinal cord and peripheral nerves. Mesenchymal elements, such as skeletal and smooth muscle cells, fibroblasts, endothelial cells, and polymorphonuclear inflammatory cells were also found to be negative (data not shown).
- The tissue reactivity of the 2B8-MX-DTPA conjugate was evaluated using a panel of sixteen human tissues which had been fixed with acetone. As previously demonstrated with the native antibody (data not shown), the 2B8-MX-DTPA conjugate recognized the CD20 antigen which exhibited a highly restricted pattern of distribution, being found only on a subset of cells of lymphoid origin. In the lymph node, immunoreactivity was observed in the B cell population. Strong reactivity was seen in the white pulp of the spleen and in the medullary lymphocytes of the thymus. Immunoreactivity was also observed in scattered lymphocytes in the bladder, heart, large intestines, liver, lung, and uterus, and was attributed to the presence of inflammatory cells present in these tissues. As with the native antibody, no reactivity was observed with neuroectodermal cells or with mesenchymal elements (data not shown).
- ii. Clinical Analysis of 12B8 (Imaging) and Y2B8 (Therapy)
- a. Phase I/II Clinical Trial Single Dose Therapy Study
- A Phase I/II clinical analysis of 12B8 (imaging) followed by treatment with a single therapeutic dose of Y2B8 is currently being conducted. For the single-dose study, the following schema is being followed:
- 1. Peripheral Stem Cell (PSC) or Bone Marrow (BM) Harvest with Purging;
- 2. I2B8 Imaging;
- 3. Y2B8 Therapy (three Dose Levels); and
- 4. PSC or Autologous BM Transplantation (if necessary based upon absolute neutrophil count below 500/mm3 for three consecutive days or platelets below 20,000/mm3 with no evidence of marrow recovery on bone marrow examination).
- The Dose Levels of Y2B8 are as follows:
Dose Level Dose (mCi) 1. 20 2. 30 3. 40 - Three patients are to be treated at each of the dose levels for determination of a Maximum Tolerated Dose (“MTD”).
- Imaging (Dosimetry) Studies are conducted as follows: each patient is involved in two in vivo biodistribution studies using I2B8. In the first study, 2 mg of 12B8 (5 mCi), is administered as an intravenous (i.v.) infusion over one hour; one week later 2B8 (ie unconjugated antibody) is administered by i.v. at a rate not to exceed 250 mg/hr followed immediately by 2 mg of I2B8 (5 mCi) administered by i.v. over one hour. In both studies, immediately following the I2B8 infusion, each patient is imaged and imaging is repeated at time t=14-18 hr (if indicated), t=24 hr; t=72 hr; and t=96 hr (if indicated). Whole body average retention times for the indium [111] label are determined; such determinations are also made for recognizable organs or tumor lesions (“regions of interest”).
- The regions of interest are compared to the whole body concentrations of the label; based upon this comparison, an estimate of the localization and concentration of Y2B8 can be determined using standard protocols. If the estimated cumulative dose of Y2B8 is greater than eight (8) times the estimated whole body dose, or if the estimated cumulative dose for the liver exceeds 1500 cGy, no treatment with Y2B8 should occur.
- If the imaging studies are acceptible, either 0.0 or 1.0 mg/kg patient body weight of 2B8 is administered by i.v. infusion at a rate not to exceed 250 mg/h. This is followed by administration of Y2B8 (10,20 or 40 mCi) at an i.v. infusion rate of 20 mCi/hr.
- b. Phase I/II Clinical Trial: Multiple Dose Therapy Study
- A Phase I/II clinical analysis of of Y2B8 is currently being conducted. For the multiple-dose study, the following schema is being followed:
- 1. PSC or BM Harvest;
- 2. I2B8 Imaging;
- 3. Y2B8 Therapy (three Dose Levels) for four doses or a total cumulative dose of 80 mCi; and
- 4. PSC or Autologous BM Transplantation (based upon decision of medical practitioner).
- The Dose Levels of Y2B8 are as follows:
Dose Level Dose (mCi) 1. 10 2. 15 3. 20 - Three patients are to be treated at each of the dose levels for determination of an MTD.
- Imaging (Dosimetry) Studies are conducted as follows: A preferred imaging dose for the unlabeled antibody (ie 2B8) will be determined with the first two patients. The first two patients will receive 100 mg of unlabeled 2B8 in 250 cc of normal saline over 4 hrs followed by 0.5 mCi of I2B8—blood will be sampled for biodistribution data at times t=0, t=10min., t=120 min., t=24 hr, and t=48 hr. Patients will be scanned with multiple regional gamma camera images at times t=2 hr, t=24 hr and t=48 hr. After scanning at t=48 hr, the patients will receive 250 mg of 2B8 as described, followed by 4.5 mCi of 12B8—blood and scanning will then follow as described. If 100 mg of 2B8 produces superior imaging, then the next two patients will receive 50 mg of 2B8 as described, followed by 0.5 mCi of I2B8 followed 48 hrs later by 100 mg 2B8 and then with 4.5 mCi of I2B8. If 250 mg of 2B8 produces superior imaging, then the next two patients will receive 250 mg of 2B8 as described, followed by 0.5 mCi of I2B8 followed 48 hrs later with 500 mg 2B8 and then with 4.5 mCi of 12B8. Subsequent patients will be treated with the lowest amount of 2B8 that provides optimal imaging. Optimal imaging will be defined by: (1) best effective imaging with the slowest disappearance of antibody; (2) best distribution minimizing compartmentalization in a single organ; and (3) best subjective resolution of the lesion (tumor/background comparison).
- For the first four patients, the first therapeutic dose of Y2B8 will begin 14 days after the last dose of 12B8; for subsequent patients, the first therapeutic dose of Y2B8 will begin between two to seven days after the I2B8.
- Prior to treatment with Y2B8, for the patients other than the first four, 2B8 will be administered as described, followed by i.v. infusion of Y2B8 over 5-10 min. Blood will be sampled for biodistribution at times t=0, t=10min., t=120 min., t=24 hr and t=48 hr. Patients will receive repetitive doses of Y2B8 (the same dose administered as with the first dose) approximately every six to eight weeks for a maximum of four doses, or total cumulative dose of 80 mCi. It is most preferred that patients not receive a subsequent dose of Y2B8 until the patients' WBC is greater than/equal to 3,000 and AGC is greater than/equal to 100,000.
- Following completion of the three-dose level study, an MTD will be defined. Additional patients will then be enrolled in the study and these will receive the MTD.
- A. Construction of Chimeric Anti-CD20 Immunoglobulin DNA Expression Vector
- RNA was isolated from the 2B8 mouse hybridoma cell (as described in Chomczynki, P. et al., “Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.”Anal. Biochem. 162:156-159 (1987)). and cDNA was prepared therefrom. The mouse immunoglobulin light chain variable region DNA was isolated from the cDNA by polymerase chain reaction using a set of DNA primers with homology to mouse light chain signal sequences at the 5′ end and mouse light chain J region at the 3′ end. Primer sequences were as follows:
1. VL Sense (SEQ. ID. NO. 3) 5′ ATC AC AGATCT CTC ACC ATG GAT TTT CAG GTG CAG ATT ATC AGC TTC 3′(The underlined portion is a Bgl II site; the above-lined portion is the start codon.) 2. VL Antisense (SEQ. ID. NO. 4) 5′ TGC AGC ATC CGTACG TTT GAT TTC CAG CTT 3′(The underlined portion is a Bsi WI site.) - See, FIGS. 1 and 2 for the corresponding Bg1 II and Bsi WI sites in
TCAE 8, and FIG. 3 for the corresponding sites in anti-CD20 inTCAE 8. - These resulting DNA fragment was cloned directly into the
TCAE 8 vector in front of the human kappa light chain constant domain and sequenced. The determined DNA sequence for the murine variable region light chain is set forth in FIG. 4 (SEQ. ID. NO. 5); see also FIG. 3,nucleotides 978 through 1362. FIG. 4 further provides the amino acid sequence from this murine variable region, and the CDR and framework regions. The mouse light chain variable region from 2B8 is in the mouse kappa VI family. See, Kabat, supra. - The mouse heavy chain variable region was similarly isolated and cloned in front of the human IgG1 constant domains. Primers were as follows:
1. VH Sense (SEQ. ID. NO. 6) 5′ GCG GCT CCC ACGCGT GTC CTG TCC CAG 3′(The underlined portion is an Mlu I site.) 2. VH Antisense (SEQ. ID. NO. 7) 5′ GG(G/C) TGT TGT GCTAGC TG(A/C) (A/G)GA GAC (G/A) GT GA 3′(The underlined portion is an Nhe I site.) - See, FIGS. 1 and 2 for corresponding Mlu I and Nhe I sites in
TCAE 8, and FIG. 3 for corresponding sites in anti-CD20 inTCAE 8. - The sequence for this mouse heavy chain is set forth in FIG. 5 (SEQ. ID. NO. 8); see also FIG. 3, nucleotide 2401 through 2820. FIG. 5 also provides the amino acid sequence from this murine variable region, and the CDR and framework regions. The mouse heavy chain variable region from 2B8 is in the mouse VH 2B family. See, Kabat, supra.
- B. Creation of Chimeric Anti-CD20 Producing CHO and SP2/0 Transfectomas
- Chinese hamster ovary (“CHO”) cells DG44 were grown in SSFM II minus hypoxanthine and thymidine media (Gibco, Grand Island, N.Y., Form No. 91-0456PK); SP2/0 mouse myeloma cells were grown in Dulbecco's Modified Eagles Medium media (“DMEM”) (Irvine Scientific, Santa Ana, Calif., Cat. No. 9024) with 5% fetal bovine serum and 20 ml/L glutamine added. Four million cells were electroporated with either 25 μg CHO or 50 μg SP2/0 plasmid DNA that had been restricted with Not I using a
BTX 600 electroporation system (BTX, San Diego, Calif.) in 0.4 ml disposable cuvettes. Conditions were either 210 volts for CHO or 180 volts for SP2/0, 400 microfaradays, 13 ohms. Each electroporation was plated into six 96 well dishes (about 7,000 cells/well). Dishes were fed with media containing G418 (GENETICIN, Gibco, Cat. No. 860-1811) at 400 μg/ml active compound for CHO (media further included 50 μM hypoxanthine and 8 μM thymidine) or 800 μg/ml for SP210, two days following electroporation and thereafter 2 or 3 days until colonies arose. Supernatant from colonies was assayed for the presence of chimeric immunoglobulin via an ELISA specific for human antibody. Colonies producing the highest amount of immunoglobulin were expanded and plated into 96 well plates containing media plus methotrexate (25 nM for SP2/0 and 5nM for CHO) and fed every two or three days. Supernatants were assayed as above and colonies producing the highest amount of immunoglobulin were examined. Chimeric anti-CD20 antibody was purified from supernatant using protein A affinity chromatography. - Purified chimeric anti-CD20 was analyzed by electrophoresis in polyacrylamide gels and estimated to be greater than about 95% pure. Affinity and specificity of the chimeric antibody was determined based upon 2B8. Chimeric anti-CD20 antibody tested in direct and competitive binding assays, when compared to murine anti-CD20 monoclonal antibody 2B8, evidenced comparable affinity and specificity on a number of CD20 positive B cells lines (data not presented). The apparent affinity constant (“Kap”) of the chimeric antibody was determined by direct binding of I125 radiolabeled chimeric anti-CD20 and compared to radiolabeled 2B8 by Scatchard plot; estimated Kap for CHO produced chimeric anti-CD20 was 5.2×10−9 M and for SP2/0 produced antibody, 7.4×10−9M. The estimated Kap for 2B8 was 3.5×10−9 M. Direct competition by radioimmunoassay was utilized to confirm both the specificity and retention of immunoreactivity of the chimeric antibody by comparing its ability to effectively compete with 2B8. Substantially equivalent amounts of chimeric anti-CD20 and 2B8 antibodies were required to produce 50% inhibition of binding to CD20 antigens on B cells (data not presented), ie there was a minimal loss of inhibiting activity of the anti-CD20 antibodies, presumably due to chimerization.
- The results of Example II.B indicate, inter alia, that chimeric anti-CD20 antibodies were generated from CHO and SP2/0 transfectomas using the
TCAE 8 vectors, and these chimeric antibodies had substantially the same specificity and binding capability as murine anti-CD20 monoclonal antibody 2B8. - C. Determination of Immunological Activity of Chimeric Anti-CD20 Antibodies
- i. Human C1g Analysis
- Chimeric anti-CD20 antibodies produced by both CHO and SP2/0 cell lines were evaluated for human C1q binding in a flow cytometry assay using fluorescein labeled C1q (C1q was obtained from Quidel, Mira Mesa, Calif., Prod. No. A400 and FITC label from Sigma, St. Louis Mo., Prod. No. F-7250; FITC. Labeling of C1q was accomplished in accordance with the protocol described inSelected Methods In Cellular Immunology, Michell & Shiigi, Ed. (W. H. Freeman & Co., San Francisco, Calif., 1980, p. 292). Analytical results were derived using a Becton Dickinson FACScan™ flow cytometer (fluorescein measured over a range of 515-545 nm). Equivalent amounts of chimeric anti-CD20 antibody, human IgG1,K myeloma protein (Binding Site, San Diego, Calif., Prod. No. BP078), and 2B8 were incubated with an equivalent number of CD20-positive SB cells, followed by a wash step with FACS buffer (.2% BSA in PBS, pH 7.4, 0.02% sodium azide) to remove unattached antibody, followed by incubation with FITC labeled C1q. Following a 30-60 min. incubation, cells were again washed. The three conditions, including FITC-labeled C1q as a control, were analyzed on the FACScan™ following manufacturing instructions. Results are presented in FIG. 6.
- As the results of FIG. 6 evidence, a significant increase in fluorescence was observed only for the chimeric anti-CD20 antibody condition; ie only SB cells with adherent chimeric anti-CD20 antibody were C1q positive, while the other conditions produced the same pattern as the control.
- ii. Complement Dependent Cell Lyses
- Chimeric anti-CD20 antibodies were analyzed for their ability to lyse lymphoma cell lines in the presence of human serum (complement source). CD20 positive SB cells were labeled with51Cr by admixing 100 μCi of 51Cr with 1×106 SB cells for 1 hr at 37° C.; labeled SB cells were then incubated in the presence of equivalent amounts of human complement and equivalent amounts (0-50 μg/ml) of either chimeric anti-CD20 antibodies or 2B8 for 4 hrsat 37° C. (see, Brunner, K. T. et al., “Quantitative assay of the lytic action of immune lymphoid cells on 51Cr-labeled allogeneic target cells in vitro.” Immunology 14:181-189 (1968). Results are presented in FIG. 7.
- The results of FIG. 7 indicate, inter alia, that chimeric anti-CD20 antibodies produced significant lysis (49%) under these conditions.
- iii. Antibody Dependent Cellular Cytotoxicity Effector Assay
- For this study, CD20 positive cells (SB) and CD20 negative cells (T cell leukemia line HSB; see, Adams, Richard, “Formal Discussion,”Can. Res. 27:2479-2482 (1967); ATCC deposit no. ATCC CCL 120.1) were utilized; both were labeled with 51Cr. Analysis was conducted following the protocol described in Brunner, K. T. et al., “Quantitative assay of the lytic action of immune lymphoid cells on 51Cr-labeled allogeneic target cells in vitro; inhibition by isoantibody and drugs.” Immunology 14:181-189 (1968); a substantial chimeric anti-CD20 antibody dependent cell mediated lysis of CD20 positive SB target cells (51Cr-labeled) at the end of a 4 hr, 37° C. incubation, was observed and this effect was observed for both CHO and SP2/0 produced antibody (effector cells were human peripheral lymphocytes; ratio of effector cells:target was 100:1). Efficient lysis of target cells was obtained at 3.9 μg/ml. In contrast, under the same conditions, the murine anti-CD20 monoclonal antibody 2B8 had a statistically insignificant effect, and CD20 negative HSB cells were not lysed. Results are presented in FIG. 8.
- The results of Example II indicate, inter alia, that the chimeric ant4-CD20 antibodies of Example I were immunologically active.
- A. Non-Human Primate Study
- Three separate non-human primate studies were conducted. For convenience, these are referred to herein as “Chimeric Anti-CD20: CHO & SP2/0;““Chimeric Anti-CD20: CHO;” and “High Dosage Chimeric Anti-CD20.“Conditions were as follows:
- Chimeric Anti-CD20: CHO & SP2/0
- Six cynomolgus monkeys ranging in weight from 4.5 to 7 kilograms (White Sands Research Center, Alamogordo, N. Mex.) were divided into three groups of two monkeys each. Both animals of each group received the same dose of immunologically active chimeric anti-CD20 antibody. One animal in each group received purified antibody produced by the CHO transfectoma; the other received antibody produced by the SP2/0 transfectoma. The three groups received antibody dosages corresponding to 0.1 mg/kg, 0.4 mg/kg, and 1.6 mg/kg each day for four (4) consecutive days. The chimeric immunologically active anti-CD20 antibody, which was admixed with sterile saline, was administered by intravenous infusion; blood samples were drawn prior to each infusion. Additional blood samples were drawn beginning 24 hrs after the last injection (T=O) and thereafter on
days day 90. - Approximately 5 ml of whole blood from each animal was centrifuged at 2000 RPM for 5 min. Plasma was removed for assay of soluble chimeric anti-CD20 antibody levels. The pellet (containing peripheral blood leukocytes and red blood cells) was resuspended in fetal calf serum for fluorescent-labeled antibody analysis (see, “Fluorescent Antibody Labeling of Lymphoid Cell Population,” infra.).
- Chimeric Anti-CD20: CHO
- Six cynomolgus monkeys ranging in weight from 4 to 6 kilograms (White Sands) were divided into three groups of two monkeys each. All animals were injected with immunologically active chimeric anti-CD20 antibodies produced from the CHO transfectoma (in sterile saline). The three groups were separated as follows:
subgroup 1 received daily intravenous injections of 0.01 mg/kg of the antibody over a four (4) day period;subgroup 2 received daily intravenous injections of 0.4 mg/kg of the antibody over a four (4) day period;subgroup 3 received a single intravenous injection of 6.4 mg/kg of the antibody. For all three subgroups, a blood sample was obtained prior to initiation of treatment; additionally, blood samples were also drawn at T=0, 1, 3, 7, 14 and 28 days following the last injection, as described above, and these samples were processed for fluorescent labeled antibody analysis (see, “Fluorescent Antibody Labeling,” infra.). In addition to peripheral blood B cell quantitation, lymph node biopsies were taken atdays - High Dosage Chimeric Anti-CD20
- Two cynomolgus monkeys (White Sands) were infused with 16.8 mg/kg of the immunologically active chimeric anti-CD20 antibodies from the CHO transfectomas (in sterile saline) weekly over a period of four consecutive weeks. At the conclusion of the treatment, both animals were anesthetized for removal of bone marrow; lymph node biopsies were also taken. Both sets of tissue were stained for the presence of B lymphocytes using Leu 16 by flow cytometry following the protocol described in Ling, N. R. et al., “B-cell and plasma cell antigens.”Leucocyte Typing III White Cell Differentiations Antigens, A. J. McMichael, Ed. (Oxford University Press, Oxford UK, 1987), p. 302.
- Fluorescent Antibody Labeling of Lymphoid Cell Population
- After removal of plasma, leukocytes were washed twice with Hanks Balanced Salt Solution (“HBSS”) and resuspended in a plasma equivalent volume of fetal bovine serum (heat inactivated at 56° C. for 30 min.). A 0.1 ml volume of the cell preparation was distributed to each of six (6), 15 ml conical centrifuge tubes Fluorescein labeled monoclonal antibodies with specificity for the human lymphocyte surface markers CD2 (AMAC, Westbrook, Me.), CD20 (Becton Dickinson) and human IgM (Binding Site, San Diego, Calif.) were added to 3 of the tubes for identifying T and B lymphocyte populations. All reagents had previously tested positive to the corresponding monkey lymphocyte antigens. Chimeric anti-CD20 antibody bound to monkey B cell surface CD20 was measured in the fourth tube using polyclonal goat anti-human IgG coupled with phycoerythrin (AMAC). This reagent was pre-adsorbed on a monkey Ig-sepharose column to prevent cross-reactivity to monkey Ig, thus allowing specific detection and quantitation of chimeric anti-CD20 antibody bound to cells. A fifth tube included both anti-IgM and anti-human IgG reagents for double stained B cell population. A sixth sample was included with no reagents for determination of autofluorescence. Cells were incubated with fluorescent antibodies for 30 min., washed and fixed with 0.5 ml of fixation buffer (0.15 M NaCl, 1% paraformaldehyde, pH7.4) and analyzed on a Becton Dickinson FACScan™ instrument. Lymphocyte populations were initially identified by forward versus right angle light scatter in a dot-plot bitmap with unlabeled leucocytes. The total lymphocyte population was then isolated by gating out all other events. Subsequent fluorescence measurements reflected only gated lymphocyte specific events.
- Depletion of Peripheral Blood B Lymphocytes
- No observable difference could be ascertained between the efficacy of CHO and SP2/0 produced antibodies in depleting B cells in vivo, although a slight increase in B cell recovery beginning after
day 7 for monkeys injected with chimeric anti-CD20 antibodies derived from CHO transfectomas at dosage levels 1.6 mg/kg and 6.4 mg/kg was observed and for the monkey injected with SP2/0 producing antibody at the 0.4 mg/kg dose level. FIGS. 9A, B and C provide the results derived from the chimeric anti-CD20:CHO & SP2/0 study, with FIG. 9A directed to the 0.4 mg/kg dose level; FIG. 9B directed to the 1.6 mg/kg dose level; and FIG. 9C directed to the 6.4 mg/kg dose level. - As is evident from FIG. 9, there was a dramatic decrease (>95%) in peripheral B cell levels after the therapeutic treatment across all tested dose ranges, and these levels were maintained up to seven (7) days post infusion; after this period, B cell recovery began, and, the time of recovery initiation was independent of dosage levels.
- In the Chimeric Anti-CD20:CHO study, a 10-fold lower antibody dosage concentration (0.01 mg/kg) over a period of four daily injections (0.04 mg/kg total) was utilized. FIG. 10 provides the results of this study. This dosage depleted the peripheral blood B cell population to approximately 50% of normal levels estimated with either the anti-surface IgM or the Leu 16 antibody. The results also indicate that saturation of the CD20 antigen on the B lymphocyte population was not achieved with immunologically active chimeric anti-CD20 antibody at this dose concentration over this period of time for non-human primates; B lymphocytes coated with the antibody were detected in the blood samples during the initial three days following therapeutic treatment. However, by
day 7, antibody coated cells were undetectable. - Table I summarizes the results of single and multiple doses of immunologically active chimeric anti-CD20 antibody on the peripheral blood populations; single dose condition was 6.4 mg/kg; multiple dose condition was 0.4 mg/kg over four (4) consecutive days (these results were derived from the monkeys described above).
TABLE I PERIPHERAL BLOOD POPULATION FROM C2B8 PRIMATE STUDY Monkey Dose Day CD2 Anti-Hu IgG A 0.4 mg/kg Prebleed 81.5 — (4 doses) 0 86.5 0.2 7 85.5 0.0 21 93.3 — 28 85.5 — B 0.4 mg/kg Prebleed 81.7 — (4 doses) 0 94.6 0.1 7 92.2 0.1 21 84.9 — 28 84.1 — C 6.4 mg/kg Prebleed 77.7 0.0 (1 dose) 7 85.7 0.1 21 86.7 — 28 76.7 — D 6.4 mg/kg Prebleed 85.7 0.1 (1 dose) 7 94.7 0.1 21 85.2 — 28 85.9 — Anti-Hu IgG + Monkey Anti-Hu IgM* Leu-16 % B Cell Depletion A — 9.4 0 0.3 0.0 97 0.1 1.2 99 — 2.1 78 — 4.1 66 B — 14.8 0 0.2 0.1 99 0.1 0.1 99 — 6.9 53 — 8.7 41 C 0.2 17.0 0 0.1 0.0 99 — 14.7 15 — 8.1 62 D 0.1 14.4 0 0.2 0.0 99 — 9.2 46 — 6.7 53 - The data summarized in Table I indicates that depletion of B cells in peripheral blood under conditions of antibody excess occurred rapidly and effectively, regardless of single or multiple dosage levels. Additionally, depletion was observed for at least seven days following the last injection, with partial B cell recovery observed by
day 21. - Table II summarizes the effect of immunologically active, chimeric anti-CD20 antibodies on cell populations of lymph nodes using the treatment regimen of Table I (4 daily doses of 0.4 mg/kg; 1 dose of 6.4 mg(kg); comparative values for normal lymph nodes (control monkey, axillary and inguinal) and normal bone marrow (two monkeys) are also provided.
TABLE II CELL POPULATIONS OF LYMPH NODES Monkey Dose Day CD2 Anti-Hu IgM A 0.4 mg/ kg 7 66.9 — (4 doses) 14 76.9 19.6 28 61.6 19.7 B 0.4 mg/ kg 7 59.4 — (4 doses) 14 83.2 9.9 28 84.1 15.7 C 6.4 mg/ kg 7 75.5 — (1 dose) 14 74.1 17.9 28 66.9 23.1 D 6.4 mg/ kg 7 83.8 — (1 dose) 14 74.1 17.9 28 84.1 12.8 Anti-Hu IgG + Monkey Anti-Hu IgM Leu-16 % B Lymphocyte Depletion A 7.4 40.1 1 0.8 22.6 44 — 26.0 36 B 29.9 52.2 0 0.7 14.5 64 — 14.6 64 C 22.3 35.2 13 1.1 23.9 41 — 21.4 47 D 12.5 19.7 51 0.2 8.7 78 — 12.9 68 % B Anti-Hu IgG + Anti-Hu Lymphocyte CD2 Anti-Hu IgM IgM Leu-16 Depletion Normal Lymph Nodes Control 1 Axillary 55.4 25.0 — 41.4 NA Inguinal 52.1 31.2 — 39.5 NA Normal Bone Marrow Control 2 65.3 19.0 — 11.4 NA Control 3 29.8 28.0 — 16.6 NA - The results of Table II evidence effective depletion of B lymphocytes for both treatment regimens. Table II further indicates that for the non-human primates, complete saturation of the B cells in the lymphatic tissue with immunologically active, chimeric anti-CD20 antibody was not achieved; additionally, antibody coated cells were observed seven (7) days after treatment, followed by a marked depletion of lymph node B cells, observed on
day 14. - Based upon this data, the single High Dosage Chimeric Anti-CD20 study referenced above was conducted, principally with an eye toward pharmacology/toxicology determination. Ie this study was conducted to evaluate any toxicity associated with the administration of the chimeric antibody, as well as the efficacy of B cell depletion from peripheral blood lymph nodes and bone marrow. Additionally, because the data of Table II indicates that for that study, the majority of lymph node B cells were depleted between 7 and 14 days following treatment, a weekly dosing regimen might evidence more efficacious results. Table III summarizes the results of the High Dosage Chimeric Anti-CD20 study.
TABLE III CELL POPULATIONS OF LYMPH NODES AM) BONE MARROW Lymphocyte Populations (%) mIgM + anti- Monkey CD2 CD20a C2B8b C2B8c Dayd Inguinal Lymph Node E 90.0 5.3 4.8 6.5 22 F 91.0 6.3 5.6 6.3 22 G 89.9 5.0 3.7 5.8 36 H 85.4 12.3 1.7 1.8 36 Bone Marrow E 46.7 4.3 2.6 2.8 22 F 41.8 3.0 2.1 2.2 22 G 35.3 0.8 1.4 1.4 36 H 25.6 4.4 4.3 4.4 36 - Both animals evaluated at 22 days post treatment cessation contained less than 5% B cells, as compared to 40% in control lymph nodes (see, Table II, supra). Similarly, in the bone marrow of animals treated with chimeric anti-CD20 antibody, the levels of CD20 positive cells were less than 3% as compared to 11-15% in the normal animals (see, Table II, supra). In the animals evaluated at 36 days post treatment cessation, one of the animals (H) had approximately 12% B cells in the lymph node and 4.4% B cells in bone marrow, while the other (G) had approximately 5% B cells in the lymph node and 0.8% in the bone marrow—the data is indicative of significant B cell depletion.
- The results of Example III.A indicate, inter alia, that low doses of immunologically active, chimeric anti-CD20 leads to long-term peripheral blood B cell depletion in primates. The data also indicates that significant depletion of B cell populations was achieved in peripheral lymph nodes and bone marrow when repetitive high doses of the antibody were administered. Continued follow-up on the test animals has indicated that even with such severe depletion of peripheral B lymphocytes during the first week of treatment, no adverse health effects have been observed. Furthermore, as recovery of B cell population was observed, a conclusion to be drawn is that the pluripotent stem cells of these primates were not adversely affected by the treatment.
- B. Clinical Analysis of C2B8
- 1. Phase I/II Clinical Trial of C2B8: Single Dose Therapy Study
- Fifteen patients having histologically documented relapsed B cell lymphoma have been treated with C2B8 in a Phase I/II Clinical Trial. Each patient received a single dose of C2B8 in a dose-escalating study; there were three patients per dose: 10 mg/m2; 50 mg/m2; 100 mg/m2; 250 mg/m2 and 500 mg/m2. Treatment was by i.v. infusion through an 0.22 micron in-line filter with C2B8 being diluted in a final volume of 250 cc or a maximal concentration of 1 mg/ml of normal saline. Initial rate was 50 cc/hr for the first hour; if no toxicity was seen, dose rate was able to be escalated to a maximum of 200 cc/hr.
- Toxicity (as indicated by the clinician) ranged from “none”, to “fever” to “moderate” (two patients) to “severe” (one patient); all patients completed the therapy treatment. Peripheral Blood Lymphocytes were analyzed to determine, inter alia, the impact of C2B8 on T-cells and B-cells. Consistently for all patients, Peripheral Blood B Lymphocytes were depleted after infusion with C2B8 and such depletion was maintained for in excess of two weeks.
- One patient (receiving 100 mg/=Lymphocytes; =CD3+cells (T cells); =CD20+ cells; =CD19+cells; =Kappa; =lambda; and =C2B8. As evidenced, the B cell markers CD20 and CD19, Kappa and Lambda, were depleted for a period in excess of two weeks; while there was a slight, initial reduction in T-cell counts, these returned to an approximate base-line level in a relatively rapid time-frame.2 of C2B8) evidenced a Partial Response to the C2B8 treatment (reduction of greater than 50% in the sum of the products of the perpendicular diameters of all measurable indicator lesions lasting greater than four weeks, during which no new lesions may appear and no existing lesions may enlarge); at least one other patient (receiving 500 mg/m2) evidenced a Minor Response to the C2B8 treatment (reduction of less than 50% but at least 25% in the sum of the products of the two longest perpendicular diameters of all measurable indicator lesions). For presentational efficiency, results of the PBLs are set forth in FIG. 14; data for the patient evidencing a PR is set forth in FIG. 14A; for the patient evidencing an MR, data is set forth in FIG. 14B. In FIG. 14, the following are applicable:
- ii. Phase I/MI Clinical Trial of C2B8: Multiple Dose Therapy Study
- Patients having histologically confirmed B cell lymphoma with measurable progressive disease are eligible for this study which is separated into two parts: in Phase I, consisting of a dose escalation to characterize dose limiting toxicities and determination of biologically active tolerated dose level, groups of three patients will receive weekly i.v. infusions of C2B8 for a total of four (4) separate infusions. Cumulative dose at each of the three levels will be as follows: 500 mg/m2 (125 mg/m2/infusion); 1000 mg/m2 (250 mg/m2/infusion); 1500 mg/m2 (375 mg/m2/infusion. A biologically active tolerated dose is defined, and will be determined, as the lowest dose with both tolerable toxicity and adequate activity); in Phase II, additional patients will receive the biologically active tolerated dose with an emphasis on determining the activity of the four doses of C2B8.
- A combination therapeutic approach using C2B8 and Y2B8 was investigated in a mouse xenographic model (nu/nu mice, female, approximately 10 weeks old) utilizing a B cell lymphoblastic tumor (Ramos tumor cells). For comparative purposes, additional mice were also treated with C2B8 and Y2B8.
- Ramos tumor cells (ATCC, CRL 1596) were maintained in culture using RPMI-1640 supplemented with 10% fetal calf serum and glutamine at 37° C. and 5% C02. Tumors were initiated in nine female nude mice approximately 7-10 weeks old by subcutaneous injection of 1.7×106 Ramos cells in a volume of 0.10 ml (HBSS) using a 1 cc syringe fitted with 25 g needle. All animals were manipulated in a laminar flow hood and all cages, bedding, food and water were autoclaved. Tumor cells were passaged by excising tumors and passing these through a 40 mesh screen; cells were washed twice with 1× HBSS (50 ml) by centrifugation (1300RPM), resuspended in 1× HBSS to 10×106 cells/ml, and frozen at −70° C. until used.
- For the experimental conditions, cells from several frozen lots were thawed, pelleted by centrifugation (1300RPM) and washed twice with 1× HBSS. Cells were then resuspended to approximately 2.0×106 cells/ml. Approximately 9 to 12 mice were injected with 0.10 ml of the cell suspension (s.c.) using a 1 cc syringe fitted with a 25 g needle; injections were made on the animal's left side, approximately mid-region. Tumors developed in approximately two weeks. Tumors were excised and processed as described above. Study mice were injected as described above with 1.67×106 cells in 0.10 ml HBSS.
- Based on preliminary dosing experiments, it was determined that 200 mg of C2B8 and 100 μCi of Y2B8 would be utilized for the study. Ninety female nu/nu mice (approximately 10 weeks old) were injected with the tumor cells. Approximately ten days later, 24 mice were assigned to four study groups (six mice/group) while attempting to maintain a comparable tumor size distribution in each group (average tumor size, expressed as a product of length x width of the tumor, was approximately 80 mm2). The following groups were treated as indicated via tail-vain injections using a 100 μl Hamilton syringe fitted with a 25 g needle:
A. Normal Saline B. Y2B8 (100 μCi) C. C2B8 (200 μg); and D. Y2B8 (100 μCi) + C2B8 (200 μg) - Groups tested with C2B8 were given a second C2B8 injection (200 μg/mouse) seven days after the initial injection. Tumor measurements were made every two or three days using a caliper.
- Preparation of treatment materials were in accordance with the following protocols:
- A. Preparation of Y2B8
- Yttrium-[90] chloride (6 mCi) was transformed to a polypropylene tube and adjusted to pH 4.1-4.4 using metal free 2M sodium acetate. 2B8-MX-DTPA (0.3 mg in normal saline; see above for preparation of 2B8-MX-DTPA) was added and gently mixed by vortexing. After 15 min. incubation, the reaction was quenched by adding 0.05×
volume 20 mM EDTA and 0.05× volume 2M sodium acetate. Radioactivity concentration was determined by diluting 5.0 μl of the reaction mixture in 2.5ml 1× PBS containing 75 mg/ml HSA and 1 mM DTPA (“formulation buffer”); counting was accomplished by adding 10.0 μl to 20 ml of Ecolume™ scintillation cocktail. The remainder of the reactive mixture was added to 3.0 ml formulation buffer, sterile filtered and stored at 2-8° C. until used. Specific activity (14 mCi/mg at time of injection) was calculated using the radioactivity concentration and the calculated protein concentration based upon the amount of antibody added to the reaction mixture..Protein-associated radioactivity was determined using instant thin-layer chromatography. Radioincorporation was 95%. Y2B8 was diluted in formulation buffer immediately before use and sterile-filtered (final radioactivity concentration was 1.0 mCi/ml). - B. Preparation of C2B8
- C2B8 was prepared as described above. C2B8 was provided as a sterile reagent in normal saline at 5.0 mg/ml. Prior to injection, the C2B8 was diluted in normal saline to 2.0 mg/ml and sterile filtered.
- C. Results
- Following treatment, tumor size was expressed as a product of length and width, and measurements were taken on the days indicated in FIG. 11 (Y2B8 vs. Saline); FIG. 12 (C2B8 vs. Saline); and FIG. 13 (Y2B8+C2B8 vs. Saline). Standard error was also determined.
- As indicated in FIG. 13, the combination of Y2B8 and C2B8 exhibited tumoricidal effects comparable to the effects evidenced by either Y2B8 or C2B8.
- Alternative therapeutic strategies recognized in view of the foregoing examples are evident. One such strategy employs the use of a therapeutic dose of C2B8 followed within about one week with a combination of either 2B8 and radioabeled 2B8 (eg Y2B8); or 2B8, C2B8 and, eg Y2B8; or C2B8 and, eg Y2B8. An additional strategy is utilization of radiolabeled C2B8—such a strategy allows for utilization of the benefits of the immunologically active portion of C2B8 plus those benefits associated with a radiolabel. Preferred radiolabels include yttrium-90 given the larger circulating half-life of C2B8 versus the murine antibody 2B8. Because of the ability of C2B8 to deplete B-cells, and the benefits to be derived from the use of a radiolabel, a preferred alternative strategy is to treat the patient with C2B8 (either with a single dose or multiple doses) such that most, if not all, peripheral B cells have been depleted. This would then be followed with the use of radiolabeled 2B8; because of the depletion of peripheral B cells, the radiolabeled 2B8 stands an increased chance of targeting tumor cells. Iodine [131] labeled 2B8 is preferably utilized, given the types of results reported in the literature with this label (see Kaminski). An alternative preference involves the use of a radiolabeled 2B8 (or C2B8) first in an effort to increase the permeability of a tumor, followed by single or multiple treatments with C2B8; the intent of this strategy is to increase the chances of the C2B8 in getting both outside and inside the tumor mass. A further strategy involved the use of chemotherapeutic agenst in combination with C2B8. These strategies include so-called “staggered” treatments, ie, treatment with chemotherapeutic agent, followed by treatment with C2B8, followed by a repetition of this protocol. Alternatively, initial treatment with a single or multiple doses of C2B8, thereafter followed with chemotherapeutic treatement, is viable. Preferred chemotherapeutic agents include, but are not limited to: cyclophlsphamide; doxorubicin; vincristine; and prednisone, See Armitage, J. O. et al.,Cancer 50:1695 (1982), incorporated herein by reference.
- The foregoing alternative therapy strategies are not intended to be limiting, but rather are presented as being representative.
- Anti-CD20 in TCAE 8 (transformed inE. coli for purposes of deposit) was deposited with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Md., 20852, under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure (“Budapest Treaty”). The microorganism was tested by the ATCC on Nov. 9, 1992, and determined to be viable on that date. The ATCC has assigned this microorganism for the following ATCC deposit number: ATCC 69119 (anti-CD20 in TCAE 8). Hybridoma 2B8 was deposited with the ATCC on Jun. 22, 1993 under the provisions of the Budapest Treaty. The viability of the culture was determined on June 25, 1993 and the ATCC has assigned this hybridoma the following ATCC deposit number: HB 11388.
Claims (20)
1. A method for the treatment of B cell lymphoma comprising the step of administering a therapeutically effective amount of at least one immunologically active, chimeric anti-CD20 antibody to a human.
2. The method of claim 1 wherein the amount of said antibody administered to said human is between about 0.001 to about 30 milligrams of antibody per kilogram body weight of said human (“mg/kg”).
3. The method of claim 1 wherein said antibody is derived from a transfectoma comprising anti-CD20 in TCAE 8 as deposited with the American Type Culture Collection as part of ATCC deposit number 69119.
4. The method of claim 1 further comprising the step of administering a second therapeutically effective amount of at least one immunologically active, chimeric anti-CD20 antibody.
5. The method of claim 4 wherein said additional administration of said antibody to said human occurs within about seven days of said first administration of said antibody to said human.
6. A method for the treatment of B cell lymphoma comprising the steps of:
1) administering, at a first administration period, a first therapeutically effective amount of immunologically active, chimeric anti-CD20 antibody to a human;
2) administering at a second subsequent administration period, a second therapeutically effective amount of said antibody;
3) administering, at a third subsequent administration period, a third therapeutically effective amount of said antibody.
7. The method of claim 6 wherein said first, second and third therapeutically effective amount of said antibody is between about 0.001 mg/kg to about 30 mg/kg.
8. The method of claim 6 wherein said second administration period is within about seven days of said first administration period.
9. The method of claim 6 wherein said third administration period is within about fourteen days of said first administration period.
10. The method of claim 6 wherein said antibody is derived from a transfectoma comprising anti-CD20 in TCAE 8 (within ATCC deposit number 69119).
11. Immunologically active, chimeric anti-CD20 produced from a transfectoma comprising anti-CD20 in TCAE 8 (within ATCC deposit number 69119).
12. A hybridoma which secretes anti-CD20 antibody, said hybridoma being identified by American Type Culture Collection deposit number HB 11388.
13. A monoclonal antibody secreted from the hybridoma of claim 12 .
14. A radiolabeled antibody according to claim 12 .
15. The radiolabeled antibody of claim 14 where the radiolabel is selected from the group consisting of yttrium [90]; indium [111], and iodine [131].
16. A method for the treatment of B cell lymphoma comprising of steps of administering a therapeutically effective amount of the antibody of claim 14 to a human.
17. The method of claim 16 when the radiolabel of said antibody is yttrium [90].
18. A method for the treatment of B cell lymphoma comprising the steps of:
1) administering, at a first administration period, an immunology active chimeric anti-CD20 antibody to human; and
2) administering, at a second administration period, a radiolabeled anti-CD20 antibody to said human.
19. The method of claim 18 when said chimeric anti-CD20 is derived from a transfectoma comprising anti-CD20 in TCAE 8 as deposited with the American Type Culture Collection as part of ATCC deposit number 69119.
20. The method of claim 8 when said radiolabeled antibody comprises a monoclonal antibody secreted from a hybridoma identified by American Type Culture Collection deposit number HB 11388.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/905,928 US20030021781A1 (en) | 1992-11-13 | 2001-07-17 | Therapeutic application of chimeric and radiolabelled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US10/956,039 US20050186205A1 (en) | 1992-11-13 | 2004-10-04 | Therapeutic application of chimeric and radiolabeled antibodies to human B Lymphocyte restricted differentiation antigen for treatment of B cell Lymphoma |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US97889192A | 1992-11-13 | 1992-11-13 | |
US08/149,099 US5736137A (en) | 1992-11-13 | 1993-11-03 | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US08/475,813 US6682734B1 (en) | 1992-11-13 | 1995-06-07 | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US09/905,928 US20030021781A1 (en) | 1992-11-13 | 2001-07-17 | Therapeutic application of chimeric and radiolabelled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/475,813 Continuation US6682734B1 (en) | 1992-11-13 | 1995-06-07 | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/956,039 Continuation US20050186205A1 (en) | 1992-11-13 | 2004-10-04 | Therapeutic application of chimeric and radiolabeled antibodies to human B Lymphocyte restricted differentiation antigen for treatment of B cell Lymphoma |
Publications (1)
Publication Number | Publication Date |
---|---|
US20030021781A1 true US20030021781A1 (en) | 2003-01-30 |
Family
ID=26846468
Family Applications (8)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/475,813 Expired - Lifetime US6682734B1 (en) | 1992-11-13 | 1995-06-07 | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US08/476,275 Expired - Lifetime US5776456A (en) | 1992-11-13 | 1995-06-07 | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US08/478,967 Expired - Lifetime US5843439A (en) | 1992-11-13 | 1995-06-07 | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US08/475,815 Expired - Lifetime US6399061B1 (en) | 1992-11-13 | 1995-06-07 | Chimeric and radiolabelled antibodies specific to human CD20 antigen and use thereof for treatment of B-cell lymphoma |
US09/905,928 Abandoned US20030021781A1 (en) | 1992-11-13 | 2001-07-17 | Therapeutic application of chimeric and radiolabelled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US09/911,692 Expired - Fee Related US7381560B2 (en) | 1992-11-13 | 2001-07-25 | Expression and use of anti-CD20 antibodies |
US09/911,703 Expired - Fee Related US7422739B2 (en) | 1992-11-13 | 2001-07-25 | Anti-CD20 antibodies |
US10/956,039 Abandoned US20050186205A1 (en) | 1992-11-13 | 2004-10-04 | Therapeutic application of chimeric and radiolabeled antibodies to human B Lymphocyte restricted differentiation antigen for treatment of B cell Lymphoma |
Family Applications Before (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/475,813 Expired - Lifetime US6682734B1 (en) | 1992-11-13 | 1995-06-07 | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US08/476,275 Expired - Lifetime US5776456A (en) | 1992-11-13 | 1995-06-07 | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US08/478,967 Expired - Lifetime US5843439A (en) | 1992-11-13 | 1995-06-07 | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US08/475,815 Expired - Lifetime US6399061B1 (en) | 1992-11-13 | 1995-06-07 | Chimeric and radiolabelled antibodies specific to human CD20 antigen and use thereof for treatment of B-cell lymphoma |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/911,692 Expired - Fee Related US7381560B2 (en) | 1992-11-13 | 2001-07-25 | Expression and use of anti-CD20 antibodies |
US09/911,703 Expired - Fee Related US7422739B2 (en) | 1992-11-13 | 2001-07-25 | Anti-CD20 antibodies |
US10/956,039 Abandoned US20050186205A1 (en) | 1992-11-13 | 2004-10-04 | Therapeutic application of chimeric and radiolabeled antibodies to human B Lymphocyte restricted differentiation antigen for treatment of B cell Lymphoma |
Country Status (23)
Country | Link |
---|---|
US (8) | US6682734B1 (en) |
EP (3) | EP0752248B1 (en) |
JP (3) | JP3095175B2 (en) |
AT (2) | ATE139900T1 (en) |
AU (1) | AU688743B2 (en) |
BG (1) | BG62386B1 (en) |
CA (1) | CA2149329C (en) |
DE (3) | DE69303494T2 (en) |
DK (2) | DK0752248T3 (en) |
ES (2) | ES2152483T3 (en) |
FI (1) | FI112033B (en) |
GR (2) | GR3020731T3 (en) |
LU (1) | LU91089I2 (en) |
LV (1) | LV11732B (en) |
MD (1) | MD1367C2 (en) |
NL (1) | NL300156I2 (en) |
NO (4) | NO321137B1 (en) |
NZ (1) | NZ258392A (en) |
PL (2) | PL174494B1 (en) |
PT (1) | PT752248E (en) |
RO (1) | RO118524B1 (en) |
RU (1) | RU2139731C1 (en) |
WO (1) | WO1994011026A2 (en) |
Cited By (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020058029A1 (en) * | 2000-09-18 | 2002-05-16 | Nabil Hanna | Combination therapy for treatment of autoimmune diseases using B cell depleting/immunoregulatory antibody combination |
US20020197255A1 (en) * | 1992-11-13 | 2002-12-26 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabelled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US20030147885A1 (en) * | 1992-11-13 | 2003-08-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US20030206903A1 (en) * | 1998-08-11 | 2003-11-06 | Idec Pharmaceuticals Corporation | Combination therapies for B-cell lynphomas comprising administration of anti-CD20 antibody |
US20040202658A1 (en) * | 2003-04-09 | 2004-10-14 | Genentech, Inc. | Therapy of autoimmune disease in a patient with an inadequate response to TNF-alpha inhibitor |
US20050032130A1 (en) * | 2003-07-29 | 2005-02-10 | Genentech, Inc. | Neutralizing antibody assay and uses therefor |
US20050053602A1 (en) * | 2003-08-29 | 2005-03-10 | Genentech, Inc. | Therapy of ocular disorders |
US20050070689A1 (en) * | 2001-08-03 | 2005-03-31 | Genentech, Inc. | Taci and br3 polypeptides and uses thereof |
US20050095243A1 (en) * | 2003-06-05 | 2005-05-05 | Genentech, Inc. | Combination therapy for B cell disorders |
US20050163775A1 (en) * | 2003-06-05 | 2005-07-28 | Genentech, Inc. | Combination therapy for B cell disorders |
US20050186206A1 (en) * | 2003-12-19 | 2005-08-25 | Genentech, Inc. | Detection of CD20 in therapy of autoimmune diseases |
US20050191297A1 (en) * | 2003-12-19 | 2005-09-01 | Genentech, Inc. | Detection of CD20 in transplant rejection |
US20050271658A1 (en) * | 2004-05-05 | 2005-12-08 | Genentech, Inc. | Preventing autoimmune disease |
US20060024295A1 (en) * | 2004-06-04 | 2006-02-02 | Genentech, Inc. | Method for treating lupus |
US20060034835A1 (en) * | 2002-12-16 | 2006-02-16 | Genentech, Inc. | Immunoglobulin variants and uses thereof |
US20060051345A1 (en) * | 2004-06-04 | 2006-03-09 | Genentech, Inc. | Method for treating multiple sclerosis |
US20060062787A1 (en) * | 2004-07-22 | 2006-03-23 | Genentech, Inc. | Method for treating Sjogren's syndrome |
US20060073146A1 (en) * | 2000-02-16 | 2006-04-06 | Genentech, Inc. | Uses of agonists and antagonists to modulate activity of TNF-related molecules |
US20060110387A1 (en) * | 2004-10-05 | 2006-05-25 | Genentech, Inc. | Method for treating vasculitis |
US20060188495A1 (en) * | 2005-01-13 | 2006-08-24 | Genentech, Inc. | Treatment method |
US20060233797A1 (en) * | 2005-04-15 | 2006-10-19 | Genentech, Inc. | Treatment of inflammatory bowel disease (IBD) |
US20060246004A1 (en) * | 2005-02-07 | 2006-11-02 | Genentech, Inc. | Antibody variants and uses thereof |
US20060263355A1 (en) * | 2005-02-28 | 2006-11-23 | Joanne Quan | Treatment of bone disorders |
US20060263349A1 (en) * | 2005-05-20 | 2006-11-23 | Genentech, Inc. | Pretreatment of a biological sample from an autoimmune disease subject |
US20070054656A1 (en) * | 2005-05-17 | 2007-03-08 | Chris Knotts | Inter-carrier digital message with user data payload service providing phone number only experience |
US20070059306A1 (en) * | 2005-07-25 | 2007-03-15 | Trubion Pharmaceuticals, Inc. | B-cell reduction using CD37-specific and CD20-specific binding molecules |
US20070212733A1 (en) * | 2005-11-23 | 2007-09-13 | Genentech, Inc. | Methods and compositions related to B cell assays |
US20080075719A1 (en) * | 2004-04-16 | 2008-03-27 | Genentech, Inc. | Method for Augmenting B Cell Depletion |
US20080171036A1 (en) * | 2002-07-25 | 2008-07-17 | Anan Chuntharapai | Taci antibodies and uses thereof |
US20080279850A1 (en) * | 2005-07-25 | 2008-11-13 | Trubion Pharmaceuticals, Inc. | B-Cell Reduction Using CD37-Specific and CD20-Specific Binding Molecules |
US20090010921A1 (en) * | 2003-11-05 | 2009-01-08 | Glycart Biotechnology Ag | Antigen binding molecules with increased Fc receptor binding affinity and effector function |
US20090074760A1 (en) * | 1998-11-09 | 2009-03-19 | Grillo-Lopez Antonio J | Use of chimeric anti-cd20 antibody as in vitro or in vivo purging agent in patients receiving bmt or pbsc transplant |
EP2077281A1 (en) | 2008-01-02 | 2009-07-08 | Bergen Teknologioverforing AS | Anti-CD20 antibodies or fragments thereof for the treatment of chronic fatigue syndrome |
US20090175867A1 (en) * | 2006-06-12 | 2009-07-09 | Trubion Pharmaceuticals, Inc. | Single-Chain Multivalent Binding Proteins with Effector Function |
US20090274692A1 (en) * | 2008-04-11 | 2009-11-05 | Trubion Pharmaceuticals, Inc. | Cd37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof |
US20100003252A1 (en) * | 1999-07-12 | 2010-01-07 | Genentech, Inc. | Blocking immune response to a graft |
US7682612B1 (en) | 1998-11-09 | 2010-03-23 | Biogen Idec Inc. | Treatment of hematologic malignancies associated with circulating tumor cells using chimeric anti-CD20 antibody |
US20100158903A1 (en) * | 2008-09-16 | 2010-06-24 | Craig Smith | Methods for treating progressive multiple sclerosis |
WO2010075249A2 (en) | 2008-12-22 | 2010-07-01 | Genentech, Inc. | A method for treating rheumatoid arthritis with b-cell antagonists |
EP2233149A1 (en) | 2007-10-16 | 2010-09-29 | ZymoGenetics, Inc. | Combination of BLYS inhibition and anti-CD20 agents for treatment of autoimmune disease |
US7820161B1 (en) | 1999-05-07 | 2010-10-26 | Biogen Idec, Inc. | Treatment of autoimmune diseases |
US20100279932A1 (en) * | 2003-07-26 | 2010-11-04 | Trubion Pharmaceuticals, Inc. | Binding constructs and methods for use thereof |
WO2011019619A1 (en) | 2009-08-11 | 2011-02-17 | Genentech, Inc. | Production of proteins in glutamine-free cell culture media |
WO2011100403A1 (en) | 2010-02-10 | 2011-08-18 | Immunogen, Inc | Cd20 antibodies and uses thereof |
EP2415483A1 (en) | 2005-07-25 | 2012-02-08 | Emergent Product Development Seattle, LLC | Single dose use of cd20-specific binding molecules |
EP2586788A1 (en) | 2007-07-09 | 2013-05-01 | Genentech, Inc. | Prevention of disulfide bond reduction during recombinant production of polypeptides |
US8483729B2 (en) | 2001-09-05 | 2013-07-09 | Telecommunication Systems, Inc. | Inter-carrier messaging service providing phone number only experience |
US8557244B1 (en) | 1999-08-11 | 2013-10-15 | Biogen Idec Inc. | Treatment of aggressive non-Hodgkins lymphoma with anti-CD20 antibody |
US8853366B2 (en) | 2001-01-17 | 2014-10-07 | Emergent Product Development Seattle, Llc | Binding domain-immunoglobulin fusion proteins |
US9005612B2 (en) | 2001-01-17 | 2015-04-14 | Emergent Product Development Seattle, Llc | Binding domain-immunoglobulin fusion proteins |
WO2017055542A1 (en) | 2015-10-02 | 2017-04-06 | F. Hoffmann-La Roche Ag | Bispecific anti-human cd20/human transferrin receptor antibodies and methods of use |
US10280227B2 (en) | 2009-09-11 | 2019-05-07 | Genentech, Inc. | Highly concentrated pharmaceutical formulations |
US10450379B2 (en) | 2005-11-15 | 2019-10-22 | Genetech, Inc. | Method for treating joint damage |
US10941205B2 (en) | 2015-10-02 | 2021-03-09 | Hoffmann-La Roche Inc. | Bispecific anti-human A-beta/human transferrin receptor antibodies and methods of use |
US11352426B2 (en) | 2015-09-21 | 2022-06-07 | Aptevo Research And Development Llc | CD3 binding polypeptides |
US11584793B2 (en) | 2015-06-24 | 2023-02-21 | Hoffmann-La Roche Inc. | Anti-transferrin receptor antibodies with tailored affinity |
Families Citing this family (1298)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6190640B1 (en) * | 1985-04-19 | 2001-02-20 | Ludwig Institute For Cancer Research | Method for treating neoplasia using humanized antibodies which bind to antigen A33 |
US5736137A (en) * | 1992-11-13 | 1998-04-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US5595721A (en) | 1993-09-16 | 1997-01-21 | Coulter Pharmaceutical, Inc. | Radioimmunotherapy of lymphoma using anti-CD20 |
FR2724182B1 (en) * | 1994-09-02 | 1996-12-13 | Pasteur Institut | OBTAINING A RECOMBINANT MONOCLONAL ANTIBODY FROM A HUMAN ANTI-RHESUS D MONOCLONAL ANTIBODY, ITS PRODUCTION IN INSECT CELLS, AND USES THEREOF |
US20030180290A1 (en) * | 1995-06-07 | 2003-09-25 | Idec Pharmaceuticals Corporation | Anti-CD80 antibody having ADCC activity for ADCC mediated killing of B cell lymphoma cells alone or in combination with other therapies |
IL125073A0 (en) | 1996-01-08 | 1999-01-26 | Genentech Inc | Wsx receptor and ligands |
US7122636B1 (en) | 1997-02-21 | 2006-10-17 | Genentech, Inc. | Antibody fragment-polymer conjugates and uses of same |
US6306393B1 (en) * | 1997-03-24 | 2001-10-23 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
US6183744B1 (en) * | 1997-03-24 | 2001-02-06 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
EP3260468A1 (en) | 1997-04-07 | 2017-12-27 | Genentech, Inc. | Anti-vegf antibodies |
EP0973804B1 (en) | 1997-04-07 | 2006-12-27 | Genentech, Inc. | Anti-vegf antibodies |
US6171586B1 (en) | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
US6991790B1 (en) | 1997-06-13 | 2006-01-31 | Genentech, Inc. | Antibody formulation |
US6610293B1 (en) | 1997-06-16 | 2003-08-26 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine | Opsonic and protective monoclonal and chimeric antibodies specific for lipoteichoic acid of gram positive bacteria |
ES2305608T3 (en) | 1997-11-21 | 2008-11-01 | Genentech, Inc. | ANTIGENS TYPE A-33 AND ITS PHARMACOLOGICAL USES. |
US7192589B2 (en) | 1998-09-16 | 2007-03-20 | Genentech, Inc. | Treatment of inflammatory disorders with STIgMA immunoadhesins |
EP1947119A3 (en) | 1997-12-12 | 2012-12-19 | Genentech, Inc. | Treatment of cancer with anti-erb2 antibodies in combination with a chemotherapeutic agent |
EP1064382B1 (en) | 1998-03-17 | 2008-08-20 | Genentech, Inc. | Polypeptides homologous to vegf and bmp1 |
AU3657899A (en) * | 1998-04-20 | 1999-11-08 | James E. Bailey | Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity |
EP1865061A3 (en) | 1998-05-15 | 2007-12-19 | Genentech, Inc. | IL-17 homologous polypeptides and therapeutic uses thereof |
EP3112468A1 (en) | 1998-05-15 | 2017-01-04 | Genentech, Inc. | Il-17 homologous polypeptides and therapeutic uses thereof |
EP2333069A3 (en) | 1998-05-15 | 2011-09-14 | Genentech, Inc. | Therapeutic uses of IL-17 homologous polypeptides |
PT1086138E (en) | 1998-06-12 | 2010-01-04 | Genentech Inc | Monoclonal antibodies, cross-reactive antibodies and method for producing the same |
US7250494B2 (en) | 1998-06-15 | 2007-07-31 | Biosynexus Incorporated | Opsonic monoclonal and chimeric antibodies specific for lipoteichoic acid of Gram positive bacteria |
US20020172678A1 (en) | 2000-06-23 | 2002-11-21 | Napoleone Ferrara | EG-VEGF nucleic acids and polypeptides and methods of use |
US6224866B1 (en) * | 1998-10-07 | 2001-05-01 | Biocrystal Ltd. | Immunotherapy of B cell involvement in progression of solid, nonlymphoid tumors |
US20010033839A1 (en) * | 1999-10-04 | 2001-10-25 | Emilio Barbera-Guillem | Vaccine and immunotherapy for solid nonlymphoid tumor and related immune dysregulation |
US6410319B1 (en) | 1998-10-20 | 2002-06-25 | City Of Hope | CD20-specific redirected T cells and their use in cellular immunotherapy of CD20+ malignancies |
EP1950300A3 (en) | 1998-11-18 | 2011-03-23 | Genentech, Inc. | Antibody variants with higher binding affinity compared to parent antibodies |
EP2075335A3 (en) | 1998-12-22 | 2009-09-30 | Genentech, Inc. | Methods and compositions for inhibiting neoplastic cell growth |
US7183387B1 (en) | 1999-01-15 | 2007-02-27 | Genentech, Inc. | Polypeptide variants with altered effector function |
HUP0104865A3 (en) | 1999-01-15 | 2004-07-28 | Genentech Inc | Polypeptide variants with altered effector function |
US20020102208A1 (en) * | 1999-03-01 | 2002-08-01 | Paul Chinn | Radiolabeling kit and binding assay |
MY133346A (en) | 1999-03-01 | 2007-11-30 | Biogen Inc | Kit for radiolabeling ligands with yttrium-90 |
US6207858B1 (en) * | 1999-03-03 | 2001-03-27 | Idec Pharmaceuticals Corporation | Regioselective synthesis of DTPA derivatives |
US8383081B2 (en) | 1999-05-10 | 2013-02-26 | Immunomedics, Inc. | Anti-CD74 immunoconjugates and methods of use |
US7829064B2 (en) * | 1999-05-10 | 2010-11-09 | Immunomedics, Inc. | Anti-CD74 immunoconjugates and methods |
US8119101B2 (en) * | 1999-05-10 | 2012-02-21 | The Ohio State University | Anti-CD74 immunoconjugates and methods of use |
US7074403B1 (en) * | 1999-06-09 | 2006-07-11 | Immunomedics, Inc. | Immunotherapy of autoimmune disorders using antibodies which target B-cells |
EP1956030B1 (en) | 1999-06-15 | 2009-11-11 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids endoding the same |
EP1189641B1 (en) | 1999-06-25 | 2009-07-29 | Genentech, Inc. | HUMANIZED ANTI-ErbB2 ANTIBODIES AND TREATMENT WITH ANTI-ErbB2 ANTIBODIES |
AU2005211669C1 (en) * | 1999-08-11 | 2017-09-21 | F. Hoffmann-La Roche Ag | Treatment of intermediate- and high-grade non-Hodgkins lymphoma with anti-CD20 antibody |
EP2264070A1 (en) * | 1999-08-11 | 2010-12-22 | Biogen-Idec Inc. | Treatment of intermediate-and high-grade non-hodgkins lymphoma with anti-CD20 antibody |
US6451284B1 (en) * | 1999-08-11 | 2002-09-17 | Idec Pharmaceuticals Corporation | Clinical parameters for determining hematologic toxicity prior to radioimmunotheraphy |
CN100389825C (en) * | 1999-08-11 | 2008-05-28 | 拜奥根Idec公司 | Treatment of patients having non-hodgkins lymphoma with bone marrow involvement with anti-CD20 antibodies |
EP1918305A1 (en) * | 1999-08-11 | 2008-05-07 | Biogen Idec Inc. | New clinical parameters for determining hematologic toxicity prior to radioimmunotherapy |
ES2330301T3 (en) | 1999-08-27 | 2009-12-09 | Genentech, Inc. | DOSAGES FOR TREATMENT WITH ANTI-ERBB2 ANTIBODIES. |
US20020028178A1 (en) * | 2000-07-12 | 2002-03-07 | Nabil Hanna | Treatment of B cell malignancies using combination of B cell depleting antibody and immune modulating antibody related applications |
EP2228446A1 (en) | 1999-12-01 | 2010-09-15 | Genentech, Inc. | Secreted and transmembrane polypeptieds and nucleic acids encoding the same |
EP2290081A3 (en) | 1999-12-23 | 2012-08-01 | Genentech, Inc. | IL-17 homologous polypeptide and therapeutic uses thereof |
EP1246917B1 (en) | 2000-01-13 | 2009-03-04 | Genentech, Inc. | Human stra6 polypeptides |
US20030185796A1 (en) * | 2000-03-24 | 2003-10-02 | Chiron Corporation | Methods of therapy for non-hodgkin's lymphoma |
ES2528794T3 (en) | 2000-04-11 | 2015-02-12 | Genentech, Inc. | Multivalent antibodies and uses thereof |
CN1437478A (en) * | 2000-04-25 | 2003-08-20 | Idec药物公司 | Intrathecal administration of Rituximab for treatment of central nervous system lymphomas |
AU6531101A (en) | 2000-06-02 | 2001-12-17 | Genentech Inc | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2001097858A2 (en) * | 2000-06-20 | 2001-12-27 | Idec Pharmaceuticals Corporation | Cold anti-cd20 antibody/radiolabeled anti-cd22 antibody combination |
AU2001265418B2 (en) * | 2000-06-22 | 2006-03-30 | Biogen Idec Inc. | Bispecific fusion protein and method of use for enhancing effector cell killing of target cells |
EP2042597B1 (en) | 2000-06-23 | 2014-05-07 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of disorders involving angiogenesis |
EP2077276A1 (en) | 2000-06-23 | 2009-07-08 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of disorders involving angiogensis |
JP2004502742A (en) * | 2000-07-12 | 2004-01-29 | アイデック ファーマスーティカルズ コーポレイション | B-cell malignant disease treatment-related application using antibodies that kill B cells and immunomodulatory antibodies in combination |
ATE415978T1 (en) | 2000-07-27 | 2008-12-15 | Genentech Inc | SEQUENTIAL ADMINISTRATION OF CPT-11 AND APO-2L POLYPEPTIDE |
ATE412009T1 (en) | 2000-08-24 | 2008-11-15 | Genentech Inc | METHOD FOR INHIBITING IL-22 INDUCED PAP1 |
EP1944317A3 (en) | 2000-09-01 | 2008-09-17 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
AU2002213357A1 (en) * | 2000-10-20 | 2002-05-06 | Idec Pharmaceuticals Corporation | Variant igg3 rituxan r and therapeutic use thereof |
JP5312721B2 (en) | 2000-11-07 | 2013-10-09 | シティ・オブ・ホープ | CD19-specific redirecting immune cells |
US7408041B2 (en) | 2000-12-08 | 2008-08-05 | Alexion Pharmaceuticals, Inc. | Polypeptides and antibodies derived from chronic lymphocytic leukemia cells and uses thereof |
US7132510B2 (en) | 2000-12-29 | 2006-11-07 | Bio-Technology General (Israel) Ltd. | Specific human antibodies for selective cancer therapy |
US20040002450A1 (en) * | 2000-12-29 | 2004-01-01 | Janette Lazarovits | Y17 - isolated molecules comprising epitopes containing sulfated moieties, antibodies to such epitopes, and uses thereof |
US20040001822A1 (en) * | 2000-12-29 | 2004-01-01 | Avigdor Levanon | Y1-isolated molecules comprising epitopes containing sulfated moieties, antibodies to such epitopes, and uses thereof |
US20040001839A1 (en) * | 2000-12-29 | 2004-01-01 | Avigdor Levanon | Multimers - isolated molecules comprising epitopes containing sulfated moieties, antibodies to such epitopes, and uses thereof |
AU2002241922B2 (en) * | 2001-01-17 | 2007-10-25 | Aptevo Research And Development Llc | Binding domain-immunoglobulin fusion proteins |
WO2002060955A2 (en) * | 2001-01-29 | 2002-08-08 | Idec Pharmaceuticals Corporation | Modified antibodies and methods of use |
US20020159996A1 (en) * | 2001-01-31 | 2002-10-31 | Kandasamy Hariharan | Use of CD23 antagonists for the treatment of neoplastic disorders |
US20030211107A1 (en) * | 2002-01-31 | 2003-11-13 | Kandasamy Hariharan | Use of CD23 antagonists for the treatment of neoplastic disorders |
US20070065436A1 (en) * | 2001-01-31 | 2007-03-22 | Biogen Idec Inc. | Anti-cd80 antibody having adcc activity for adcc mediated killing of b cell lymphoma cells alone or in combination with other therapies |
AU2007234621B2 (en) * | 2001-01-31 | 2010-08-26 | Biogen Idec Inc. | Use of immunoregulatory antibodies in the treatment of neoplastic disorders |
WO2002060485A2 (en) | 2001-01-31 | 2002-08-08 | Idec Pharmaceuticals Corporation | Use of immunoregulatory antibodies in the treatment of neoplastic disorders |
CA2444661A1 (en) * | 2001-01-31 | 2002-08-08 | Idec Pharmaceutical Corporation | Use of cd23 antagonists for the treatment of neoplastic disorders |
US20030103971A1 (en) * | 2001-11-09 | 2003-06-05 | Kandasamy Hariharan | Immunoregulatory antibodies and uses thereof |
EP1998266A3 (en) | 2001-02-19 | 2009-02-11 | Merck Patent GmbH | Method for identification of T-cell epitopes and use for preparing molecules with reduced immunogenicity |
DE60239931D1 (en) * | 2001-04-02 | 2011-06-16 | Genentech Inc | COMBINATION THERAPY |
US20030003097A1 (en) * | 2001-04-02 | 2003-01-02 | Idec Pharmaceutical Corporation | Recombinant antibodies coexpressed with GnTIII |
US20020193569A1 (en) * | 2001-06-04 | 2002-12-19 | Idec Pharmaceuticals Corporation | Bispecific fusion protein and method of use for enhancing effector cell killing of target cells |
US20070160576A1 (en) | 2001-06-05 | 2007-07-12 | Genentech, Inc. | IL-17A/F heterologous polypeptides and therapeutic uses thereof |
EP1992643A3 (en) | 2001-06-20 | 2008-12-10 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
NZ592087A (en) | 2001-08-03 | 2012-11-30 | Roche Glycart Ag | Antibody glycosylation variants having increased antibody-dependent cellular cytotoxicity |
WO2003024392A2 (en) | 2001-09-18 | 2003-03-27 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2131198B1 (en) | 2001-09-20 | 2013-03-27 | Board of Regents, The University of Texas System | Measuring circulating therapeutic antibody, antigen and antigen/antibody complexes using ELISA assays |
WO2003088808A2 (en) | 2002-04-16 | 2003-10-30 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US20030157641A1 (en) * | 2001-11-16 | 2003-08-21 | Idec Pharmaceuticals Corporation | Polycistronic expression of antibodies |
ATE420964T1 (en) | 2001-11-16 | 2009-01-15 | Biogen Idec Inc | POLYCISTRONIC EXPRESSION OF ANTIBODIES IN CHO CELLS |
AR037756A1 (en) | 2001-12-17 | 2004-12-01 | Bayer Corp | ANTIBODY INHIBITING THE ACTIVITY OF THE PRECURSOR CELL FACTOR AND ITS USE FOR THE TREATMENT OF ASTHMA. |
US20040052779A1 (en) * | 2001-12-21 | 2004-03-18 | Stinson Jeffrey R. | Opsonic monoclonal and chimeric antibodies specific for lipoteichoic acid of Gram positive bacteria |
EP1575571A4 (en) | 2002-01-02 | 2008-06-25 | Genentech Inc | Compositions and methods for the diagnosis and treatment of tumor |
AU2003202297C1 (en) | 2002-01-25 | 2006-05-18 | G2 Therapies Ltd | Anti-C5aR antibodies and uses thereof |
AU2003210802B2 (en) | 2002-02-05 | 2009-09-10 | Genentech Inc. | Protein purification |
US8287864B2 (en) | 2002-02-14 | 2012-10-16 | Immunomedics, Inc. | Structural variants of antibodies for improved therapeutic characteristics |
CA2476166C (en) * | 2002-02-14 | 2011-11-15 | Immunomedics, Inc. | Anti-cd20 antibodies and fusion proteins thereof and methods of use |
JP2005526501A (en) * | 2002-02-21 | 2005-09-08 | デューク・ユニヴァーシティ | Reagents and therapeutic methods for autoimmune diseases |
CA2476518A1 (en) | 2002-02-22 | 2003-09-04 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
EP2110434A1 (en) | 2002-02-25 | 2009-10-21 | Genentech, Inc. | Type-1 cytokine receptor GLM-R |
EP2865688A1 (en) * | 2002-03-01 | 2015-04-29 | Immunomedics, Inc. | Internalizing anti-CD74 antibodies and methods of use |
US20160279239A1 (en) | 2011-05-02 | 2016-09-29 | Immunomedics, Inc. | Subcutaneous administration of anti-cd74 antibody for systemic lupus erythematosus and autoimmune disease |
US20090042291A1 (en) * | 2002-03-01 | 2009-02-12 | Xencor, Inc. | Optimized Fc variants |
US9770517B2 (en) | 2002-03-01 | 2017-09-26 | Immunomedics, Inc. | Anti-Trop-2 antibody-drug conjugates and uses thereof |
US20040132101A1 (en) | 2002-09-27 | 2004-07-08 | Xencor | Optimized Fc variants and methods for their generation |
US8658773B2 (en) | 2011-05-02 | 2014-02-25 | Immunomedics, Inc. | Ultrafiltration concentration of allotype selected antibodies for small-volume administration |
CN102659946A (en) | 2002-03-13 | 2012-09-12 | 拜奥根Idec马萨诸塞公司 | Anti-alpha v beta 6 antibodies |
US20030180292A1 (en) * | 2002-03-14 | 2003-09-25 | Idec Pharmaceuticals | Treatment of B cell malignancies using anti-CD40L antibodies in combination with anti-CD20 antibodies and/or chemotherapeutics and radiotherapy |
CA2481515C (en) | 2002-04-10 | 2013-10-01 | Genentech, Inc. | Anti-her2 antibody variants |
EP2305710A3 (en) | 2002-06-03 | 2013-05-29 | Genentech, Inc. | Synthetic antibody phage libraries |
US20040202665A1 (en) * | 2002-07-01 | 2004-10-14 | Janette Lazarovits | Compositions and methods for therapeutic treatment |
US20040208877A1 (en) * | 2002-07-01 | 2004-10-21 | Avigdor Levanon | Antibodies and uses thereof |
AU2003247806B2 (en) | 2002-07-08 | 2009-11-12 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
AU2003265264A1 (en) * | 2002-07-09 | 2004-01-23 | Point Therapeutics, Inc. | Methods and compositions relating to isoleucine boroproline compounds |
PT1585966E (en) | 2002-07-15 | 2012-02-20 | Hoffmann La Roche | Treatment of cancer with the anti-erbb2 antibody rhumab 2c4 |
EP1590363A4 (en) | 2002-09-09 | 2006-11-02 | Dana Farber Cancer Inst Inc | Bh3 peptides and method of use thereof |
WO2004024072A2 (en) | 2002-09-11 | 2004-03-25 | Genentech, Inc. | Novel compositions and methods for the treatment of immune related diseases |
JP5401001B2 (en) | 2002-09-11 | 2014-01-29 | ジェネンテック, インコーポレイテッド | Novel compositions and methods for the treatment of immune related diseases |
EP2444409A2 (en) | 2002-09-16 | 2012-04-25 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
EP1585482A4 (en) | 2002-09-25 | 2009-09-09 | Genentech Inc | Nouvelles compositions et methodes de traitement du psoriasis |
BRPI0314814C1 (en) | 2002-09-27 | 2021-07-27 | Xencor Inc | antibody comprising an fc variant |
SI1558648T1 (en) * | 2002-10-17 | 2012-05-31 | Genmab As | Human monoclonal antibodies against cd20 |
EP2322202A3 (en) | 2002-10-29 | 2011-07-27 | Genentech, Inc. | Compositions and methods for the treatment of immune diseases |
CA2503748A1 (en) | 2002-11-08 | 2004-05-27 | Genentech, Inc. | Compositions and methods for the treatment of natural killer cell related diseases |
WO2004047728A2 (en) | 2002-11-26 | 2004-06-10 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
US8420086B2 (en) | 2002-12-13 | 2013-04-16 | Immunomedics, Inc. | Camptothecin conjugates of anti-CD22 antibodies for treatment of B cell diseases |
US7534427B2 (en) * | 2002-12-31 | 2009-05-19 | Immunomedics, Inc. | Immunotherapy of B cell malignancies and autoimmune diseases using unconjugated antibodies and conjugated antibodies and antibody combinations and fusion proteins |
ES2574993T3 (en) | 2003-01-22 | 2016-06-23 | Roche Glycart Ag | Fusion constructs and use thereof to produce antibodies with higher Fc receptor binding affinity and effector function |
MXPA05007940A (en) * | 2003-01-27 | 2007-06-14 | Biogen Idec Inc | Compositions and methods for treating cancer using igsf9 and liv-1. |
ES2566778T3 (en) | 2003-02-01 | 2016-04-15 | Tanox, Inc. | High affinity anti-human IgE antibodies |
GB0304576D0 (en) * | 2003-02-28 | 2003-04-02 | Lonza Biologics Plc | Protein a chromatography |
US20090010920A1 (en) | 2003-03-03 | 2009-01-08 | Xencor, Inc. | Fc Variants Having Decreased Affinity for FcyRIIb |
BRPI0403964B8 (en) | 2003-04-04 | 2021-05-25 | Genentech Inc | stable liquid formulations, article of manufacture and use of these formulations for the treatment of ige-mediated dysfunction |
WO2005000901A2 (en) * | 2003-05-09 | 2005-01-06 | Duke University | Cd20-specific antibodies and methods of employing same |
JP4884224B2 (en) | 2003-05-09 | 2012-02-29 | ディアデクサス インコーポレーテッド | Ovr110 antibody compositions and methods of use |
AR044388A1 (en) * | 2003-05-20 | 2005-09-07 | Applied Molecular Evolution | CD20 UNION MOLECULES |
JP4745242B2 (en) * | 2003-05-20 | 2011-08-10 | アプライド モレキュラー エボリューション,インコーポレイテッド | CD20 binding molecule |
MXPA05012723A (en) | 2003-05-30 | 2006-02-08 | Genentech Inc | Treatment with anti-vegf antibodies. |
EP2367008A3 (en) | 2003-06-06 | 2014-12-24 | Genentech, Inc. | Modulating the interaction between HGF beta chain and C-Met |
US20050232931A1 (en) * | 2003-06-13 | 2005-10-20 | Oncomax Acquisition Corp. | Preparation and application of anti-tumor bifunctional fusion proteins |
US20040254108A1 (en) * | 2003-06-13 | 2004-12-16 | Jing Ma | Preparation and application of anti-tumor bifunctional fusion proteins |
US20050152906A1 (en) * | 2003-06-30 | 2005-07-14 | Avigdor Levanon | Specific human antibodies |
US20050069955A1 (en) * | 2003-06-30 | 2005-03-31 | Daniel Plaksin | Antibodies and uses thereof |
US20050266009A1 (en) * | 2003-06-30 | 2005-12-01 | Savient Pharmaceuticals, Inc. | Antibodies and uses thereof |
JP5026072B2 (en) | 2003-07-01 | 2012-09-12 | イミューノメディクス、インコーポレイテッド | Multispecific carrier of bispecific antibody |
SI1641822T1 (en) | 2003-07-08 | 2013-08-30 | Genentech, Inc. | Il-17 a/f heterologous polypeptides and therapeutic uses thereof |
AR046071A1 (en) | 2003-07-10 | 2005-11-23 | Hoffmann La Roche | ANTIBODIES AGAINST RECEIVER I OF THE INSULINAL TYPE GROWTH FACTOR AND THE USES OF THE SAME |
US7834155B2 (en) * | 2003-07-21 | 2010-11-16 | Immunogen Inc. | CA6 antigen-specific cytotoxic conjugate and methods of using the same |
AU2004258955C1 (en) * | 2003-07-21 | 2012-07-26 | Immunogen, Inc. | A CA6 antigen-specific cytotoxic conjugate and methods of using the same |
PL1651612T3 (en) | 2003-07-22 | 2012-09-28 | Astex Therapeutics Ltd | 3,4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (cdk) and glycogen synthase kinase-3 (gsk-3) modulators |
US7754209B2 (en) | 2003-07-26 | 2010-07-13 | Trubion Pharmaceuticals | Binding constructs and methods for use thereof |
US20050106667A1 (en) | 2003-08-01 | 2005-05-19 | Genentech, Inc | Binding polypeptides with restricted diversity sequences |
WO2005019258A2 (en) | 2003-08-11 | 2005-03-03 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
US8147832B2 (en) * | 2003-08-14 | 2012-04-03 | Merck Patent Gmbh | CD20-binding polypeptide compositions and methods |
US9714282B2 (en) | 2003-09-26 | 2017-07-25 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
JP4810431B2 (en) | 2003-11-04 | 2011-11-09 | ノバルティス バクシンズ アンド ダイアグノスティックス,インコーポレーテッド | Method for treating cancer associated with B cells |
WO2005044998A2 (en) | 2003-11-05 | 2005-05-19 | Palingen, Inc. | Enhanced b cell cytotoxicity of cdim binding antibody |
CA2545603A1 (en) | 2003-11-12 | 2005-05-26 | Biogen Idec Ma Inc. | Neonatal fc receptor (fcrn)-binding polypeptide variants, dimeric fc binding proteins and methods related thereto |
EP1689432B1 (en) | 2003-11-17 | 2009-12-30 | Genentech, Inc. | Compositions and methods for the treatment of tumor of hematopoietic origin |
US7750123B2 (en) | 2003-11-25 | 2010-07-06 | Dana Farber Cancer Institute, Inc. | Antibodies against SARS-CoV and methods of use thereof |
US7312320B2 (en) | 2003-12-10 | 2007-12-25 | Novimmune Sa | Neutralizing antibodies and methods of use thereof |
CA2548282A1 (en) | 2003-12-11 | 2005-06-30 | Genentech, Inc. | Methods and compositions for inhibiting c-met dimerization and activation |
PT1718677E (en) | 2003-12-19 | 2012-07-18 | Genentech Inc | Monovalent antibody fragments useful as therapeutics |
DK1704166T3 (en) | 2004-01-07 | 2015-06-01 | Novartis Vaccines & Diagnostic | M-CSF-SPECIFIC MONOCLONAL ANTIBODY AND APPLICATIONS THEREOF |
US8883160B2 (en) * | 2004-02-13 | 2014-11-11 | Ibc Pharmaceuticals, Inc. | Dock-and-lock (DNL) complexes for therapeutic and diagnostic use |
US9550838B2 (en) | 2004-02-13 | 2017-01-24 | Ibc Pharmaceuticals, Inc. | Dock-and-lock (DNL) complexes for therapeutic and diagnostic use |
US20110171126A1 (en) * | 2010-01-11 | 2011-07-14 | Center For Molecular Medicine And Immunology | Enhanced Cytotoxicity of Anti-CD74 and Anti-HLA-DR Antibodies with Interferon-Gamma |
EP2168986A3 (en) | 2004-02-19 | 2010-07-28 | Genentech, Inc. | CDR-repaired antibodies |
US7658925B2 (en) | 2004-03-03 | 2010-02-09 | Iq Therapeutics Bv | Human anthrax toxin neutralizing monoclonal antibodies and methods of use thereof |
CA2885854C (en) | 2004-04-13 | 2017-02-21 | F. Hoffmann-La Roche Ag | Anti-p-selectin antibodies |
RU2006140374A (en) * | 2004-04-16 | 2008-05-27 | Дженентек, Инк. (Us) | TREATMENT OF VIOLATIONS |
JP5848861B2 (en) | 2004-04-20 | 2016-01-27 | ジェンマブ エー/エスGenmab A/S | Human monoclonal antibody against CD20 |
SV2006002143A (en) | 2004-06-16 | 2006-01-26 | Genentech Inc | USE OF AN ANTIBODY FOR THE TREATMENT OF CANCER RESISTANT TO PLATINUM |
CN101035802A (en) | 2004-07-02 | 2007-09-12 | 健泰科生物技术公司 | Inhibitors of IAP |
KR101250127B1 (en) * | 2004-07-09 | 2013-04-02 | 바이엘 파마 악티엔게젤샤프트 | Combination therapy with radiolabeled anti-cd20 antibody in the treatment of b-cell lymphoma |
EP1919950A1 (en) | 2004-07-15 | 2008-05-14 | Xencor, Inc. | Optimized fc variants |
ZA200701183B (en) | 2004-07-20 | 2008-05-28 | Genentech Inc | Inhibitors of angiopoietin-like 4 protein, combinations, an their use |
KR20160096228A (en) | 2004-07-22 | 2016-08-12 | 제넨테크, 인크. | Her2 antibody composition |
NZ551908A (en) | 2004-07-26 | 2009-10-30 | Genentech Inc | Methods and compositions for modulating hepatocyte growth factor HGF activation |
WO2006017574A1 (en) * | 2004-08-03 | 2006-02-16 | Mayo Foundation For Medical Education And Research | Improving treatments |
EA012464B1 (en) | 2004-08-04 | 2009-10-30 | Эпплайд Молекьюлар Эволюшн, Инк. | Antibody against cd20 and use thereof |
RS57636B1 (en) | 2004-09-03 | 2018-11-30 | Genentech Inc | Humanized anti-beta7 antagonists and uses therefor |
TWI380996B (en) | 2004-09-17 | 2013-01-01 | Hoffmann La Roche | Anti-ox40l antibodies |
EP1791565B1 (en) | 2004-09-23 | 2016-04-20 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
US20100111856A1 (en) | 2004-09-23 | 2010-05-06 | Herman Gill | Zirconium-radiolabeled, cysteine engineered antibody conjugates |
WO2006038212A2 (en) * | 2004-10-04 | 2006-04-13 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Methods and compositions for the diagnosis and treatment of cancer |
JO3000B1 (en) | 2004-10-20 | 2016-09-05 | Genentech Inc | Antibody Formulations. |
EP1814544A4 (en) * | 2004-11-05 | 2009-12-02 | Cephalon Inc | Cancer treatments |
US8367805B2 (en) | 2004-11-12 | 2013-02-05 | Xencor, Inc. | Fc variants with altered binding to FcRn |
CN102746404B (en) | 2004-11-12 | 2016-01-20 | 赞科股份有限公司 | To FcRn in conjunction with reformed Fc variant |
FR2879204B1 (en) * | 2004-12-15 | 2007-02-16 | Lab Francais Du Fractionnement | CYTOTOXIC ANTIBODY AGAINST HEMATOPOIETIC B-TYPE HEMATOPOIETIC PROLIFERATIONS |
EP1836201B2 (en) | 2004-12-20 | 2013-09-04 | Genentech, Inc. | Pyrrolidine inhibitors of iap |
ATE432921T1 (en) | 2004-12-23 | 2009-06-15 | Gpc Biotech Ag | SQUARE ACID DERIVATIVES WITH ANTIPROLIFERATIVE EFFECT |
SG173313A1 (en) | 2005-01-05 | 2011-08-29 | Biogen Idec Inc | Cripto binding molecules |
US7964195B2 (en) | 2005-01-07 | 2011-06-21 | Diadexus, Inc. | Ovr110 antibody compositions and methods of use |
US8436190B2 (en) | 2005-01-14 | 2013-05-07 | Cephalon, Inc. | Bendamustine pharmaceutical compositions |
US8404718B2 (en) | 2005-01-21 | 2013-03-26 | Astex Therapeutics Limited | Combinations of pyrazole kinase inhibitors |
ES2552338T3 (en) | 2005-01-21 | 2015-11-27 | Astex Therapeutics Limited | Pharmaceutical compounds |
EP3698807A1 (en) | 2005-01-21 | 2020-08-26 | Genentech, Inc. | Fixed dosing of her antibodies |
AR054425A1 (en) | 2005-01-21 | 2007-06-27 | Astex Therapeutics Ltd | PIPERIDIN ADDITION SALTS 4-IL-ACID AMID 4- (2,6-DICLORO-BENZOILAMINO) 1H-PIRAZOL-3-CARBOXILICO. |
US8029783B2 (en) | 2005-02-02 | 2011-10-04 | Genentech, Inc. | DR5 antibodies and articles of manufacture containing same |
KR20070108402A (en) * | 2005-02-15 | 2007-11-09 | 노바티스 백신즈 앤드 다이아그노스틱스 인코포레이티드 | Methods for treating lymphomas using a combination of a chemotherapeutic agent and il-2 and optionally an anti-cd20 antibody |
EP1871807B1 (en) | 2005-02-18 | 2012-11-28 | Dana-Farber Cancer Institute, Inc. | Antibodies against cxcr4 and methods of use thereof |
AU2006216732C1 (en) | 2005-02-23 | 2017-07-20 | Genentech, Inc. | Extending time to disease progression or survival in cancer patients using a HER dimerization inhibitor |
US20160355591A1 (en) | 2011-05-02 | 2016-12-08 | Immunomedics, Inc. | Subcutaneous anti-hla-dr monoclonal antibody for treatment of hematologic malignancies |
US9707302B2 (en) | 2013-07-23 | 2017-07-18 | Immunomedics, Inc. | Combining anti-HLA-DR or anti-Trop-2 antibodies with microtubule inhibitors, PARP inhibitors, bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer |
US10058621B2 (en) | 2015-06-25 | 2018-08-28 | Immunomedics, Inc. | Combination therapy with anti-HLA-DR antibodies and kinase inhibitors in hematopoietic cancers |
JPWO2006109533A1 (en) * | 2005-03-31 | 2008-10-23 | 国立大学法人大阪大学 | Methods for producing and assaying antibodies against cell membrane surface antigen epitopes |
US8475794B2 (en) | 2005-04-06 | 2013-07-02 | Ibc Pharmaceuticals, Inc. | Combination therapy with anti-CD74 antibodies provides enhanced toxicity to malignancies, Autoimmune disease and other diseases |
US8349332B2 (en) | 2005-04-06 | 2013-01-08 | Ibc Pharmaceuticals, Inc. | Multiple signaling pathways induced by hexavalent, monospecific and bispecific antibodies for enhanced toxicity to B-cell lymphomas and other diseases |
EP1865981A2 (en) | 2005-04-07 | 2007-12-19 | Chiron Corporation | Cacna1e in cancer diagnosis, detection and treatment |
EP1871911A2 (en) | 2005-04-07 | 2008-01-02 | Chiron Corporation | Cancer-related genes (prlr) |
KR20070122497A (en) * | 2005-04-22 | 2007-12-31 | 제넨테크, 인크. | Method for treating dementia or alzheimer's disease with a cd20 antibody |
JP2008539731A (en) * | 2005-05-02 | 2008-11-20 | コールド スプリング ハーバー ラボラトリー | Compositions and methods for diagnosis and treatment of cancer |
PL1899364T3 (en) | 2005-05-17 | 2020-08-24 | University Of Connecticut | Compositions and methods for immunomodulation in an organism |
JP2009508467A (en) | 2005-05-24 | 2009-03-05 | アベスタゲン リミテッド | Methods for generating monoclonal antibodies against CD20 for the treatment of B-cell lymphoma |
GB0510790D0 (en) | 2005-05-26 | 2005-06-29 | Syngenta Crop Protection Ag | Anti-CD16 binding molecules |
US7858843B2 (en) | 2005-06-06 | 2010-12-28 | Genentech, Inc. | Gene disruptions, compositions and methods relating thereto |
WO2007094842A2 (en) | 2005-12-02 | 2007-08-23 | Genentech, Inc. | Binding polypeptides and uses thereof |
CN102875681A (en) | 2005-07-08 | 2013-01-16 | 拜奥根Idec马萨诸塞公司 | Anti-alpha v beta 6 antibodies and uses thereof |
ES2530265T3 (en) | 2005-07-21 | 2015-02-27 | Genmab A/S | Binding potency assays of an antibody drug substance to an FC receptor |
JP5457671B2 (en) | 2005-07-28 | 2014-04-02 | ノバルティス アーゲー | M-CSF specific monoclonal antibody and use thereof |
AU2006280321A1 (en) | 2005-08-15 | 2007-02-22 | Genentech, Inc. | Gene disruptions, compositions and methods relating thereto |
EP1762575A1 (en) * | 2005-09-12 | 2007-03-14 | Ganymed Pharmaceuticals AG | Identification of tumor-associated antigens for diagnosis and therapy |
EP1931709B1 (en) | 2005-10-03 | 2016-12-07 | Xencor, Inc. | Fc variants with optimized fc receptor binding properties |
ES2577292T3 (en) | 2005-11-07 | 2016-07-14 | Genentech, Inc. | Binding polypeptides with diversified VH / VL hypervariable sequences and consensus |
UA96139C2 (en) | 2005-11-08 | 2011-10-10 | Дженентек, Інк. | Anti-neuropilin-1 (nrp1) antibody |
CN101360826B (en) | 2005-11-18 | 2014-04-30 | 格兰马克药品股份有限公司 | Anti-alpha2 integrin antibodies and their uses |
AU2006335053A1 (en) | 2005-11-21 | 2007-07-19 | Genentech, Inc. | Novel gene disruptions, compositions and methods relating thereto |
CN105859886A (en) | 2005-12-02 | 2016-08-17 | 健泰科生物技术公司 | Compositions and methods associated with antibodies that bind to IL-22 and IL-22R |
WO2007064911A1 (en) * | 2005-12-02 | 2007-06-07 | Biogen Idec Inc. | Anti-mouse cd20 antibodies and uses thereof |
US8466263B2 (en) | 2005-12-02 | 2013-06-18 | Dana-Farber Cancer Institute, Inc. | Carbonic anhydrase IX (G250) anitbodies |
US7763245B2 (en) | 2005-12-15 | 2010-07-27 | Genentech, Inc. | Methods and compositions for targeting polyubiquitin |
WO2007106192A2 (en) | 2005-12-19 | 2007-09-20 | Genentech, Inc. | Inhibitors of iap |
RU2450020C2 (en) | 2006-01-05 | 2012-05-10 | Дженентек, Инк. | ANTI-EphB4 ANTIBODIES AND METHODS OF USING SAID ANTIBODIES |
KR101617108B1 (en) | 2006-01-20 | 2016-04-29 | 제넨테크, 인크. | Anti-ephrinb2 antibodies and methods using same |
EP1982181B1 (en) | 2006-02-06 | 2010-12-15 | Rhode Island Hospital | Gpr30 estrogen receptor in breast cancers |
CA2638821A1 (en) | 2006-02-17 | 2007-10-11 | Genentech, Inc. | Gene disruptons, compositions and methods relating thereto |
WO2007103470A2 (en) * | 2006-03-06 | 2007-09-13 | Medimmune, Inc. | Humanized anti-cd22 antibodies and their use in treatment of oncology, transplantation and autoimmune disease |
EP2540741A1 (en) | 2006-03-06 | 2013-01-02 | Aeres Biomedical Limited | Humanized anti-CD22 antibodies and their use in treatment of oncology, transplantation and autoimmune disease |
JPWO2007102200A1 (en) | 2006-03-07 | 2009-07-23 | 国立大学法人大阪大学 | Anti-CD20 monoclonal antibody |
EP1999269B1 (en) | 2006-03-08 | 2014-12-10 | Wake Forest University Health Sciences | Soluble monomeric ephrin a1 |
AR059851A1 (en) | 2006-03-16 | 2008-04-30 | Genentech Inc | ANTIBODIES OF EGFL7 AND METHODS OF USE |
EP2010569A4 (en) | 2006-03-20 | 2009-09-09 | Xoma Technology Ltd | Human antibodies specific for gastrin materials and methods |
US20100278821A1 (en) | 2006-03-21 | 2010-11-04 | The Regents Of The University Of California | N-cadherin: target for cancer diagnosis and therapy |
ES2544957T3 (en) | 2006-03-21 | 2015-09-07 | Genentech, Inc. | Combined therapy involving alpha5beta1 antagonists |
CA2646597A1 (en) | 2006-03-21 | 2007-09-27 | The Regents Of The University Of California | N-cadherin and ly6 e: targets for cancer diagnosis and therapy |
EP2389948A1 (en) | 2006-03-23 | 2011-11-30 | Novartis AG | Anti-tumor cell antigen antibody therapeutics |
EP2008106A2 (en) | 2006-03-31 | 2008-12-31 | Dana-Farber Cancer Institute | Methods of determining cellular chemosensitivity |
EP2614839A3 (en) | 2006-04-05 | 2015-01-28 | Genentech, Inc. | Method for using BOC/CDO to modulate hedgehog signaling |
US7846724B2 (en) | 2006-04-11 | 2010-12-07 | Hoffmann-La Roche Inc. | Method for selecting CHO cell for production of glycosylated antibodies |
US20080014203A1 (en) | 2006-04-11 | 2008-01-17 | Silke Hansen | Antibodies against insulin-like growth factor I receptor and uses thereof |
JP2009541208A (en) | 2006-04-13 | 2009-11-26 | ノバルティス・バクシーンズ・アンド・ダイアグノスティクス・インコーポレイテッド | How to treat, diagnose, or detect cancer |
EP2011870A4 (en) | 2006-04-14 | 2010-09-15 | Medical & Biol Lab Co Ltd | Mutant polypeptide having effector function |
EP2082645A1 (en) | 2006-04-19 | 2009-07-29 | Genentech, Inc. | Novel gene disruptions, compositions and methods relating thereto |
US7727525B2 (en) * | 2006-05-11 | 2010-06-01 | City Of Hope | Engineered anti-CD20 antibody fragments for in vivo targeting and therapeutics |
AR060978A1 (en) | 2006-05-30 | 2008-07-23 | Genentech Inc | ANTIBODIES AND IMMUNOCATE PLAYERS AND THEIR USES |
RU2499001C2 (en) | 2006-06-30 | 2013-11-20 | Ново Нордиск А/С | Antibodies to nkg2a and their applications |
CA2662905A1 (en) | 2006-07-10 | 2008-01-17 | Biogen Idec Ma Inc. | Compositions and methods for inhibiting growth of smad4-deficient cancers |
EP2471815B1 (en) | 2006-07-11 | 2016-03-30 | University Of Medicine And Dentistry Of New Jersey | Proteins, nucleic acids encoding the same and associated methods of use |
WO2008008917A2 (en) * | 2006-07-12 | 2008-01-17 | Mayo Foundation For Medical Education And Research | Hydroxyapatite particles |
CA2659820A1 (en) | 2006-08-04 | 2008-02-14 | Novartis Ag | Ephb3-specific antibody and uses thereof |
US8586006B2 (en) | 2006-08-09 | 2013-11-19 | Institute For Systems Biology | Organ-specific proteins and methods of their use |
GEP20125612B (en) | 2006-08-18 | 2012-08-27 | Novartis Ag | Prlr-specific antibody and usage thereof |
BRPI0715703A2 (en) | 2006-08-22 | 2013-09-17 | G2 Inflammation Pty Ltd | anti-c5ar antibodies with enhanced properties |
JP2010501172A (en) | 2006-08-25 | 2010-01-21 | オンコセラピー・サイエンス株式会社 | Prognostic markers and therapeutic targets for lung cancer |
US20080058922A1 (en) * | 2006-08-31 | 2008-03-06 | Cardiac Pacemakers, Inc. | Methods and devices employing vap-1 inhibitors |
US8372399B2 (en) * | 2006-08-31 | 2013-02-12 | Cardiac Pacemakers, Inc. | Bispecific antibodies and agents to enhance stem cell homing |
US8636995B2 (en) * | 2006-08-31 | 2014-01-28 | Cardiac Pacemakers, Inc. | Methods and devices to regulate stem cell homing |
CA2662236A1 (en) | 2006-09-12 | 2008-03-20 | Genentech, Inc. | Methods and compositions for the diagnosis and treatment of cancer |
KR101161923B1 (en) | 2006-10-03 | 2012-07-03 | 유니버시티 오브 메디신 앤드 덴티스트리 오브 뉴 저지 | Atap peptides, nucleic acids encoding the same and associated methods of use |
US9382327B2 (en) | 2006-10-10 | 2016-07-05 | Vaccinex, Inc. | Anti-CD20 antibodies and methods of use |
US8916552B2 (en) | 2006-10-12 | 2014-12-23 | Astex Therapeutics Limited | Pharmaceutical combinations |
EP2073807A1 (en) | 2006-10-12 | 2009-07-01 | Astex Therapeutics Limited | Pharmaceutical combinations |
SI2502938T1 (en) | 2006-10-27 | 2015-05-29 | Genentech, Inc. | Antibodies and immunoconjugates and uses therefor |
WO2008140477A2 (en) | 2006-11-02 | 2008-11-20 | Capon Daniel J | Hybrid immunoglobulins with moving parts |
AU2007325838B2 (en) | 2006-11-22 | 2013-09-19 | Bristol-Myers Squibb Company | Targeted therapeutics based on engineered proteins for tyrosine kinases receptors, including IGF-IR |
JP5391073B2 (en) | 2006-11-27 | 2014-01-15 | ディアデクサス インコーポレーテッド | Ovr110 antibody compositions and methods of use |
WO2008070780A1 (en) | 2006-12-07 | 2008-06-12 | Novartis Ag | Antagonist antibodies against ephb3 |
KR20090094461A (en) | 2006-12-19 | 2009-09-07 | 제넨테크, 인크. | Imidazopyridine inhibitors of iap |
US20100144599A1 (en) | 2007-02-02 | 2010-06-10 | Bristol-Myers Squibb Company | Vegf pathway blockade |
CA2676766A1 (en) | 2007-02-09 | 2008-08-21 | Genentech, Inc. | Anti-robo4 antibodies and uses therefor |
PL2716301T3 (en) | 2007-02-16 | 2017-10-31 | Merrimack Pharmaceuticals Inc | Antibodies against erbb3 and uses thereof |
US7875431B2 (en) | 2007-02-22 | 2011-01-25 | Genentech, Inc. | Methods for detecting inflammatory bowel disease |
WO2008109440A2 (en) | 2007-03-02 | 2008-09-12 | Genentech, Inc. | Predicting response to a her dimerisation inhibitor based on low her3 expression |
US8280711B2 (en) | 2007-03-12 | 2012-10-02 | ESBATech, an Alcon Biomedical Research Unit, LLC. | Sequence based engineering and optimization of single chain antibodies |
JP2010521180A (en) | 2007-03-14 | 2010-06-24 | ノバルティス アーゲー | APCDD1 inhibitor for treating, diagnosing or detecting cancer |
US7960139B2 (en) | 2007-03-23 | 2011-06-14 | Academia Sinica | Alkynyl sugar analogs for the labeling and visualization of glycoconjugates in cells |
WO2008127656A1 (en) | 2007-04-12 | 2008-10-23 | The Brigham And Women's Hospital, Inc. | Targeting abcb5 for cancer therapy |
FR2915398B1 (en) * | 2007-04-25 | 2012-12-28 | Lab Francais Du Fractionnement | "SET OF MEANS FOR THE TREATMENT OF MALIGNANT PATHOLOGY, AUTOIMMUNE DISEASE OR INFECTIOUS DISEASE" |
MX2009011783A (en) | 2007-04-30 | 2009-12-04 | Genentech Inc | Inhibitors of iap. |
PL2173381T3 (en) | 2007-05-14 | 2014-03-31 | Novimmune Sa | Fc receptor-binding polypeptides with modified effector functions |
EP2019101A1 (en) * | 2007-07-26 | 2009-01-28 | GPC Biotech AG | Pyrazol[3,4-d]pyrimidin-4-one useful as Kinase Inhibitor |
PE20090321A1 (en) | 2007-06-04 | 2009-04-20 | Genentech Inc | ANTI-NOTCH1 NRR ANTIBODIES, METHOD OF PREPARATION AND PHARMACEUTICAL COMPOSITION |
KR101572700B1 (en) | 2007-06-07 | 2015-11-30 | 제넨테크, 인크. | C3b antibodies and methods for the prevention and treatment of complement-associated disorders |
NZ581468A (en) | 2007-06-25 | 2012-09-28 | Esbatech Alcon Biomed Res Unit | Methods of modifying antibodies, and modified antibodies with improved functional properties |
WO2009000098A2 (en) * | 2007-06-25 | 2008-12-31 | Esbatech Ag | Sequence based engineering and optimization of single chain antibodies |
TW200918089A (en) | 2007-07-16 | 2009-05-01 | Genentech Inc | Humanized anti-CD79b antibodies and immunoconjugates and methods of use |
JP5469600B2 (en) | 2007-07-16 | 2014-04-16 | ジェネンテック, インコーポレイテッド | Anti-CD79b antibody and immunoconjugate and method of use thereof |
PL2178916T3 (en) * | 2007-07-31 | 2015-08-31 | Regeneron Pharma | Human antibodies to human cd20 and method of using thereof |
MX2010001307A (en) | 2007-08-02 | 2010-07-30 | Novimmune Sa | Anti-rantes antibodies and methods of use thereof. |
EP2190478B1 (en) | 2007-08-24 | 2016-03-23 | Oncotherapy Science, Inc. | Dkk1 oncogene as therapeutic target for cancer and a diagnosing marker |
BRPI0815757A2 (en) | 2007-08-24 | 2015-02-18 | Oncotherapy Science Inc | PKIB AND NAALAD2 GENES AS TARGETS OF PROSTATE CANCER TREATMENT AND DIAGNOSIS |
AU2008298904B2 (en) | 2007-09-14 | 2014-10-16 | Amgen Inc. | Homogeneous antibody populations |
CL2008002886A1 (en) | 2007-09-26 | 2009-12-04 | Chugai Pharmaceutical Co Ltd | Constant region of a human antibody; anti-interleukin-6 (yl-6) receptor antibody and pharmaceutical composition comprising it. |
RS53850B2 (en) * | 2007-10-30 | 2018-07-31 | Genentech Inc | Antibody purification by cation exchange chromatography |
SI2514436T1 (en) | 2007-11-07 | 2018-04-30 | Genentech, Inc. | Il-22 for use in treating microbial disorders |
EP2209807A1 (en) | 2007-11-08 | 2010-07-28 | Genentech, Inc. | Anti-factor b antibodies and their uses |
KR20100097691A (en) | 2007-11-12 | 2010-09-03 | 테라클론 사이언시스, 아이엔씨. | Compositions and methods for the therapy and diagnosis of influenza |
US8715941B2 (en) | 2007-11-16 | 2014-05-06 | Arca Biopharma, Inc. | Antibodies to LRP6 |
AR069501A1 (en) | 2007-11-30 | 2010-01-27 | Genentech Inc | ANTI-VEGF ANTIBODIES (VASCULAR ENDOTELIAL GROWTH FACTOR) |
NZ586611A (en) | 2007-12-06 | 2012-09-28 | Dana Farber Cancer Inst Inc | Antibodies against influenza virus and methods of use thereof |
SI2808343T1 (en) | 2007-12-26 | 2019-10-30 | Xencor Inc | Fc variants with altered binding to FcRn |
US8962806B2 (en) | 2007-12-28 | 2015-02-24 | Dana-Farber Cancer Institute, Inc. | Humanized monoclonal antibodies and methods of use |
US7914785B2 (en) | 2008-01-02 | 2011-03-29 | Bergen Teknologieverforing As | B-cell depleting agents, like anti-CD20 antibodies or fragments thereof for the treatment of chronic fatigue syndrome |
WO2009089295A2 (en) | 2008-01-07 | 2009-07-16 | Government Of The United States Of America, As Represented By The Secretary, Dept. Of Health And Human Services | Anti-hiv domain antibodies and method of making and using same |
ATE548052T1 (en) | 2008-01-17 | 2012-03-15 | Philogen Spa | COMBINATION OF AN ANTI-EDB-FIBRONECTIN ANTIBODY-IL-2 FUSION PROTEIN AND A B-CELL-BINDING MOLECULE, B-CELL PRECURSORS AND/OR THEIR CARCINOGENIC ANTEPANT |
EP2247617B1 (en) | 2008-01-18 | 2013-02-27 | Genentech, Inc. | Methods and compositions for targeting polyubiquitin |
AR070141A1 (en) | 2008-01-23 | 2010-03-17 | Glenmark Pharmaceuticals Sa | SPECIFIC HUMANIZED ANTIBODIES FOR VON WILLEBRAND FACTOR |
EP2247619A1 (en) | 2008-01-24 | 2010-11-10 | Novo Nordisk A/S | Humanized anti-human nkg2a monoclonal antibody |
TWI472339B (en) | 2008-01-30 | 2015-02-11 | Genentech Inc | Composition comprising antibody that binds to domain ii of her2 and acidic variants thereof |
SI2657253T1 (en) | 2008-01-31 | 2017-10-30 | Genentech, Inc. | Anti-CD79b antibodies and immunoconjugates and methods of use |
AU2009217224B2 (en) | 2008-02-20 | 2014-09-11 | G2 Inflammation Pty Ltd | Humanized anti-C5aR antibodies |
US20090252725A1 (en) * | 2008-03-07 | 2009-10-08 | Biogen Idec Ma Inc. | Use of CD23 Antibodies to Treat Malignancies in Patients with Poor Prognosis |
AU2009223688B2 (en) | 2008-03-10 | 2014-12-11 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of cytomegalovirus infections |
AR072777A1 (en) | 2008-03-26 | 2010-09-22 | Cephalon Inc | SOLID FORMS OF BENDAMUSTINE CHLORHYDRATE |
SG10201402815VA (en) | 2008-04-09 | 2014-09-26 | Genentech Inc | Novel compositions and methods for the treatment of immune related diseases |
EP2112152A1 (en) | 2008-04-22 | 2009-10-28 | GPC Biotech AG | Dihydropteridinones as Plk Inhibitors |
EP2112150B1 (en) | 2008-04-22 | 2013-10-16 | Forma Therapeutics, Inc. | Improved raf inhibitors |
SG190572A1 (en) | 2008-04-29 | 2013-06-28 | Abbott Lab | Dual variable domain immunoglobulins and uses thereof |
AR071874A1 (en) | 2008-05-22 | 2010-07-21 | Bristol Myers Squibb Co | ARMAZON DOMAIN PROTEINS BASED ON MULTIVALENT FIBRONECTINE |
CA2726087A1 (en) | 2008-06-03 | 2009-12-10 | Tariq Ghayur | Dual variable domain immunoglobulins and uses thereof |
RU2010153578A (en) | 2008-06-03 | 2012-07-20 | Эбботт Лэборетриз (Us) | IMMUNOGLOBULINS WITH DOUBLE VARIABLE DOMAINS AND THEIR APPLICATION |
PE20140407A1 (en) | 2008-06-10 | 2014-04-25 | Abbott Lab | NEW TRICYCLIC COMPOUNDS |
RU2514658C2 (en) | 2008-06-25 | 2014-04-27 | ИЭсБиЭйТЕК, ЭН АЛЬКОН БАЙОМЕДИКАЛ РИСЕРЧ ЮНИТ ЭлЭлСи | Optimising solubility of immunobinders |
RU2011104348A (en) * | 2008-07-08 | 2012-08-20 | Эбботт Лэборетриз (Us) | IMMUNOGLOBULINS WITH DOUBLE VARIABLE DOMAIN AGAINST PROSTAGLANDINE E2 AND THEIR APPLICATION |
JP5986745B2 (en) | 2008-07-15 | 2016-09-06 | アカデミア シニカAcademia Sinica | Glycan arrays on PTFE-like aluminum-coated glass slides and related methods |
NZ590330A (en) | 2008-07-21 | 2012-08-31 | Immunomedics Inc | Structural variants of anti-cd20 antibodies for improved therapeutic characteristics |
AU2009274512A1 (en) | 2008-07-25 | 2010-01-28 | The Regents Of The University Of Colorado | Clip inhibitors and methods of modulating immune function |
NZ590550A (en) | 2008-08-02 | 2013-05-31 | Genentech Inc | Inhibitors of Apoptosis (IAP) for treating cancer |
EP2307443B1 (en) | 2008-08-07 | 2013-10-02 | Yeda Research And Development Company Ltd. | Affinity purification by cohesin-dockerin interaction |
US20120128684A1 (en) | 2008-08-25 | 2012-05-24 | Burnham Institute For Medical Research | Conserved Hemagglutinin Epitope, Antibodies to the Epitope and Methods of Use |
AU2009296734B2 (en) | 2008-09-25 | 2016-02-18 | Cephalon Llc | Liquid formulations of bendamustine |
AR073717A1 (en) | 2008-10-01 | 2010-11-24 | Genentech Inc | ANTI-NOTCH2 ANTIBODIES OF MURINE AND HUMAN, AND METHODS OF USE |
JP5775458B2 (en) | 2008-11-06 | 2015-09-09 | グレンマーク ファーマシューティカルズ, エセ.アー. | Treatment using anti-α2 integrin antibody |
EP2752189B1 (en) | 2008-11-22 | 2016-10-26 | F. Hoffmann-La Roche AG | Use of anti-vegf antibody in combination with chemotherapy for treating breast cancer |
TWI496582B (en) | 2008-11-24 | 2015-08-21 | 必治妥美雅史谷比公司 | Bispecific egfr/igfir binding molecules |
US20110293614A1 (en) | 2008-11-25 | 2011-12-01 | Klaus Elenius | Isoform specific anti-her4 antibodies |
US20110318370A1 (en) | 2008-11-27 | 2011-12-29 | Andreas Bikfalvi | Cxcl4l1 as a biomarker of pancreatic cancer |
SI2376535T1 (en) | 2008-12-09 | 2017-07-31 | F. Hoffmann-La Roche Ag | Anti-pd-l1 antibodies and their use to enhance t-cell function |
KR20110101212A (en) | 2008-12-17 | 2011-09-15 | 제넨테크, 인크. | Hepatitis c virus combination therapy |
US20110142836A1 (en) * | 2009-01-02 | 2011-06-16 | Olav Mella | B-cell depleting agents for the treatment of chronic fatigue syndrome |
EP2373339B1 (en) | 2009-01-06 | 2017-04-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A b cell depleting agent for the treatment of atherosclerosis |
AU2010204765A1 (en) * | 2009-01-15 | 2011-07-28 | Cephalon, Inc. | Novel forms of bendamustine free base |
JP5936112B2 (en) | 2009-02-11 | 2016-06-15 | アルブミディクス アクティーゼルスカブ | Albumin variants and complexes |
EP3243527B1 (en) | 2009-02-13 | 2019-06-05 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
EP2402439B1 (en) | 2009-02-27 | 2018-12-12 | Order-made Medical Research Inc. | A method for preparing a hybridoma cell by transplanting breast cancer cells |
SI3260136T1 (en) | 2009-03-17 | 2021-05-31 | Theraclone Sciences, Inc. | Human immunodeficiency virus (hiv) -neutralizing antibodies |
ES2572728T3 (en) | 2009-03-20 | 2016-06-02 | F. Hoffmann-La Roche Ag | Bispecific anti-HER antibodies |
NZ594343A (en) | 2009-03-25 | 2013-10-25 | Genentech Inc | Novel anti-alpha5beta1 antibodies and uses thereof |
CA2754163C (en) | 2009-03-25 | 2019-04-09 | Genentech, Inc. | Anti-fgfr3 antibodies and methods using same |
AU2010236787A1 (en) | 2009-04-01 | 2011-11-10 | Genentech, Inc. | Anti-FcRH5 antibodies and immunoconjugates and methods of use |
CA2756244A1 (en) | 2009-04-02 | 2010-10-07 | Roche Glycart Ag | Multispecific antibodies comprising full length antibodies and single chain fab fragments |
WO2010118243A2 (en) | 2009-04-08 | 2010-10-14 | Genentech, Inc. | Use of il-27 antagonists to treat lupus |
WO2010121125A1 (en) | 2009-04-17 | 2010-10-21 | Wake Forest University Health Sciences | Il-13 receptor binding peptides |
CA2759506A1 (en) | 2009-04-23 | 2010-10-28 | Theraclone Sciences, Inc. | Granulocyte-macrophage colony-stimulating factor (gm-csf) neutralizing antibodies |
RU2011148918A (en) * | 2009-05-01 | 2013-06-10 | Эбботт Лэборетриз | IMMUNOGLOBULIN WITH TWO VARIABLE DOMAINS AND ITS APPLICATION |
PE20160652A1 (en) | 2009-05-05 | 2016-07-09 | Novimmune Sa | ANTIBODIES THAT JOIN IL-17F |
AU2010249787A1 (en) | 2009-05-20 | 2011-12-22 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
US8815242B2 (en) | 2009-05-27 | 2014-08-26 | Synageva Biopharma Corp. | Avian derived antibodies |
EP3248619A3 (en) | 2009-06-04 | 2018-03-07 | Novartis AG | Methods for identification of sites for igg conjugation |
US20100316639A1 (en) | 2009-06-16 | 2010-12-16 | Genentech, Inc. | Biomarkers for igf-1r inhibitor therapy |
US20120101262A1 (en) | 2009-06-25 | 2012-04-26 | Bristol-Myers Squibb Company | Protein purification by caprylic acid (octanoic acid) precipitation |
EP2448966B1 (en) | 2009-07-03 | 2018-11-14 | Avipep Pty Ltd | Immuno-conjugates and methods for producing them |
US8765431B2 (en) | 2009-07-23 | 2014-07-01 | The Regents Of The University Of Michigan | Method for enzymatic production of decarboxylated polyketides and fatty acids |
NZ597531A (en) | 2009-07-31 | 2014-05-30 | Genentech Inc | Inhibition of tumor metastasis using bv8- or g-csf-antagonists |
WO2011022264A1 (en) | 2009-08-15 | 2011-02-24 | Genentech, Inc. | Anti-angiogenesis therapy for the treatment of previously treated breast cancer |
US9493578B2 (en) | 2009-09-02 | 2016-11-15 | Xencor, Inc. | Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens |
US9321823B2 (en) | 2009-09-02 | 2016-04-26 | Genentech, Inc. | Mutant smoothened and methods of using the same |
RU2015153109A (en) | 2009-09-16 | 2019-01-15 | Дженентек, Инк. | SUPERSPIRAL AND / OR BINDING PROTEIN COMPLEXES AND THEIR APPLICATIONS |
CA2774260C (en) | 2009-09-16 | 2018-10-09 | Immunomedics, Inc. | Class i anti-cea antibodies and uses thereof |
WO2011037983A1 (en) | 2009-09-23 | 2011-03-31 | Medarex, Inc. | Cation exchange chromatography |
EP2482212A4 (en) | 2009-09-25 | 2014-02-26 | Sh Nat Eng Res Ct Nanotech Co | Method of acquiring proteins with high affinity by computer aided design |
AU2010306677B2 (en) * | 2009-10-15 | 2013-05-23 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
US8535912B2 (en) | 2009-10-15 | 2013-09-17 | Genentech, Inc. | Chimeric fibroblast growth factors with altered receptor specificity |
PL2488873T3 (en) | 2009-10-16 | 2016-01-29 | Novartis Ag | Biomarkers of tumor pharmacodynamic response |
JP5889794B2 (en) | 2009-10-19 | 2016-03-22 | ジェネンテック, インコーポレイテッド | Regulation of hepatocyte growth factor activator |
NZ599337A (en) | 2009-10-22 | 2013-05-31 | Genentech Inc | Anti-hepsin antibodies and methods using same |
BR112012009409A2 (en) | 2009-10-22 | 2017-02-21 | Genentech Inc | method of identifying an inhibitory substance, antagonist molecule, isolated nucleic acid, vector, host cell, method of making the molecule, composition, article of manufacture, method of inhibiting a biological activity, method of treating a pathological condition, method for detect msp in a sample and method to detect hepsin in a sample |
WO2011056502A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Bone morphogenetic protein receptor type ii compositions and methods of use |
WO2011056497A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Activin receptor type iib compositions and methods of use |
KR101436219B1 (en) | 2009-10-26 | 2014-09-01 | 에프. 호프만-라 로슈 아게 | Method for the production of a glycosylated immunoglobulin |
WO2011056494A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Activin receptor-like kinase-1 antagonist and vegfr3 antagonist combinations |
EP2325185A1 (en) | 2009-10-28 | 2011-05-25 | GPC Biotech AG | Plk inhibitor |
UY32979A (en) * | 2009-10-28 | 2011-02-28 | Abbott Lab | IMMUNOGLOBULINS WITH DUAL VARIABLE DOMAIN AND USES OF THE SAME |
CN105567699A (en) | 2009-10-30 | 2016-05-11 | 诺维信生物制药丹麦公司 | Albumin variants |
EP2496944A2 (en) | 2009-11-05 | 2012-09-12 | Novartis AG | Biomarkers predictive of progression of fibrosis |
RU2585488C2 (en) | 2009-11-05 | 2016-05-27 | Дженентек, Инк. | Methods and composition for secretion of heterologous polypeptides |
US9260517B2 (en) | 2009-11-17 | 2016-02-16 | Musc Foundation For Research Development | Human monoclonal antibodies to human nucleolin |
AR079217A1 (en) | 2009-11-30 | 2012-01-04 | Genentech Inc | COMPOSITIONS AND METHODS FOR DIAGNOSIS AND TUMOR TREATMENT |
TW201802091A (en) | 2009-12-01 | 2018-01-16 | 艾伯維有限公司 | Novel tricyclic compounds |
PE20130005A1 (en) | 2009-12-01 | 2013-02-16 | Abbvie Inc | NEW TRICYCLIC COMPOUNDS |
US11377485B2 (en) | 2009-12-02 | 2022-07-05 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
US10087236B2 (en) | 2009-12-02 | 2018-10-02 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
EP2506881B1 (en) | 2009-12-02 | 2024-03-06 | Immunomedics, Inc. | Combining radioimmunotherapy and antibody-drug conjugates for improved cancer therapy |
EP2507381A4 (en) | 2009-12-04 | 2016-07-20 | Hoffmann La Roche | Multispecific antibodies, antibody analogs, compositions, and methods |
ES2722300T3 (en) | 2009-12-10 | 2019-08-09 | Hoffmann La Roche | Antibodies that preferentially bind to extracellular domain 4 of CSF1R and its use |
TWI505836B (en) | 2009-12-11 | 2015-11-01 | Genentech Inc | Anti-vegf-c antibodies and methods using same |
KR101989628B1 (en) | 2009-12-21 | 2019-06-14 | 제넨테크, 인크. | Antibody formulation |
CA2784610C (en) | 2009-12-23 | 2020-07-14 | Avipep Pty Ltd | Immuno-conjugates and methods for producing them |
SI2516465T1 (en) | 2009-12-23 | 2016-08-31 | F. Hoffmann-La Roche Ag | Anti-bv8 antibodies and uses thereof |
EP3450459B1 (en) | 2009-12-28 | 2021-05-26 | OncoTherapy Science, Inc. | Anti-cdh3 antibodies and uses thereof |
US20110159588A1 (en) | 2009-12-30 | 2011-06-30 | Kui Lin | Methods for Modulating a PDGF-AA Mediated Biological Response |
AU2011203879A1 (en) | 2010-01-11 | 2012-08-02 | Alexion Pharmaceuticals, Inc. | Biomarkers of immunomodulatory effects in humans treated with anti-CD200 antibodies |
US20120288499A1 (en) | 2010-01-15 | 2012-11-15 | Armand Bensussan | Methods for diagnosis and treatment of cutaneous t cell lymphomas |
WO2011097527A2 (en) | 2010-02-04 | 2011-08-11 | Xencor, Inc. | Immunoprotection of therapeutic moieties using enhanced fc regions |
MX2012009318A (en) | 2010-02-10 | 2012-09-07 | Novartis Ag | Methods and compounds for muscle growth. |
TW201129383A (en) * | 2010-02-10 | 2011-09-01 | Immunogen Inc | CD20 antibodies and uses thereof |
NZ601580A (en) | 2010-02-11 | 2014-11-28 | Alexion Pharma Inc | Therapeutic methods using anti-cd200 antibodies |
JP5981853B2 (en) | 2010-02-18 | 2016-08-31 | ジェネンテック, インコーポレイテッド | Neuregulin antagonists and their use in the treatment of cancer |
AU2011218243A1 (en) | 2010-02-18 | 2012-10-04 | Bristol-Myers Squibb Company | Fibronectin based scaffold domain proteins that bind IL-23 |
JP5972176B2 (en) | 2010-02-23 | 2016-08-17 | サノフイ | Anti-alpha2 integrin antibodies and uses thereof |
AU2011221229B2 (en) | 2010-02-23 | 2015-06-18 | F. Hoffmann-La Roche Ag | Anti-angiogenesis therapy for the treatment of ovarian cancer |
MX2012009215A (en) | 2010-02-23 | 2012-11-23 | Genentech Inc | Compositions and methods for the diagnosis and treatment of tumor. |
CA2789076C (en) | 2010-03-05 | 2017-11-21 | F. Hoffmann-La Roche Ag | Antibodies against human colony stimulating factor-1 receptor and uses thereof |
BR112012022046A2 (en) | 2010-03-05 | 2017-02-14 | F Hoffamann-La Roche Ag | "antibody, pharmaceutical composition, nucleic acid, expression vectors, host cell and method for producing a recombinant antibody". |
NZ602040A (en) | 2010-03-24 | 2014-12-24 | Genentech Inc | Anti-lrp6 antibodies |
TW201138821A (en) | 2010-03-26 | 2011-11-16 | Roche Glycart Ag | Bispecific antibodies |
WO2011120135A1 (en) | 2010-03-29 | 2011-10-06 | Zymeworks, Inc. | Antibodies with enhanced or suppressed effector function |
HUE038788T2 (en) | 2010-03-31 | 2018-11-28 | Boehringer Ingelheim Int | Anti-CD40 antibodies |
EP2374816B1 (en) | 2010-04-07 | 2016-09-28 | Agency For Science, Technology And Research | Binding molecules against Chikungunya virus and uses thereof |
CN106977608A (en) | 2010-04-09 | 2017-07-25 | 阿尔布麦狄克斯公司 | Albumin derivant and variant |
WO2011130332A1 (en) | 2010-04-12 | 2011-10-20 | Academia Sinica | Glycan arrays for high throughput screening of viruses |
US8420098B2 (en) | 2010-04-13 | 2013-04-16 | Bristol-Myers Squibb Company | Fibronectin based scaffold domain proteins that bind to PCSK9 |
WO2011133931A1 (en) | 2010-04-22 | 2011-10-27 | Genentech, Inc. | Use of il-27 antagonists for treating inflammatory bowel disease |
ES2617777T5 (en) | 2010-04-23 | 2022-10-13 | Hoffmann La Roche | Production of heteromultimeric proteins |
MA34291B1 (en) | 2010-05-03 | 2013-06-01 | Genentech Inc | COMPOSITIONS AND METHODS FOR DIAGNOSING AND TREATING A TUMOR |
TW201138808A (en) | 2010-05-03 | 2011-11-16 | Bristol Myers Squibb Co | Serum albumin binding molecules |
MX2012012441A (en) | 2010-05-04 | 2013-02-26 | Merrimack Pharmaceuticals Inc | Antibodies against epidermal growth factor receptor (egfr) and uses thereof. |
WO2011140151A1 (en) | 2010-05-04 | 2011-11-10 | Dyax Corp. | Antibodies against epidermal growth factor receptor (egfr) |
WO2011146568A1 (en) | 2010-05-19 | 2011-11-24 | Genentech, Inc. | Predicting response to a her inhibitor |
ES2637613T5 (en) | 2010-05-25 | 2022-07-20 | Hoffmann La Roche | Polypeptide purification procedures |
ES2573108T3 (en) | 2010-05-26 | 2016-06-06 | Bristol-Myers Squibb Company | Fibronectin-based framework proteins that have improved stability |
JP2013534515A (en) | 2010-06-01 | 2013-09-05 | モナシュ ユニバーシティ | Antibody to unprocessed receptor tyrosine kinase c-MET |
EP3957653A1 (en) | 2010-06-02 | 2022-02-23 | Dana Farber Cancer Institute, Inc. | Humanized monoclonal antibodies and methods of use |
WO2011153243A2 (en) | 2010-06-02 | 2011-12-08 | Genentech, Inc. | Anti-angiogenesis therapy for treating gastric cancer |
BR112012029866A2 (en) | 2010-06-03 | 2017-03-07 | Genentech Inc | method for determining the presence of a steap-1 protein |
CA3220104A1 (en) | 2010-06-08 | 2011-12-15 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
RU2577986C2 (en) | 2010-06-18 | 2016-03-20 | Дженентек, Инк. | Antibodies against axl and their application |
NZ603581A (en) | 2010-06-19 | 2015-05-29 | Sloan Kettering Inst Cancer | Anti-gd2 antibodies |
WO2011161119A1 (en) | 2010-06-22 | 2011-12-29 | F. Hoffmann-La Roche Ag | Antibodies against insulin-like growth factor i receptor and uses thereof |
WO2011161189A1 (en) | 2010-06-24 | 2011-12-29 | F. Hoffmann-La Roche Ag | Anti-hepsin antibodies and methods of use |
WO2012010582A1 (en) | 2010-07-21 | 2012-01-26 | Roche Glycart Ag | Anti-cxcr5 antibodies and methods of use |
WO2012012750A1 (en) | 2010-07-23 | 2012-01-26 | Trustees Of Boston University | ANTI-DEsupR INHIBITORS AS THERAPEUTICS FOR INHIBITION OF PATHOLOGICAL ANGIOGENESIS AND TUMOR CELL INVASIVENESS AND FOR MOLECULAR IMAGING AND TARGETED DELIVERY |
CN103153341B (en) | 2010-08-03 | 2015-05-27 | 霍夫曼-拉罗奇有限公司 | Chronic lymphocytic leukemia (Cll) biomarkers |
KR20130100118A (en) | 2010-08-03 | 2013-09-09 | 아비에 인코포레이티드 | Dual variable domain immunoglobulins and uses therof |
EP3578205A1 (en) | 2010-08-06 | 2019-12-11 | ModernaTX, Inc. | A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof |
JP2013540701A (en) | 2010-08-12 | 2013-11-07 | セラクローン サイエンシーズ, インコーポレイテッド | Anti-hemagglutinin antibody composition and method of use thereof |
BR112013003279A2 (en) | 2010-08-13 | 2016-06-14 | Genentech In | "Methods for treating a disease, method for neutralizing or blocking il-1ß and / or il-18 activity, antibody, uses of an antibody and uses of a monoclonal antibody" |
BR112013002444A2 (en) | 2010-08-13 | 2016-05-24 | Roche Glycart Ag | isolated antibody, polynucleotide and polypeptide, composition, vector, host cell, antibody conjugate, pharmaceutical formulation, use of the antibody, methods of producing an antibody, treating an individual, inducing cell lysis of a tumor cell and diagnosing a disease in an individual |
SG187746A1 (en) | 2010-08-13 | 2013-03-28 | Roche Glycart Ag | Anti-fap antibodies and methods of use |
WO2012025530A1 (en) | 2010-08-24 | 2012-03-01 | F. Hoffmann-La Roche Ag | Bispecific antibodies comprising a disulfide stabilized - fv fragment |
EP2444484B1 (en) | 2010-08-25 | 2019-02-06 | Order-made Medical Research Inc. | Method for producing antibodies using cancer cells |
CA2809433A1 (en) | 2010-08-26 | 2012-03-01 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
SG10201506782XA (en) | 2010-08-27 | 2015-10-29 | Stem Centrx Inc | Notum protein modulators and methods of use |
SG10201408229WA (en) | 2010-08-31 | 2015-02-27 | Genentech Inc | Biomarkers and methods of treatment |
PT3556396T (en) | 2010-08-31 | 2022-07-04 | Scripps Research Inst | Human immunodeficiency virus (hiv)-neutralizing antibodies |
WO2012030512A1 (en) | 2010-09-03 | 2012-03-08 | Percivia Llc. | Flow-through protein purification process |
CN106620693A (en) | 2010-09-03 | 2017-05-10 | 艾伯维施特姆森特克斯有限责任公司 | Novel modulators and methods of use |
PT2621526T (en) | 2010-09-29 | 2018-08-02 | Seattle Genetics Inc | Antibody drug conjugates (adc) that bind to 191p4d12 proteins |
US20120237975A1 (en) | 2010-10-01 | 2012-09-20 | Jason Schrum | Engineered nucleic acids and methods of use thereof |
WO2012047968A2 (en) | 2010-10-05 | 2012-04-12 | Genentech, Inc. | Mutant smoothened and methods of using the same |
CA2814026C (en) | 2010-10-08 | 2017-07-11 | Shanghai Kexin Biotech Co., Ltd. | Moesin fragments associated with aplastic anemia |
CA2814023C (en) | 2010-10-08 | 2018-01-16 | Shanghai Kexin Biotech Co., Ltd. | Moesin fragments and uses thereof |
JP6080763B2 (en) | 2010-10-08 | 2017-02-15 | シャンハイ クーシン バイオテック カンパニー,リミテッド | Moesin modulator and use thereof |
WO2012045279A1 (en) | 2010-10-08 | 2012-04-12 | Shanghai Kexin Biotech Co., Ltd. | Moesin fragments associated with immune thrombocytopenia |
US9345765B2 (en) | 2010-10-08 | 2016-05-24 | Shanghai Kexin Biotech Co., Ltd. | Diagnostic and therapeutic uses of moesin fragments |
EA030436B1 (en) | 2010-11-04 | 2018-08-31 | Бёрингер Ингельхайм Интернациональ Гмбх | ANTI-IL-23p19 ANTIBODIES OR ANTIGEN-BINDING FRAGMENTS THEREOF, USE THEREOF, PHARMACEUTICAL COMPOSITIONS COMPRISING THESE ANTIBODIES, METHOD FOR PRODUCING SAME, ISOLATED POLYNUCLEOTIDES, EXPRESSION VECTORS AND CELLS FOR PRODUCING ANTIBODIES |
EP3351559A3 (en) | 2010-11-08 | 2018-10-31 | F. Hoffmann-La Roche AG | Subcutaneously administered anti-il-6 receptor antibody |
WO2012064836A1 (en) | 2010-11-10 | 2012-05-18 | Genentech, Inc. | Methods and compositions for neural disease immunotherapy |
RU2013127625A (en) | 2010-11-18 | 2014-12-27 | Зе Дженерал Хоспитал Корпорейшен | NEW COMPOSITIONS AND APPLICATIONS OF ANTIHYPERTENSIVE MEDICINES FOR CANCER THERAPY |
EP2648748A1 (en) | 2010-12-08 | 2013-10-16 | Stem Centrx, Inc. | Novel modulators and methods of use |
AU2011343570B2 (en) | 2010-12-16 | 2016-11-03 | Genentech, Inc. | Diagnosis and treatments relating to TH2 inhibition |
MX345519B (en) | 2010-12-20 | 2017-02-01 | Genentech Inc | Anti-mesothelin antibodies and immunoconjugates. |
MA34818B1 (en) | 2010-12-22 | 2014-01-02 | Genentech Inc | ANTI-PCSK9 ANTIBODIES AND METHODS OF USE |
JP2014504587A (en) | 2010-12-22 | 2014-02-24 | ブリストル−マイヤーズ スクイブ カンパニー | Fibronectin-based scaffold domain protein that binds to IL-23 |
JP6147670B2 (en) | 2010-12-22 | 2017-06-14 | テバ・ファーマシューティカルズ・オーストラリア・ピーティワイ・リミテッド | Modified antibodies with improved half-life |
SG191153A1 (en) | 2010-12-23 | 2013-07-31 | Hoffmann La Roche | Polypeptide-polynucleotide-complex and its use in targeted effector moiety delivery |
WO2012092539A2 (en) | 2010-12-31 | 2012-07-05 | Takeda Pharmaceutical Company Limited | Antibodies to dll4 and uses thereof |
WO2012097313A2 (en) | 2011-01-14 | 2012-07-19 | The Regents Of The University Of California | Therapeutic antibodies against ror-1 protein and methods for use of same |
CA2825064C (en) | 2011-02-04 | 2022-08-30 | Genentech, Inc. | Fc variants and methods for their production |
US10689447B2 (en) | 2011-02-04 | 2020-06-23 | Genentech, Inc. | Fc variants and methods for their production |
AU2012217867A1 (en) | 2011-02-14 | 2013-09-05 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
SA112330278B1 (en) | 2011-02-18 | 2015-10-09 | ستيم سينتركس، انك. | Novel modulators and methods of use |
CA2827759C (en) | 2011-03-10 | 2018-10-16 | Omeros Corporation | Generation of anti-fn14 monoclonal antibodies by ex-vivo accelerated antibody evolution |
WO2012122528A1 (en) | 2011-03-10 | 2012-09-13 | Hco Antibody, Inc. | Bispecific three-chain antibody-like molecules |
EP2685968A1 (en) | 2011-03-15 | 2014-01-22 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
TWI622597B (en) | 2011-03-28 | 2018-05-01 | 賽諾菲公司 | Dual variable region antibody-like binding proteins having cross-over binding region orientation |
PT2691417T (en) | 2011-03-29 | 2018-10-31 | Roche Glycart Ag | Antibody fc variants |
EP2691101A2 (en) | 2011-03-31 | 2014-02-05 | Moderna Therapeutics, Inc. | Delivery and formulation of engineered nucleic acids |
JP2014516511A (en) | 2011-04-07 | 2014-07-17 | ジェネンテック, インコーポレイテッド | Anti-FGFR4 antibody and method of use |
HUE033008T2 (en) | 2011-04-13 | 2017-11-28 | Bristol Myers Squibb Co | Fc fusion proteins comprising novel linkers or arrangements |
JP2014514313A (en) | 2011-04-20 | 2014-06-19 | ロシュ グリクアート アクチェンゲゼルシャフト | Methods and constructs for pH-dependent passage of the blood brain barrier |
WO2012142662A1 (en) | 2011-04-21 | 2012-10-26 | Garvan Institute Of Medical Research | Modified variable domain molecules and methods for producing and using them b |
WO2012154983A2 (en) | 2011-05-10 | 2012-11-15 | Biocare Medical, Llc | Systems and methods for anti-pax8 antibodies |
CN103842383B (en) | 2011-05-16 | 2017-11-03 | 健能隆医药技术(上海)有限公司 | Polyspecific FAB fusion proteins and its application method |
WO2012158704A1 (en) | 2011-05-16 | 2012-11-22 | Genentech, Inc. | Fgfr1 agonists and methods of use |
US20140107321A1 (en) | 2011-05-26 | 2014-04-17 | Dr. Reddy's Laboratories Limited | Purification of antibodies |
SG10201902706VA (en) | 2011-06-03 | 2019-04-29 | Xoma Technology Ltd | Antibodies specific for tgf-beta |
US8691231B2 (en) | 2011-06-03 | 2014-04-08 | Merrimack Pharmaceuticals, Inc. | Methods of treatment of tumors expressing predominantly high affinity EGFR ligands or tumors expressing predominantly low affinity EGFR ligands with monoclonal and oligoclonal anti-EGFR antibodies |
DK2718322T3 (en) | 2011-06-06 | 2018-12-03 | Novo Nordisk As | THERAPEUTIC ANTIBODIES |
RU2011122942A (en) | 2011-06-08 | 2012-12-20 | Общество С Ограниченной Ответственностью "Асинэкс Медхим" | NEW KINAZ INHIBITORS |
EP2537933A1 (en) | 2011-06-24 | 2012-12-26 | Institut National de la Santé et de la Recherche Médicale (INSERM) | An IL-15 and IL-15Ralpha sushi domain based immunocytokines |
JP2014518080A (en) | 2011-06-27 | 2014-07-28 | バルネバ | Cell screening method |
WO2013003680A1 (en) | 2011-06-30 | 2013-01-03 | Genentech, Inc. | Anti-c-met antibody formulations |
JP2013040160A (en) | 2011-07-01 | 2013-02-28 | Genentech Inc | Use of anti-cd83 agonist antibody for treating autoimmune disease |
RU2013156435A (en) * | 2011-07-06 | 2015-08-20 | МорфоСис АГ | THERAPEUTIC COMBINATIONS ANTI-CD20 AND ANTI-GM-CSF ANTIBODIES AND THEIR APPLICATIONS |
US9738707B2 (en) | 2011-07-15 | 2017-08-22 | Biogen Ma Inc. | Heterodimeric Fc regions, binding molecules comprising same, and methods relating thereto |
US20130022551A1 (en) | 2011-07-22 | 2013-01-24 | Trustees Of Boston University | DEspR ANTAGONISTS AND AGONISTS AS THERAPEUTICS |
AR087364A1 (en) * | 2011-07-29 | 2014-03-19 | Pf Medicament | ANTI-CXCR4 ANTIBODY AND ITS USE FOR CANCERES DETECTION AND DIANOSTIC |
JP5944994B2 (en) | 2011-08-12 | 2016-07-05 | オメロス コーポレーション | Anti-FZD10 monoclonal antibodies and methods for their use |
CN103890008A (en) | 2011-08-17 | 2014-06-25 | 霍夫曼-拉罗奇有限公司 | Inhibition of angiogenesis in refractory tumors |
MX2014001766A (en) | 2011-08-17 | 2014-05-01 | Genentech Inc | Neuregulin antibodies and uses thereof. |
RU2617970C2 (en) | 2011-08-23 | 2017-04-28 | Рош Гликарт Аг | ANTIBODIES WITHOUT Fc-FRAGMENT INCLUDING TWO FAB-FRAGMENT AND METHODS OF APPLICATION |
KR101870555B1 (en) | 2011-08-23 | 2018-06-22 | 로슈 글리카트 아게 | Bispecific antibodies specific for t-cell activating antigens and a tumor antigen and methods of use |
US9309306B2 (en) | 2011-08-23 | 2016-04-12 | Roche Glycart Ag | Anti-MCSP antibodies |
US8822651B2 (en) | 2011-08-30 | 2014-09-02 | Theraclone Sciences, Inc. | Human rhinovirus (HRV) antibodies |
US20130058947A1 (en) | 2011-09-02 | 2013-03-07 | Stem Centrx, Inc | Novel Modulators and Methods of Use |
WO2013035345A2 (en) | 2011-09-09 | 2013-03-14 | Osaka University | Dengue-virus serotype neutralizing antibodies |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
KR20140068062A (en) | 2011-09-15 | 2014-06-05 | 제넨테크, 인크. | Methods of promoting differentiation |
MX2014002990A (en) | 2011-09-19 | 2014-05-21 | Genentech Inc | Combination treatments comprising c-met antagonists and b-raf antagonists. |
MX2014002996A (en) | 2011-09-23 | 2014-05-28 | Roche Glycart Ag | Bispecific anti-egfr/anti igf-1r antibodies. |
WO2013049362A2 (en) | 2011-09-27 | 2013-04-04 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Method of treating multiple sclerosis by intrathecal depletion of b cells and biomarkers to select patients with progressive multiple sclerosis |
CA2850624A1 (en) | 2011-10-03 | 2013-04-11 | Moderna Therapeutics, Inc. | Modified nucleosides, nucleotides, and nucleic acids, and uses thereof |
US9663573B2 (en) | 2011-10-05 | 2017-05-30 | Genentech, Inc. | Methods of treating liver conditions using Notch2 antagonists |
EP3418306B1 (en) | 2011-10-11 | 2023-12-06 | F. Hoffmann-La Roche AG | Improved assembly of bispecific antibodies |
KR102102862B1 (en) | 2011-10-14 | 2020-04-22 | 제넨테크, 인크. | ANTI-HtrA1 ANTIBODIES AND METHODS OF USE |
KR20140084164A (en) | 2011-10-15 | 2014-07-04 | 제넨테크, 인크. | Scd1 antagonists for treating cancer |
CA2852800A1 (en) | 2011-10-21 | 2013-04-25 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | A m-dc8+ monocyte depleting agent for the prevention or the treatment of a condition associated with a chronic hyperactivation of the immune system |
EP3378489A1 (en) | 2011-10-26 | 2018-09-26 | Elanco Tiergesundheit AG | Monoclonal antibodies and methods of use |
AU2012328980A1 (en) | 2011-10-28 | 2014-04-24 | Genentech, Inc. | Therapeutic combinations and methods of treating melanoma |
EP3559049A4 (en) | 2011-10-28 | 2019-12-04 | Teva Pharmaceuticals Australia Pty Ltd | Polypeptide constructs and uses thereof |
US9522951B2 (en) | 2011-10-31 | 2016-12-20 | Bristol-Myers Squibb Company | Fibronectin binding domains with reduced immunogenicity |
JP6356607B2 (en) | 2011-11-02 | 2018-07-11 | ジェネンテック, インコーポレイテッド | Overload / elution chromatography |
CN112812183A (en) | 2011-11-16 | 2021-05-18 | 勃林格殷格翰国际有限公司 | anti-IL-36R antibodies |
WO2013075066A2 (en) | 2011-11-18 | 2013-05-23 | Eleven Biotherapeutics, Inc. | Proteins with improved half-life and other properties |
BR112014012005A2 (en) | 2011-11-21 | 2017-12-19 | Genentech Inc | compositions, methods, pharmaceutical formulation and article |
BR112014013205A2 (en) | 2011-12-01 | 2020-10-27 | Protevobio, Inc. | fusion protein, its use and production method, pharmaceutical composition, nucleic acid, and kit |
CA2853138A1 (en) | 2011-12-05 | 2013-06-13 | Immunomedics, Inc. | Therapeutic use of anti-cd22 antibodies for inducing trogocytosis |
US9757458B2 (en) | 2011-12-05 | 2017-09-12 | Immunomedics, Inc. | Crosslinking of CD22 by epratuzumab triggers BCR signaling and caspase-dependent apoptosis in hematopoietic cancer cells |
CN104159921B (en) | 2011-12-15 | 2018-05-04 | 霍夫曼-拉罗奇有限公司 | Antibody for people CSF-1R and application thereof |
KR20140102759A (en) | 2011-12-16 | 2014-08-22 | 모더나 세라퓨틱스, 인코포레이티드 | Modified nucleoside, nucleotide, and nucleic acid compositions |
US20130195851A1 (en) | 2011-12-23 | 2013-08-01 | Genentech, Inc. | Articles of manufacture and methods for co-administration of antibodies |
WO2013101771A2 (en) | 2011-12-30 | 2013-07-04 | Genentech, Inc. | Compositions and method for treating autoimmune diseases |
TW201333035A (en) | 2011-12-30 | 2013-08-16 | Abbvie Inc | Dual specific binding proteins directed against IL-13 and/or IL-17 |
WO2013106489A1 (en) | 2012-01-09 | 2013-07-18 | The Scripps Research Institute | Humanized antibodies with ultralong cdr3s |
WO2013106485A2 (en) | 2012-01-09 | 2013-07-18 | The Scripps Research Institute | Ultralong complementarity determining regions and uses thereof |
JP6242813B2 (en) | 2012-01-18 | 2017-12-06 | ジェネンテック, インコーポレイテッド | Anti-LRP5 antibody and method of use |
CN104168920A (en) | 2012-01-18 | 2014-11-26 | 霍夫曼-拉罗奇有限公司 | Methods of using FGF19 modulators |
WO2013116287A1 (en) | 2012-01-31 | 2013-08-08 | Genentech, Inc. | Anti-ig-e m1' antibodies and methods using same |
WO2013116686A1 (en) | 2012-02-02 | 2013-08-08 | Massachusetts Institute Of Technology | Methods and products related to targeted cancer therapy |
SI2812443T1 (en) | 2012-02-06 | 2019-10-30 | Inhibrx Inc | Cd47 antibodies and methods of use thereof |
KR20140127854A (en) | 2012-02-10 | 2014-11-04 | 제넨테크, 인크. | Single-chain antibodies and other heteromultimers |
BR112014019741A2 (en) | 2012-02-11 | 2020-12-22 | Genentech, Inc | USES OF AN ANTAGONIST OF THE WNT VIA, USE OF ANTI-CANCER THERAPY, METHOD OF IDENTIFICATION OF AN INDIVIDUAL WITH CANCER, METHODS FOR PREVENTING, METHOD OF INHIBITION OF A CANCER CELL PROLIFERATION, USE OF AN ANGONIST ANTAGONIST TRANSLOCATION OF ISOLATED R-SPONDINA |
JP6152120B2 (en) | 2012-02-15 | 2017-06-21 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Affinity chromatography based on Fc receptors |
JP6401060B2 (en) | 2012-02-24 | 2018-10-03 | アッヴィ・ステムセントルクス・エル・エル・シー | Anti-SEZ6 antibody and method of use |
DK2817338T3 (en) | 2012-02-24 | 2017-10-23 | Abbvie Stemcentrx Llc | DLL3 modulators and methods of use |
BR112014018679A2 (en) | 2012-03-16 | 2017-07-04 | Novozymes Biopharma Dk As | albumin variants |
HUE037613T2 (en) | 2012-03-29 | 2018-09-28 | Novimmune Sa | Anti-tlr4 antibodies and uses thereof |
US10316103B1 (en) | 2012-03-30 | 2019-06-11 | Biocare Medical, Llc | Systems and methods for anti-Uroplakin III antibodies |
AR090549A1 (en) | 2012-03-30 | 2014-11-19 | Genentech Inc | ANTI-LGR5 AND IMMUNOCATE PLAYERS |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
US9878056B2 (en) | 2012-04-02 | 2018-01-30 | Modernatx, Inc. | Modified polynucleotides for the production of cosmetic proteins and peptides |
CA2868398A1 (en) | 2012-04-02 | 2013-10-10 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of cosmetic proteins and peptides |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US10130714B2 (en) | 2012-04-14 | 2018-11-20 | Academia Sinica | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
WO2013163631A2 (en) | 2012-04-27 | 2013-10-31 | Cytomx Therapeutics, Inc. | Activatable antibodies that bind epidermal growth factor receptor and methods of use thereof |
RU2014148162A (en) | 2012-05-01 | 2016-06-20 | Дженентек, Инк. | ANTI-PMEL17 ANTIBODIES AND THEIR IMMUNO CONJUGATES |
EP2844737B1 (en) | 2012-05-02 | 2018-03-21 | Life Technologies Corporation | High yield transient expression in mammalian cells using unique pairing of high density growth and transfection medium and expression enhancers |
CN109206516A (en) | 2012-05-03 | 2019-01-15 | 勃林格殷格翰国际有限公司 | Anti-il-23 p 19 antibodies |
AU2013256010B2 (en) | 2012-05-04 | 2018-01-04 | Dana-Farber Cancer Institute, Inc. | Affinity matured anti-CCR4 humanized monoclonal antibodies and methods of use |
WO2013170191A1 (en) | 2012-05-11 | 2013-11-14 | Genentech, Inc. | Methods of using antagonists of nad biosynthesis from nicotinamide |
CN104364266A (en) | 2012-06-15 | 2015-02-18 | 霍夫曼-拉罗奇有限公司 | Anti-PCSK9 antibodies, formulations, dosing, and methods of use |
RU2015100656A (en) | 2012-06-27 | 2016-08-20 | Ф. Хоффманн-Ля Рош Аг | METHOD FOR PRODUCING ANTIBODY FC-FRAGMENT CONNECTING, INCLUDING AT LEAST ONE CONNECTING GROUP, WHICH SPECIALLY RELATED TO THE TARGET, AND THEIR APPLICATION |
BR112014029888A2 (en) | 2012-06-27 | 2020-05-12 | Hoffmann La Roche | METHODS OF PRODUCTION OF AN ANTIBODY, DETERMINATION OF A COMBINATION OF BINDING SITES AND TREATMENT OF AN INDIVIDUAL WITH CANCER, PHARMACEUTICAL FORMULATION, ANTIBODY AND USE OF AN ANTIBODY |
WO2014001324A1 (en) | 2012-06-27 | 2014-01-03 | Hoffmann-La Roche Ag | Method for selection and production of tailor-made highly selective and multi-specific targeting entities containing at least two different binding entities and uses thereof |
ES2604012T3 (en) | 2012-07-04 | 2017-03-02 | F. Hoffmann-La Roche Ag | Covalently bound antigen-antibody conjugates |
MX353951B (en) | 2012-07-04 | 2018-02-07 | Hoffmann La Roche | Anti-theophylline antibodies and methods of use. |
CA2872192A1 (en) | 2012-07-04 | 2014-01-09 | F. Hoffmann-La Roche Ag | Anti-biotin antibodies and methods of use |
CA2874904A1 (en) | 2012-07-09 | 2014-01-16 | Genentech, Inc. | Immunoconjugates comprising anti-cd22 antibodies |
SG11201500096YA (en) | 2012-07-09 | 2015-02-27 | Genentech Inc | Immunoconjugates comprising anti - cd79b antibodies |
TW201408698A (en) | 2012-07-09 | 2014-03-01 | Genentech Inc | Anti-CD79b antibodies and immunoconjugates |
SG11201500087VA (en) | 2012-07-09 | 2015-02-27 | Genentech Inc | Immunoconjugates comprising anti-cd22 antibodies |
HUE056217T2 (en) | 2012-07-13 | 2022-02-28 | Roche Glycart Ag | Bispecific anti-vegf/anti-ang-2 antibodies and their use in the treatment of ocular vascular diseases |
WO2014022759A1 (en) | 2012-08-03 | 2014-02-06 | Dana-Farber Cancer Institute, Inc. | Agents that modulate immune cell activation and methods of use thereof |
US9315567B2 (en) | 2012-08-14 | 2016-04-19 | Ibc Pharmaceuticals, Inc. | T-cell redirecting bispecific antibodies for treatment of disease |
AU2013306098A1 (en) | 2012-08-18 | 2015-02-12 | Academia Sinica | Cell-permeable probes for identification and imaging of sialidases |
SG10201701424QA (en) | 2012-08-23 | 2017-04-27 | Agensys Inc | Antibody drug conjugates (adc) that bind to 158p1d7 proteins |
MY172863A (en) | 2012-09-13 | 2019-12-13 | Bristol Myers Squibb Co | Fibronectin based scaffold domain proteins that bind to myostatin |
US10393733B2 (en) | 2012-09-19 | 2019-08-27 | Dana-Farber Cancer Institute, Inc. | Dynamic BH3 profiling |
JOP20200236A1 (en) | 2012-09-21 | 2017-06-16 | Regeneron Pharma | Anti-cd3 antibodies, bispecific antigen-binding molecules that bind cd3 and cd20, and uses thereof |
EP2900265B1 (en) | 2012-09-27 | 2018-05-30 | Biocare Medical, LLC | Anti-uroplakin ii antibodies systems and methods |
EP2903641A2 (en) | 2012-10-04 | 2015-08-12 | Dana-Farber Cancer Institute, Inc. | Human monoclonal anti-pd-l1 antibodies and methods of use |
WO2014056783A1 (en) | 2012-10-08 | 2014-04-17 | Roche Glycart Ag | Fc-free antibodies comprising two fab-fragments and methods of use |
CA2890263C (en) | 2012-11-01 | 2020-03-10 | Abbvie Inc. | Anti-vegf/dll4 dual variable domain immunoglobulins and uses thereof |
CN104797599A (en) | 2012-11-05 | 2015-07-22 | 全药工业株式会社 | Antibody and antibody composition production method |
MX2015005363A (en) | 2012-11-08 | 2015-11-06 | Novozymes Biopharma Dk As | Albumin variants. |
CA2884431A1 (en) | 2012-11-08 | 2014-05-15 | F. Hoffmann-La Roche Ag | Her3 antigen binding proteins binding to the beta-hairpin of her3 |
WO2014078268A2 (en) | 2012-11-13 | 2014-05-22 | Genentech, Inc. | Anti-hemagglutinin antibodies and methods of use |
CN105051528A (en) | 2012-11-15 | 2015-11-11 | 弗·哈夫曼-拉罗切有限公司 | Ionic strength-mediated ph gradient ion exchange chromatography |
WO2014079886A1 (en) | 2012-11-20 | 2014-05-30 | Sanofi | Anti-ceacam5 antibodies and uses thereof |
JP6144355B2 (en) | 2012-11-26 | 2017-06-07 | モデルナティエックス インコーポレイテッドModernaTX,Inc. | Chemically modified mRNA |
JP6392770B2 (en) | 2012-12-03 | 2018-09-19 | ノビミューン エスアー | Anti-CD47 antibody and method of use thereof |
US9107960B2 (en) | 2012-12-13 | 2015-08-18 | Immunimedics, Inc. | Antibody-SN-38 immunoconjugates with a CL2A linker |
US9492566B2 (en) | 2012-12-13 | 2016-11-15 | Immunomedics, Inc. | Antibody-drug conjugates and uses thereof |
US9931417B2 (en) | 2012-12-13 | 2018-04-03 | Immunomedics, Inc. | Antibody-SN-38 immunoconjugates with a CL2A linker |
HRP20220399T1 (en) | 2012-12-13 | 2022-05-13 | Immunomedics, Inc. | Dosages of immunoconjugates of antibodies and sn-38 for improved efficacy and decreased toxicity |
US10206918B2 (en) | 2012-12-13 | 2019-02-19 | Immunomedics, Inc. | Efficacy of anti-HLA-DR antiboddy drug conjugate IMMU-140 (hL243-CL2A-SN-38) in HLA-DR positive cancers |
US10413539B2 (en) | 2012-12-13 | 2019-09-17 | Immunomedics, Inc. | Therapy for metastatic urothelial cancer with the antibody-drug conjugate, sacituzumab govitecan (IMMU-132) |
US10137196B2 (en) | 2012-12-13 | 2018-11-27 | Immunomedics, Inc. | Dosages of immunoconjugates of antibodies and SN-38 for improved efficacy and decreased toxicity |
US10744129B2 (en) | 2012-12-13 | 2020-08-18 | Immunomedics, Inc. | Therapy of small-cell lung cancer (SCLC) with a topoisomerase-I inhibiting antibody-drug conjugate (ADC) targeting Trop-2 |
US10429390B2 (en) | 2012-12-18 | 2019-10-01 | Biocare Medical, Llc | Antibody cocktail systems and methods for classification of histologic subtypes in lung cancer |
EA201690004A1 (en) | 2012-12-27 | 2016-07-29 | Санофи | ANTIBODIES AGAINST LAMP1 AND CONJUGATES ANTIBODIES AND MEDICINES AND THEIR APPLICATION |
WO2014107739A1 (en) | 2013-01-07 | 2014-07-10 | Eleven Biotherapeutics, Inc. | Antibodies against pcsk9 |
WO2014116749A1 (en) | 2013-01-23 | 2014-07-31 | Genentech, Inc. | Anti-hcv antibodies and methods of using thereof |
EP2951206A2 (en) | 2013-02-01 | 2015-12-09 | Bristol-Myers Squibb Company | Fibronectin based scaffold proteins |
KR102276974B1 (en) | 2013-02-06 | 2021-07-13 | 인히브릭스, 인크. | Non-platelet depleting and non-red blood cell depleting cd47 antibodies and methods of use thereof |
MX2015010682A (en) | 2013-02-22 | 2016-05-31 | Stemcentrx Inc | Novel antibody conjugates and uses thereof. |
JP2016509045A (en) | 2013-02-22 | 2016-03-24 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | How to treat cancer and prevent drug resistance |
CA2896259A1 (en) | 2013-02-26 | 2014-09-04 | Roche Glycart Ag | Anti-mcsp antibodies |
JP6445467B2 (en) | 2013-02-28 | 2019-01-09 | バイオケア メディカル, エルエルシー | Anti-P40 antibody system and method |
US9925240B2 (en) | 2013-03-06 | 2018-03-27 | Genentech, Inc. | Methods of treating and preventing cancer drug resistance |
HUE049707T2 (en) | 2013-03-13 | 2020-11-30 | Hoffmann La Roche | Formulations with reduced oxidation |
CN110075293A (en) | 2013-03-13 | 2019-08-02 | 霍夫曼-拉罗奇有限公司 | Aoxidize reduced preparaton |
US10653779B2 (en) | 2013-03-13 | 2020-05-19 | Genentech, Inc. | Formulations with reduced oxidation |
BR112015022210A8 (en) | 2013-03-13 | 2018-01-23 | Genentech Inc | antibody formulations |
AR095398A1 (en) | 2013-03-13 | 2015-10-14 | Genentech Inc | FORMULATIONS WITH REDUCED OXIDATION |
WO2014165093A2 (en) | 2013-03-13 | 2014-10-09 | Bristol-Myers Squibb Company | Fibronectin based scaffold domains linked to serum albumin or a moiety binding thereto |
CA2905070A1 (en) | 2013-03-14 | 2014-09-25 | Genentech, Inc. | Methods of treating cancer and preventing cancer drug resistance |
US9562099B2 (en) | 2013-03-14 | 2017-02-07 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
WO2014159835A1 (en) | 2013-03-14 | 2014-10-02 | Genentech, Inc. | Anti-b7-h4 antibodies and immunoconjugates |
MX2015012872A (en) | 2013-03-15 | 2016-02-03 | Ac Immune Sa | Anti-tau antibodies and methods of use. |
WO2014143739A2 (en) | 2013-03-15 | 2014-09-18 | Biogen Idec Ma Inc. | Anti-alpha v beta 6 antibodies and uses thereof |
KR102207859B1 (en) | 2013-03-15 | 2021-01-27 | 메모리얼 슬로안 케터링 캔서 센터 | High affinity anti-gd2 antibodies |
BR112015021521A2 (en) | 2013-03-15 | 2017-10-10 | Genentech Inc | anti-crth2 antibodies and methods for their use |
AU2014227909C1 (en) | 2013-03-15 | 2021-11-25 | Dana-Farber Cancer Institute, Inc. | Flavivirus neutralizing antibodies and methods of use thereof |
EP2972373B1 (en) | 2013-03-15 | 2019-10-09 | F.Hoffmann-La Roche Ag | Biomarkers and methods of treating pd-1 and pd-l1 related conditions |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
WO2014144466A1 (en) | 2013-03-15 | 2014-09-18 | Biogen Idec Ma Inc. | Anti-alpha v beta 6 antibodies and uses thereof |
WO2014145098A1 (en) | 2013-03-15 | 2014-09-18 | Genentech, Inc. | Cell culture compositions with antioxidants and methods for polypeptide production |
MX2015011899A (en) | 2013-03-15 | 2016-05-05 | Genentech Inc | Methods of treating cancer and preventing cancer drug resistance. |
JP6527132B2 (en) | 2013-03-15 | 2019-06-05 | ジェネンテック, インコーポレイテッド | Compositions and methods for diagnosis and treatment of liver cancer |
US9441035B2 (en) | 2013-03-15 | 2016-09-13 | Genentech, Inc. | Cell culture media and methods of antibody production |
WO2014144280A2 (en) | 2013-03-15 | 2014-09-18 | Abbvie Inc. | DUAL SPECIFIC BINDING PROTEINS DIRECTED AGAINST IL-1β AND / OR IL-17 |
BR112015025347A2 (en) | 2013-04-09 | 2017-07-18 | Boston Biomedical Inc | 2-acetyl naphtho [2-3-b] furan-4,9-dione for use in cancer treatment |
AR095882A1 (en) | 2013-04-22 | 2015-11-18 | Hoffmann La Roche | ANTIBODY COMBINATION THERAPY AGAINST HUMAN CSF-1R WITH A TLR9 AGONIST |
RU2687043C2 (en) | 2013-04-29 | 2019-05-06 | Ф. Хоффманн-Ля Рош Аг | Fc-RECEPTOR BINDING MODIFIED ASYMMETRIC ANTIBODIES AND METHODS OF USE |
EP2992329A1 (en) | 2013-05-03 | 2016-03-09 | Eleven Biotherapeutics, Inc. | Albumin variants binding to fcrn |
EP2999716A2 (en) | 2013-05-20 | 2016-03-30 | F. Hoffmann-La Roche AG | Anti-transferrin receptor antibodies and methods of use |
US9517276B2 (en) | 2013-06-04 | 2016-12-13 | Cytomx Therapeutics, Inc. | Compositions and methods for conjugating activatable antibodies |
US10086054B2 (en) | 2013-06-26 | 2018-10-02 | Academia Sinica | RM2 antigens and use thereof |
EP3013347B1 (en) | 2013-06-27 | 2019-12-11 | Academia Sinica | Glycan conjugates and use thereof |
WO2015006686A1 (en) | 2013-07-12 | 2015-01-15 | Genentech, Inc. | Elucidation of ion exchange chromatography input optimization |
EP3022224A2 (en) | 2013-07-18 | 2016-05-25 | Fabrus, Inc. | Antibodies with ultralong complementarity determining regions |
CN105814074B (en) | 2013-07-18 | 2020-04-21 | 图鲁斯生物科学有限责任公司 | Humanized antibodies with ultralong complementarity determining regions |
US11253606B2 (en) | 2013-07-23 | 2022-02-22 | Immunomedics, Inc. | Combining anti-HLA-DR or anti-Trop-2 antibodies with microtubule inhibitors, PARP inhibitors, Bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer |
HRP20220553T1 (en) | 2013-07-25 | 2022-06-10 | Cytomx Therapeutics Inc. | Multispecific antibodies, multispecific activatable antibodies and methods of using the same |
AU2014297217B2 (en) * | 2013-07-30 | 2020-01-16 | Sbi Biotech Co., Ltd. | Medicament comprising anti-phospholipase D4 antibody |
JP6510518B2 (en) | 2013-08-01 | 2019-05-08 | アジェンシス,インコーポレイテッド | Antibody-drug conjugate (ADC) that binds to the CD37 protein |
US10093978B2 (en) | 2013-08-12 | 2018-10-09 | Genentech, Inc. | Compositions for detecting complement factor H (CFH) and complement factor I (CFI) polymorphisms |
US10077304B2 (en) | 2013-08-14 | 2018-09-18 | The Governing Council Of The University Of Toronto | Antibodies against frizzled receptor |
EP3338793A1 (en) | 2013-08-28 | 2018-06-27 | AbbVie Stemcentrx LLC | Novel sez6 modulators and methods of use |
EP3892294A1 (en) | 2013-08-28 | 2021-10-13 | AbbVie Stemcentrx LLC | Site-specific antibody conjugation methods and compositions |
WO2015035180A1 (en) | 2013-09-05 | 2015-03-12 | Genentech, Inc. | Method for chromatography reuse |
CN105682666B (en) | 2013-09-06 | 2021-06-01 | 中央研究院 | Activation of human iNKT cells using glycolipids |
AR097584A1 (en) | 2013-09-12 | 2016-03-23 | Hoffmann La Roche | ANTIBODY COMBINATION THERAPY AGAINST HUMAN CSF-1R AND ANTIBODIES AGAINST HUMAN PD-L1 |
NZ756749A (en) | 2013-09-13 | 2022-05-27 | Genentech Inc | Methods and compositions comprising purified recombinant polypeptides |
RU2016107435A (en) | 2013-09-13 | 2017-10-18 | Дженентек, Инк. | COMPOSITIONS AND METHODS FOR DETECTING AND QUANTITATIVE DETERMINATION OF THE PROTEIN OF CELLS-OWNERS IN CELL LINES AND RECOMBINANT POLYPEPTIDE PRODUCTS |
CN105518027A (en) | 2013-09-17 | 2016-04-20 | 豪夫迈·罗氏有限公司 | Methods of using anti-LGR5 antibodies |
JP6663852B2 (en) | 2013-09-19 | 2020-03-13 | デイナ ファーバー キャンサー インスティチュート,インコーポレイテッド | BH3 profiling method |
CA3214529A1 (en) | 2013-09-25 | 2015-04-02 | Cytomx Therapeutics, Inc. | Matrix metalloproteinase substrates and other cleavable moieties and methods of use thereof |
EP3049442A4 (en) | 2013-09-26 | 2017-06-28 | Costim Pharmaceuticals Inc. | Methods for treating hematologic cancers |
SG11201602283UA (en) | 2013-09-27 | 2016-04-28 | Genentech Inc | Anti-pdl1 antibody formulations |
EP3052106A4 (en) | 2013-09-30 | 2017-07-19 | ModernaTX, Inc. | Polynucleotides encoding immune modulating polypeptides |
WO2015051320A2 (en) | 2013-10-03 | 2015-04-09 | Biocare Medical, Llc | Anti-sox10 antibody systems and methods |
JP2016538829A (en) | 2013-10-03 | 2016-12-15 | モデルナ セラピューティクス インコーポレイテッドModerna Therapeutics,Inc. | Polynucleotide encoding low density lipoprotein receptor |
MX2016004579A (en) | 2013-10-10 | 2016-12-09 | Beth Israel Deaconess Medical Ct Inc | Tm4sf1 binding proteins and methods of using same. |
MX2016004802A (en) | 2013-10-18 | 2016-07-18 | Genentech Inc | Anti-rsp02 and/or anti-rsp03 antibodies and their uses. |
US9540440B2 (en) | 2013-10-30 | 2017-01-10 | Cytomx Therapeutics, Inc. | Activatable antibodies that bind epidermal growth factor receptor and methods of use thereof |
PE20160724A1 (en) | 2013-11-04 | 2016-08-04 | Glenmark Pharmaceuticals Sa | PRODUCTION OF T-CELL REDIRECTING HETERODIMERIC IMMUNOGLOBULINS |
KR20160072268A (en) | 2013-11-04 | 2016-06-22 | 화이자 인코포레이티드 | Anti-efna4 antibody-drug conjugates |
RU2016122041A (en) | 2013-11-06 | 2017-12-11 | ЭББВИ СТЕМСЕНТРКС ЭлЭлСи | NEW ANTI-CLAUDIN ANTIBODIES AND WAYS OF THEIR APPLICATION |
US20160264648A1 (en) | 2013-11-06 | 2016-09-15 | Osaka University | Antibody having broad neutralization activity against group 1 influenza a viruses |
WO2015070210A1 (en) | 2013-11-11 | 2015-05-14 | Wake Forest University Health Sciences | Epha3 and multi-valent targeting of tumors |
CN113861293A (en) | 2013-12-09 | 2021-12-31 | 爱乐科斯公司 | anti-Siglec-8 antibodies and methods of use thereof |
WO2015089283A1 (en) | 2013-12-11 | 2015-06-18 | Cytomx Therapeutics, Inc. | Antibodies that bind activatable antibodies and methods of use thereof |
MA39095A1 (en) | 2013-12-13 | 2018-08-31 | Genentech Inc | Anti-cd33 antibodies and immunoconjugates |
EP3083692B1 (en) | 2013-12-17 | 2020-02-19 | F.Hoffmann-La Roche Ag | Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies |
CA2934028A1 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
WO2015095410A1 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Methods of treating cancer using pd-1 axis binding antagonists and an anti-cd20 antibody |
TWI728373B (en) | 2013-12-23 | 2021-05-21 | 美商建南德克公司 | Antibodies and methods of use |
EP3089996B1 (en) | 2014-01-03 | 2021-07-28 | F. Hoffmann-La Roche AG | Bispecific anti-hapten/anti-blood brain barrier receptor antibodies, complexes thereof and their use as blood brain barrier shuttles |
BR112016012666A2 (en) | 2014-01-03 | 2017-09-26 | Hoffmann La Roche | conjugate, antibodies, pharmaceutical formulation and uses of conjugate |
JP6521464B2 (en) | 2014-01-03 | 2019-05-29 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Covalently linked polypeptide toxin-antibody conjugates |
WO2016114819A1 (en) | 2015-01-16 | 2016-07-21 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US9982041B2 (en) | 2014-01-16 | 2018-05-29 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US10150818B2 (en) | 2014-01-16 | 2018-12-11 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
WO2015112909A1 (en) | 2014-01-24 | 2015-07-30 | Genentech, Inc. | Methods of using anti-steap1 antibodies and immunoconjugates |
WO2015116902A1 (en) | 2014-01-31 | 2015-08-06 | Genentech, Inc. | G-protein coupled receptors in hedgehog signaling |
WO2016039801A1 (en) | 2014-01-31 | 2016-03-17 | Boehringer Ingelheim International Gmbh | Novel anti-baff antibodies |
AU2015210862B2 (en) | 2014-01-31 | 2020-04-23 | Cytomx Therapeutics, Inc | Matriptase and u-plasminogen activator substrates and other cleavable moieties and methods of use thereof |
WO2015120075A2 (en) | 2014-02-04 | 2015-08-13 | Genentech, Inc. | Mutant smoothened and methods of using the same |
AU2015217271B2 (en) | 2014-02-12 | 2018-10-25 | Genentech, Inc. | Anti-Jagged1 antibodies and methods of use |
BR112016018980A2 (en) | 2014-02-21 | 2017-10-10 | Genentech Inc | method of treating a disorder, multispecific antibody, isolated nucleic acid, host cell, methods of producing an antibody, producing an antibody half or multispecific antibody, and producing a multispecific, immunoconjugate antibody and pharmaceutical formulation |
JP2017514143A (en) | 2014-02-21 | 2017-06-01 | アッヴィ・ステムセントルクス・エル・エル・シー | Anti-DLL3 antibodies and drug conjugates for use in melanoma |
MX2016010683A (en) | 2014-02-21 | 2017-05-11 | Ibc Pharmaceuticals Inc | Disease therapy by inducing immune response to trop-2 expressing cells. |
CN106029098A (en) | 2014-02-25 | 2016-10-12 | 免疫医疗公司 | Humanized RFB4 anti-CD22 antibody |
JP6825909B2 (en) | 2014-02-28 | 2021-02-03 | アラコス インコーポレイテッド | Methods and Compositions for Treating SIGLEC-8 Related Diseases |
CN106103465B (en) | 2014-03-10 | 2021-01-08 | 吉瑞工厂 | Immunoglobulin purification using a precleaning step |
MA39746A (en) | 2014-03-14 | 2021-04-28 | Hoffmann La Roche | HETEROLOGICAL POLYPEPTIDE SECRETION COMPOSITIONS AND ASSOCIATED PROCESSES |
US9738702B2 (en) | 2014-03-14 | 2017-08-22 | Janssen Biotech, Inc. | Antibodies with improved half-life in ferrets |
TWI701042B (en) | 2014-03-19 | 2020-08-11 | 美商再生元醫藥公司 | Methods and antibody compositions for tumor treatment |
AU2015231164B2 (en) | 2014-03-19 | 2020-04-09 | Dana-Farber Cancer Institute, Inc. | Immunogenetic restriction on elicitation of antibodies |
CA2943241C (en) | 2014-03-20 | 2023-09-19 | Bristol-Myers Squibb Company | Serum albumin-binding fibronectin type iii domains |
EP3647322B1 (en) | 2014-03-20 | 2021-10-20 | Bristol-Myers Squibb Company | Stabilized fibronectin based scaffold molecules |
BR112016021383A2 (en) | 2014-03-24 | 2017-10-03 | Genentech Inc | METHOD TO IDENTIFY A PATIENT WITH CANCER WHO IS LIKE OR LESS LIKELY TO RESPOND TO TREATMENT WITH A CMET ANTAGONIST, METHOD TO IDENTIFY A PATIENT WITH PREVIOUSLY TREATED CANCER, METHOD TO DETERMINE THE EXPRESSION OF THE HGF BIOMARKER, ANTI-C-MET ANTAGONIST AND ITS USE, DIAGNOSTIC KIT AND ITS PREPARATION METHOD |
TWI687428B (en) | 2014-03-27 | 2020-03-11 | 中央研究院 | Reactive labelling compounds and uses thereof |
CN103897059B (en) * | 2014-03-27 | 2016-03-23 | 中国人民解放军军事医学科学院生物工程研究所 | The antibody L5H7 of anti-CD20 antigen and application thereof |
WO2015153514A1 (en) | 2014-03-31 | 2015-10-08 | Genentech, Inc. | Combination therapy comprising anti-angiogenesis agents and ox40 binding agonists |
EP3632934A1 (en) | 2014-03-31 | 2020-04-08 | F. Hoffmann-La Roche AG | Anti-ox40 antibodies and methods of use |
EP3134111B1 (en) | 2014-04-25 | 2022-06-08 | Dana-Farber Cancer Institute, Inc. | Middle east respiratory syndrome coronavirus neutralizing antibodies and methods of use thereof |
LT3137114T (en) | 2014-04-30 | 2021-03-25 | Pfizer Inc. | Anti-ptk7 antibody-drug conjugates |
BR112016024462B1 (en) | 2014-05-06 | 2022-12-27 | Genentech, Inc | METHODS FOR PREPARING AN ANTIBODY |
MX2016015162A (en) | 2014-05-22 | 2017-03-03 | Genentech Inc | Anti-gpc3 antibodies and immunoconjugates. |
CN106661622B (en) | 2014-05-23 | 2020-08-21 | 豪夫迈·罗氏有限公司 | MIT biomarkers and methods of using the same |
CN106573971A (en) | 2014-05-27 | 2017-04-19 | 中央研究院 | Anti-CD20 glycoantibodies and uses thereof |
US10118969B2 (en) | 2014-05-27 | 2018-11-06 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
EP3149161B1 (en) | 2014-05-27 | 2021-07-28 | Academia Sinica | Fucosidase from bacteroides and methods using the same |
AU2015267045B2 (en) | 2014-05-27 | 2021-02-25 | Academia Sinica | Anti-HER2 glycoantibodies and uses thereof |
TWI732738B (en) | 2014-05-28 | 2021-07-11 | 中央研究院 | Anti-tnf-alpha glycoantibodies and uses thereof |
PT3148581T (en) | 2014-05-30 | 2020-01-06 | Henlix Biotech Co Ltd | Anti-epidermal growth factor receptor (egfr) antibodies |
JP2017517552A (en) | 2014-06-13 | 2017-06-29 | ジェネンテック, インコーポレイテッド | Treatment and prevention of anticancer drug resistance |
TWI695011B (en) | 2014-06-18 | 2020-06-01 | 美商梅爾莎納醫療公司 | Monoclonal antibodies against her2 epitope and methods of use thereof |
US9580495B2 (en) | 2014-06-24 | 2017-02-28 | Immunomedics, Inc. | Anti-histone therapy for vascular necrosis in severe glomerulonephritis |
KR20170026362A (en) | 2014-06-26 | 2017-03-08 | 에프. 호프만-라 로슈 아게 | Anti-brdu antibodies and methods of use |
EP3166627A1 (en) | 2014-07-11 | 2017-05-17 | Genentech, Inc. | Notch pathway inhibition |
EP3166974A1 (en) | 2014-07-11 | 2017-05-17 | Genentech, Inc. | Anti-pd-l1 antibodies and diagnostic uses thereof |
EP3708679A1 (en) | 2014-07-24 | 2020-09-16 | Boehringer Ingelheim International GmbH | Biomarkers useful in the treatment of il-23a related diseases |
WO2016014974A2 (en) | 2014-07-25 | 2016-01-28 | Cytomx Therapeutics, Inc. | Anti-cd3 antibodies, activatable anti-cd3 antibodies, multispecific anti-cd3 antibodies, multispecific activatable anti-cd3 antibodies, and methods of using the same |
ES2726645T3 (en) | 2014-08-01 | 2019-10-08 | Inst Nat Sante Rech Med | An anti-CD45RC antibody to use as a medicine |
AU2015308818B2 (en) | 2014-08-28 | 2021-02-25 | Bioatla Llc | Conditionally active chimeric antigen receptors for modified T-cells |
TWI751102B (en) | 2014-08-28 | 2022-01-01 | 美商奇諾治療有限公司 | Antibodies and chimeric antigen receptors specific for cd19 |
WO2016040369A2 (en) | 2014-09-08 | 2016-03-17 | Academia Sinica | HUMAN iNKT CELL ACTIVATION USING GLYCOLIPIDS |
CA2957354A1 (en) | 2014-09-12 | 2016-03-17 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
US9751946B2 (en) | 2014-09-12 | 2017-09-05 | Genentech, Inc. | Anti-CLL-1 antibodies and immunoconjugates |
EP3191518B1 (en) | 2014-09-12 | 2020-01-15 | Genentech, Inc. | Anti-b7-h4 antibodies and immunoconjugates |
EA201790545A1 (en) | 2014-09-12 | 2017-07-31 | Дженентек, Инк. | ANTIBODIES AND IMMUNOCONJUGATES AGAINST HER2 |
BR112017004393A2 (en) | 2014-09-15 | 2018-02-27 | Genentech Inc | antibody formulations |
JP6730261B2 (en) | 2014-09-17 | 2020-07-29 | ジェネンテック, インコーポレイテッド | Immune complex containing anti-HER2 antibody |
PL3262071T3 (en) | 2014-09-23 | 2020-08-10 | F. Hoffmann-La Roche Ag | Method of using anti-cd79b immunoconjugates |
AU2015327781A1 (en) | 2014-10-03 | 2017-04-20 | Dana-Farber Cancer Institute, Inc. | Glucocorticoid-induced tumor necrosis factor receptor (GITR) antibodies and methods of use thereof |
EP3699196A1 (en) | 2014-10-06 | 2020-08-26 | Dana Farber Cancer Institute, Inc. | Humanized cc chemokine receptor 4 (ccr4) antibodies and methods of use thereof |
CN106999517A (en) | 2014-10-07 | 2017-08-01 | 免疫医疗公司 | The new adjuvant purposes of antibody drug conjugate |
WO2016061389A2 (en) | 2014-10-16 | 2016-04-21 | Genentech, Inc. | Anti-alpha-synuclein antibodies and methods of use |
CN107148283A (en) | 2014-10-31 | 2017-09-08 | 豪夫迈·罗氏有限公司 | Anti- IL 17A and IL 17F cross reacting antibodies variant, the composition comprising it and its preparation and application |
CN114381521A (en) | 2014-11-03 | 2022-04-22 | 豪夫迈·罗氏有限公司 | Methods and biomarkers for efficacy prediction and assessment of OX40 agonist treatment |
CA2966523A1 (en) | 2014-11-03 | 2016-05-12 | Genentech, Inc. | Assays for detecting t cell immune subsets and methods of use thereof |
WO2016073401A1 (en) | 2014-11-03 | 2016-05-12 | Bristol-Myers Squibb Company | Use of caprylic acid precipitation for protein purification |
US11773166B2 (en) | 2014-11-04 | 2023-10-03 | Ichnos Sciences SA | CD3/CD38 T cell retargeting hetero-dimeric immunoglobulins and methods of their production |
CA2961439A1 (en) | 2014-11-05 | 2016-05-12 | Genentech, Inc. | Anti-fgfr2/3 antibodies and methods using same |
CA2960797A1 (en) | 2014-11-06 | 2016-05-12 | F. Hoffmann-La Roche Ag | Fc-region variants with modified fcrn-binding and methods of use |
WO2016073157A1 (en) | 2014-11-06 | 2016-05-12 | Genentech, Inc. | Anti-ang2 antibodies and methods of use thereof |
CR20170240A (en) | 2014-11-10 | 2018-04-03 | Genentech Inc | ANTI-INTERLEUCINA-33 ANTIBODIES AND THEIR USES |
WO2016081490A1 (en) | 2014-11-17 | 2016-05-26 | Regeneron Pharmaceuticals, Inc. | Methods for tumor treatment using cd3xcd20 bispecific antibody |
WO2016081384A1 (en) | 2014-11-17 | 2016-05-26 | Genentech, Inc. | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
US10508151B2 (en) | 2014-11-19 | 2019-12-17 | Genentech, Inc. | Anti-transferrin receptor antibodies and methods of use |
US11008403B2 (en) | 2014-11-19 | 2021-05-18 | Genentech, Inc. | Anti-transferrin receptor / anti-BACE1 multispecific antibodies and methods of use |
WO2016081639A1 (en) | 2014-11-19 | 2016-05-26 | Genentech, Inc. | Antibodies against bace1 and use thereof for neural disease immunotherapy |
EP3224277B1 (en) | 2014-11-25 | 2020-08-26 | Bristol-Myers Squibb Company | Novel pd-l1 binding polypeptides for imaging |
EP3227332B1 (en) | 2014-12-03 | 2019-11-06 | F.Hoffmann-La Roche Ag | Multispecific antibodies |
US9975949B2 (en) | 2014-12-05 | 2018-05-22 | Genentech, Inc. | Anti-CD79b antibodies and methods of use |
CA2968352A1 (en) | 2014-12-08 | 2016-06-16 | Dana-Farber Cancer Institute, Inc. | Methods for upregulating immune responses using combinations of anti-rgmb and anti-pd-1 agents |
RU2017120039A (en) | 2014-12-10 | 2019-01-10 | Дженентек, Инк. | ANTIBODIES TO HEMATOENCEPHALIC BARRIER RECEPTORS AND METHODS OF APPLICATION |
US10093733B2 (en) | 2014-12-11 | 2018-10-09 | Abbvie Inc. | LRP-8 binding dual variable domain immunoglobulin proteins |
MX2017007503A (en) | 2014-12-17 | 2017-10-04 | Hoffmann La Roche | Novel methods for enzyme mediated polypeptide conjugation using sortase. |
RU2746356C2 (en) | 2014-12-19 | 2021-04-12 | Чугаи Сейяку Кабусики Кайся | C5 antibodies and their application methods |
AU2015364396B2 (en) | 2014-12-19 | 2018-08-09 | Alkermes, Inc. | Single chain Fc fusion proteins |
US9975965B2 (en) | 2015-01-16 | 2018-05-22 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US10495645B2 (en) | 2015-01-16 | 2019-12-03 | Academia Sinica | Cancer markers and methods of use thereof |
US20160208018A1 (en) | 2015-01-16 | 2016-07-21 | Juno Therapeutics, Inc. | Antibodies and chimeric antigen receptors specific for ror1 |
MA41374A (en) | 2015-01-20 | 2017-11-28 | Cytomx Therapeutics Inc | MATRIX METALLOPROTEASE CLIVABLE AND SERINE PROTEASE CLIVABLE SUBSTRATES AND METHODS OF USE THEREOF |
WO2016117346A1 (en) | 2015-01-22 | 2016-07-28 | Chugai Seiyaku Kabushiki Kaisha | A combination of two or more anti-c5 antibodies and methods of use |
EP3248005B1 (en) | 2015-01-24 | 2020-12-09 | Academia Sinica | Novel glycan conjugates and methods of use thereof |
WO2016118961A1 (en) | 2015-01-24 | 2016-07-28 | Academia Sinica | Cancer markers and methods of use thereof |
AU2016211176B2 (en) | 2015-01-30 | 2021-01-28 | Academia Sinica; | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
EA201791734A1 (en) | 2015-02-04 | 2018-01-31 | Бёрингер Ингельхайм Интернациональ Гмбх | METHOD OF TREATING INFLAMMATORY DISEASES |
US10330683B2 (en) | 2015-02-04 | 2019-06-25 | Genentech, Inc. | Mutant smoothened and methods of using the same |
KR20170110129A (en) | 2015-02-05 | 2017-10-10 | 추가이 세이야쿠 가부시키가이샤 | Antibodies comprising ionic concentration dependent antigen binding domains, Fc region variants, antibodies that bind to IL-8, and their use |
MD1009Z (en) * | 2015-03-02 | 2016-09-30 | Алёна НИКОРИЧ | Method for determining the susceptibility of a person to the development of non-Hodgkin lymphoma |
US10472395B2 (en) | 2015-03-05 | 2019-11-12 | Sirenas Llc | Cyclic peptide analogs and conjugates thereof |
SG11201707383PA (en) | 2015-03-13 | 2017-10-30 | Cytomx Therapeutics Inc | Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof |
AU2016233557B2 (en) | 2015-03-13 | 2021-06-24 | Bristol-Myers Squibb Company | Use of alkaline washes during chromatography to remove impurities |
US20180105555A1 (en) | 2015-03-20 | 2018-04-19 | Bristol-Myers Squibb Company | Use of dextran for protein purification |
JP6903587B2 (en) | 2015-04-03 | 2021-07-14 | ユーリカ セラピューティックス, インコーポレイテッド | Constructs targeting AFP peptide / MHC complexes and their use |
CN107709364A (en) | 2015-04-07 | 2018-02-16 | 豪夫迈·罗氏有限公司 | Antigen binding complex and application method with agonist activity |
WO2016164835A1 (en) | 2015-04-08 | 2016-10-13 | Dana-Farber Cancer Institute, Inc. | Humanized influenza monoclonal antibodies and methods of use thereof |
AU2016247921A1 (en) | 2015-04-14 | 2017-08-31 | Boehringer Ingelheim International Gmbh | Methods of treating diseases |
MX2017013383A (en) | 2015-04-20 | 2017-12-07 | Tolero Pharmaceuticals Inc | Predicting response to alvocidib by mitochondrial profiling. |
EP3286224A4 (en) | 2015-04-22 | 2018-11-14 | Immunomedics, Inc. | Isolation, detection, diagnosis and/or characterization of circulating trop-2-positive cancer cells |
CN107787332B (en) | 2015-04-24 | 2022-09-09 | 豪夫迈·罗氏有限公司 | Multispecific antigen binding proteins |
JP7044553B2 (en) | 2015-04-24 | 2022-03-30 | ジェネンテック, インコーポレイテッド | How to identify bacteria containing bound polypeptides |
WO2016171980A1 (en) | 2015-04-24 | 2016-10-27 | Bristol-Myers Squibb Company | Polypeptides targeting hiv fusion |
JP6802185B2 (en) | 2015-04-27 | 2020-12-16 | デイナ ファーバー キャンサー インスティチュート,インコーポレイテッド | High-throughput BH3 profiling: a rapid and scaleable technique for BH3 profiling in small cells |
JP2018520642A (en) | 2015-05-01 | 2018-08-02 | ジェネンテック, インコーポレイテッド | Mask anti-CD3 antibody and method of use thereof |
KR20170138556A (en) | 2015-05-01 | 2017-12-15 | 다나-파버 캔서 인스티튜트 인크. | Methods for mediating cytokine expression using anti-CCR4 antibodies |
AU2016258988A1 (en) | 2015-05-04 | 2017-12-07 | Cytomx Therapeutics, Inc | Anti-ITGa3 antibodies, activatable anti-ITGa3 antibodies, and methods of use thereof |
CA2984948A1 (en) | 2015-05-04 | 2016-11-10 | Cytomx Therapeutics, Inc. | Anti-cd166 antibodies, activatable anti-cd166 antibodies, and methods of use thereof |
EP3292149B1 (en) | 2015-05-04 | 2021-12-01 | CytomX Therapeutics, Inc. | Activatable anti-cd71 antibodies, and methods of use thereof |
WO2016179518A2 (en) | 2015-05-06 | 2016-11-10 | Janssen Biotech, Inc. | Prostate specific membrane antigen (psma) bispecific binding agents and uses thereof |
EP4238994A3 (en) | 2015-05-11 | 2024-02-07 | F. Hoffmann-La Roche AG | Compositions and methods of treating lupus nephritis |
ES2835866T3 (en) | 2015-05-12 | 2021-06-23 | Hoffmann La Roche | Therapeutic and diagnostic procedures for cancer |
WO2016187068A1 (en) | 2015-05-15 | 2016-11-24 | The General Hospital Corporation | Antagonistic anti-tumor necrosis factor receptor superfamily antibodies |
KR102608921B1 (en) | 2015-05-18 | 2023-12-01 | 스미토모 파마 온콜로지, 인크. | Albocidip prodrug with increased bioavailability |
WO2016191750A1 (en) | 2015-05-28 | 2016-12-01 | Genentech, Inc. | Cell-based assay for detecting anti-cd3 homodimers |
EP3302563A1 (en) | 2015-05-29 | 2018-04-11 | H. Hoffnabb-La Roche Ag | Humanized anti-ebola virus glycoprotein antibodies and methods of use |
WO2016196381A1 (en) | 2015-05-29 | 2016-12-08 | Genentech, Inc. | Pd-l1 promoter methylation in cancer |
KR20180012753A (en) | 2015-05-29 | 2018-02-06 | 제넨테크, 인크. | Treatment and Diagnosis Methods for Cancer |
CN107849096B (en) | 2015-05-30 | 2022-05-24 | 分子模板公司 | Deimmunized shiga toxin a subunit scaffolds and cell targeting molecules comprising them |
TW201717935A (en) | 2015-06-03 | 2017-06-01 | 波士頓生醫公司 | Compositions and methods for treating cancer |
CN107849124B (en) | 2015-06-05 | 2021-09-24 | 基因泰克公司 | anti-TAU antibodies and methods of use |
CA2988420A1 (en) | 2015-06-08 | 2016-12-15 | Genentech, Inc. | Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists |
EP3303399A1 (en) | 2015-06-08 | 2018-04-11 | H. Hoffnabb-La Roche Ag | Methods of treating cancer using anti-ox40 antibodies |
TW201710286A (en) | 2015-06-15 | 2017-03-16 | 艾伯維有限公司 | Binding proteins against VEGF, PDGF, and/or their receptors |
TWI731861B (en) | 2015-06-16 | 2021-07-01 | 美商建南德克公司 | HUMANIZED AND AFFINITY MATURED ANTIBODIES TO FcRH5 AND METHODS OF USE |
CN107847568B (en) | 2015-06-16 | 2022-12-20 | 豪夫迈·罗氏有限公司 | anti-CLL-1 antibodies and methods of use |
WO2016204966A1 (en) | 2015-06-16 | 2016-12-22 | Genentech, Inc. | Anti-cd3 antibodies and methods of use |
MX2017016353A (en) | 2015-06-17 | 2018-05-02 | Genentech Inc | Methods of treating locally advanced or metastatic breast cancers using pd-1 axis binding antagonists and taxanes. |
JP2018524312A (en) | 2015-06-17 | 2018-08-30 | ジェネンテック, インコーポレイテッド | Anti-HER2 antibody and method of use |
JP6846362B2 (en) | 2015-06-17 | 2021-03-24 | アラコス インコーポレイテッド | Methods and Compositions for Treating Fibrous Diseases |
US10195175B2 (en) | 2015-06-25 | 2019-02-05 | Immunomedics, Inc. | Synergistic effect of anti-Trop-2 antibody-drug conjugate in combination therapy for triple-negative breast cancer when used with microtubule inhibitors or PARP inhibitors |
WO2016210292A1 (en) | 2015-06-25 | 2016-12-29 | Children's Medical Center Corporation | Methods and compositions relating to hematopoietic stem cell expansion, enrichment, and maintenance |
WO2016210108A1 (en) | 2015-06-25 | 2016-12-29 | Immunomedics, Inc. | Combining anti-hla-dr or anti-trop-2 antibodies with microtubule inhibitors, parp inhibitors, bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer |
JP2018520153A (en) | 2015-06-29 | 2018-07-26 | ジェネンテック, インコーポレイテッド | Type II anti-CD20 antibody for use in organ transplantation |
ES2898065T3 (en) | 2015-06-29 | 2022-03-03 | Ventana Med Syst Inc | Materials and Procedures for Performing Histochemical Assays for Human Proepiregulin and Amphiregulin |
SI3316885T1 (en) | 2015-07-01 | 2021-09-30 | Immunomedics, Inc. | Antibody-sn-38 immunoconjugates with a cl2a linker |
US20170016043A1 (en) | 2015-07-13 | 2017-01-19 | Life Technologies Corporation | System and method for improved transient protein expression in cho cells |
MX2018001289A (en) | 2015-08-03 | 2018-04-30 | Tolero Pharmaceuticals Inc | Combination therapies for treatment of cancer. |
TWI797060B (en) | 2015-08-04 | 2023-04-01 | 美商再生元醫藥公司 | Taurine supplemented cell culture medium and methods of use |
HU231463B1 (en) | 2015-08-04 | 2024-01-28 | Richter Gedeon Nyrt. | Method for increasing the galactose content of recombinant proteins |
ES2944982T3 (en) | 2015-08-05 | 2023-06-27 | Janssen Biotech Inc | Anti-CD154 antibodies and methods of using them |
EP3331569A1 (en) | 2015-08-07 | 2018-06-13 | Gamamabs Pharma | Antibodies, antibody drug conjugates and methods of use |
CN105384825B (en) | 2015-08-11 | 2018-06-01 | 南京传奇生物科技有限公司 | A kind of bispecific chimeric antigen receptor and its application based on single domain antibody |
SG10202101105XA (en) | 2015-08-13 | 2021-03-30 | Amgen Inc | Charged depth filtration of antigen-binding proteins |
WO2017029407A1 (en) | 2015-08-20 | 2017-02-23 | Albumedix A/S | Albumin variants and conjugates |
EP3341415B1 (en) | 2015-08-28 | 2021-03-24 | H. Hoffnabb-La Roche Ag | Anti-hypusine antibodies and uses thereof |
WO2017041027A1 (en) | 2015-09-04 | 2017-03-09 | Obi Pharma, Inc. | Glycan arrays and method of use |
TWI799366B (en) | 2015-09-15 | 2023-04-21 | 美商建南德克公司 | Cystine knot scaffold platform |
TWI733695B (en) | 2015-09-18 | 2021-07-21 | 德商百靈佳殷格翰國際股份有限公司 | Methods of treating inflammatory diseases |
CA2999369C (en) | 2015-09-22 | 2023-11-07 | Spring Bioscience Corporation | Anti-ox40 antibodies and diagnostic uses thereof |
KR20180056701A (en) | 2015-09-23 | 2018-05-29 | 브리스톨-마이어스 스큅 컴퍼니 | Fast-off-rate serum albumin binding fibronectin type III domain |
EP3733698A1 (en) | 2015-09-23 | 2020-11-04 | Bristol-Myers Squibb Company | Glypican-3 binding fibronectin based scafflold molecules |
WO2017053807A2 (en) | 2015-09-23 | 2017-03-30 | Genentech, Inc. | Optimized variants of anti-vegf antibodies |
WO2017053906A1 (en) | 2015-09-24 | 2017-03-30 | Abvitro Llc | Hiv antibody compositions and methods of use |
JP6861702B2 (en) | 2015-09-25 | 2021-04-21 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Recombinant immunoglobulin heavy chains containing sortase-conjugated loops and their conjugates |
CN108026560A (en) | 2015-09-25 | 2018-05-11 | 豪夫迈·罗氏有限公司 | Reacted in eutectic solvent using the acid amides that turns of sorting enzyme |
EP3353291B1 (en) | 2015-09-25 | 2021-06-09 | F. Hoffmann-La Roche AG | Novel soluble sortase a |
JP6895953B2 (en) | 2015-09-25 | 2021-06-30 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Method for making thioester using sortase A |
WO2017059132A1 (en) | 2015-09-29 | 2017-04-06 | The General Hospital Corporation | Methods of treating and diagnosing disease using biomarkers for bcg therapy |
CN109069622A (en) | 2015-09-30 | 2018-12-21 | 詹森生物科技公司 | Specifically bind the antagonistic antibodies and application method of people CD40 |
AU2016329251B2 (en) | 2015-10-02 | 2023-02-02 | F. Hoffmann-La Roche Ag | Anti-PD1 antibodies and methods of use |
KR102146319B1 (en) | 2015-10-02 | 2020-08-25 | 에프. 호프만-라 로슈 아게 | Bispecific antibodies specific for PD1 and TIM3 |
IL293708A (en) | 2015-10-06 | 2022-08-01 | Genentech Inc | Method for treating multiple sclerosis |
US11365198B2 (en) | 2015-10-16 | 2022-06-21 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11512092B2 (en) | 2015-10-16 | 2022-11-29 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
SG10201913986YA (en) | 2015-10-16 | 2020-03-30 | Abbvie Inc | PROCESSES FOR THE PREPARATION OF (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2-a]PYRROLO[2,3-e]-PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROETHYL)PYRROLIDINE-1-CARBOXAMIDE AND SOLID STATE FORMS THEREOF |
US10550126B2 (en) | 2015-10-16 | 2020-02-04 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-A]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11207393B2 (en) | 2015-10-16 | 2021-12-28 | President And Fellows Of Harvard College | Regulatory T cell PD-1 modulation for regulating T cell effector immune responses |
US11773106B2 (en) | 2015-10-16 | 2023-10-03 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11524964B2 (en) | 2015-10-16 | 2022-12-13 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10604577B2 (en) | 2015-10-22 | 2020-03-31 | Allakos Inc. | Methods and compositions for treating systemic mastocytosis |
EP3184547A1 (en) | 2015-10-29 | 2017-06-28 | F. Hoffmann-La Roche AG | Anti-tpbg antibodies and methods of use |
ES2904553T3 (en) | 2015-10-30 | 2022-04-05 | Hoffmann La Roche | Hinge Modified Antibody Fragments and Preparation Procedures |
BR112018008904A2 (en) | 2015-11-03 | 2018-11-27 | Janssen Biotech Inc | antibodies specifically binding to tim-3 and their uses |
JP6998869B2 (en) | 2015-11-08 | 2022-02-04 | ジェネンテック, インコーポレイテッド | Screening method for multispecific antibody |
CA3006759A1 (en) | 2015-11-30 | 2017-06-08 | The Regents Of The University Of California | Tumor-specific payload delivery and immune activation using a human antibody targeting a highly specific tumor cell surface antigen |
EP3178848A1 (en) | 2015-12-09 | 2017-06-14 | F. Hoffmann-La Roche AG | Type ii anti-cd20 antibody for reducing formation of anti-drug antibodies |
JP7325186B2 (en) | 2015-12-09 | 2023-08-14 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Type II anti-CD20 antibody for reducing the formation of anti-drug antibodies |
PL3390442T3 (en) | 2015-12-18 | 2024-03-18 | Chugai Seiyaku Kabushiki Kaisha | Anti-c5 antibodies and methods of use |
US11433136B2 (en) | 2015-12-18 | 2022-09-06 | The General Hospital Corporation | Polyacetal polymers, conjugates, particles and uses thereof |
CN108430455A (en) | 2015-12-30 | 2018-08-21 | 豪夫迈·罗氏有限公司 | Tryptophan derivative is used for the purposes of protein preparaton |
EP3397287A1 (en) | 2015-12-30 | 2018-11-07 | Genentech, Inc. | Formulations with reduced degradation of polysorbate |
MX2018008347A (en) | 2016-01-08 | 2018-12-06 | Hoffmann La Roche | Methods of treating cea-positive cancers using pd-1 axis binding antagonists and anti-cea/anti-cd3 bispecific antibodies. |
CN109073635A (en) | 2016-01-25 | 2018-12-21 | 豪夫迈·罗氏有限公司 | Method for measuring T cell dependence bispecific antibody |
CA3019952A1 (en) | 2016-02-04 | 2017-08-10 | Curis, Inc. | Mutant smoothened and methods of using the same |
CA3011372A1 (en) | 2016-02-10 | 2017-08-17 | Immunomedics, Inc. | Combination of abcg2 inhibitors with sacituzumab govitecan (immu-132) overcomes resistance to sn-38 in trop-2 expressing cancers |
CN109196121B (en) | 2016-02-29 | 2022-01-04 | 基因泰克公司 | Methods for treatment and diagnosis of cancer |
WO2017148880A1 (en) | 2016-03-01 | 2017-09-08 | F. Hoffmann-La Roche Ag | Obinutuzumab variants having altered cell death induction |
TW201808978A (en) | 2016-03-08 | 2018-03-16 | 中央研究院 | Methods for modular synthesis of N-glycans and arrays thereof |
US10947317B2 (en) | 2016-03-15 | 2021-03-16 | Mersana Therapeutics, Inc. | NaPi2b-targeted antibody-drug conjugates and methods of use thereof |
EP3429603B1 (en) | 2016-03-15 | 2021-12-29 | Children's Medical Center Corporation | Methods and compositions relating to hematopoietic stem cell expansion |
EP3430058A4 (en) | 2016-03-15 | 2019-10-23 | Generon (Shanghai) Corporation Ltd. | Multispecific fab fusion proteins and use thereof |
TW202248213A (en) | 2016-03-15 | 2022-12-16 | 日商中外製藥股份有限公司 | Methods of treating cancers using pd-1 axis binding antagonists and anti-gpc3 antibodies |
KR20180121786A (en) | 2016-03-29 | 2018-11-08 | 오비아이 파머 인코퍼레이티드 | Antibodies, pharmaceutical compositions and methods |
US10980894B2 (en) | 2016-03-29 | 2021-04-20 | Obi Pharma, Inc. | Antibodies, pharmaceutical compositions and methods |
JP6727325B2 (en) | 2016-03-30 | 2020-07-22 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Improved sortase |
WO2017180864A1 (en) | 2016-04-14 | 2017-10-19 | Genentech, Inc. | Anti-rspo3 antibodies and methods of use |
KR20190006495A (en) | 2016-04-15 | 2019-01-18 | 알파인 이뮨 사이언시즈, 인코포레이티드 | CD80 variant immunoregulatory proteins and uses thereof |
CA3021086C (en) | 2016-04-15 | 2023-10-17 | Bioatla, Llc | Anti-axl antibodies, antibody fragments and their immunoconjugates and uses thereof |
ES2850428T3 (en) | 2016-04-15 | 2021-08-30 | Hoffmann La Roche | Cancer monitoring and treatment procedures |
EP3443005A1 (en) | 2016-04-15 | 2019-02-20 | Boehringer Ingelheim International GmbH | Methods of treating inflammatory diseases |
US10202435B2 (en) | 2016-04-15 | 2019-02-12 | Alder Biopharmaceuticals, Inc. | Anti-PACAP antibodies and uses thereof |
KR20230051602A (en) | 2016-04-15 | 2023-04-18 | 알파인 이뮨 사이언시즈, 인코포레이티드 | Icos ligand variant immunomodulatory proteins and uses thereof |
JP2019515670A (en) | 2016-04-15 | 2019-06-13 | ジェネンテック, インコーポレイテッド | Methods for monitoring and treating cancer |
EP3454864A4 (en) | 2016-04-21 | 2021-01-13 | Abbvie Stemcentrx LLC | Novel anti-bmpr1b antibodies and methods of use |
KR20230110820A (en) | 2016-04-22 | 2023-07-25 | 오비아이 파머 인코퍼레이티드 | Cancer immunotherapy by immune activation or immune modulation via globo series antigens |
WO2017189279A1 (en) | 2016-04-27 | 2017-11-02 | Immunomedics, Inc. | Efficacy of anti-trop-2-sn-38 antibody drug conjugates for therapy of tumors relapsed/refractory to checkpoint inhibitors |
UA123323C2 (en) | 2016-05-02 | 2021-03-17 | Ф. Хоффманн-Ля Рош Аг | The contorsbody - a single chain target binder |
EP3455252B1 (en) | 2016-05-11 | 2022-02-23 | F. Hoffmann-La Roche AG | Modified anti-tenascin antibodies and methods of use |
SI3455261T1 (en) | 2016-05-13 | 2023-01-31 | Bioatla, Inc. | Anti-ror2 antibodies, antibody fragments, their immunoconjugates and uses thereof |
US11623958B2 (en) | 2016-05-20 | 2023-04-11 | Harpoon Therapeutics, Inc. | Single chain variable fragment CD3 binding proteins |
US10994033B2 (en) | 2016-06-01 | 2021-05-04 | Bristol-Myers Squibb Company | Imaging methods using 18F-radiolabeled biologics |
CN109562195A (en) | 2016-06-01 | 2019-04-02 | 百时美施贵宝公司 | PET imaging is carried out with PD-L1 combination polypeptide |
TW201902512A (en) | 2016-06-02 | 2019-01-16 | 瑞士商赫孚孟拉羅股份公司 | treatment method |
EP3252078A1 (en) | 2016-06-02 | 2017-12-06 | F. Hoffmann-La Roche AG | Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer |
UA126021C2 (en) | 2016-06-03 | 2022-08-03 | Янссен Байотек, Інк. | Serum albumin-binding fibronectin type iii domains |
CN109563124A (en) | 2016-06-17 | 2019-04-02 | 豪夫迈·罗氏有限公司 | The purifying of multi-specificity antibody |
JP2019524706A (en) | 2016-07-08 | 2019-09-05 | ジェネンテック, インコーポレイテッド | Use of human epididymis protein 4 (HE4) to assess responsiveness of MUC16 positive cancer treatment |
WO2018014260A1 (en) | 2016-07-20 | 2018-01-25 | Nanjing Legend Biotech Co., Ltd. | Multispecific antigen binding proteins and methods of use thereof |
WO2018018039A2 (en) | 2016-07-22 | 2018-01-25 | Dana-Farber Cancer Institute, Inc. | Glucocorticoid-induced tumor necrosis factor receptor (gitr) antibodies and methods of use thereof |
US20190330318A1 (en) | 2016-07-25 | 2019-10-31 | Biogen Ma Inc. | Anti-hspa5 (grp78) antibodies and uses thereof |
CN110072545A (en) | 2016-07-27 | 2019-07-30 | 台湾浩鼎生技股份有限公司 | Immunogenicity/therapeutic glycan pool object and application thereof |
WO2018022945A1 (en) | 2016-07-28 | 2018-02-01 | Alpine Immune Sciences, Inc. | Cd112 variant immunomodulatory proteins and uses thereof |
CN110088127A (en) | 2016-07-28 | 2019-08-02 | 高山免疫科学股份有限公司 | CD155 variant immune modulator and application thereof |
CN110088133B (en) | 2016-07-29 | 2023-12-08 | 朱诺治疗学股份有限公司 | Anti-idiotype antibodies and related methods |
KR102528998B1 (en) | 2016-07-29 | 2023-05-03 | 오비아이 파머 인코퍼레이티드 | Human Antibodies, Pharmaceutical Compositions and Methods |
CN116251182A (en) | 2016-08-05 | 2023-06-13 | 中外制药株式会社 | Compositions for preventing or treating IL-8 related diseases |
EP3494139B1 (en) | 2016-08-05 | 2022-01-12 | F. Hoffmann-La Roche AG | Multivalent and multiepitopic anitibodies having agonistic activity and methods of use |
JP7250674B2 (en) | 2016-08-08 | 2023-04-03 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | CANCER TREATMENT AND DIAGNOSTIC METHOD |
CN109790201A (en) | 2016-08-12 | 2019-05-21 | 百时美施贵宝公司 | Method for purifying proteins |
WO2018035025A1 (en) | 2016-08-15 | 2018-02-22 | Genentech, Inc. | Chromatography method for quantifying a non-ionic surfactant in a composition comprising the non-ionic surfactant and a polypeptide |
JP7213549B2 (en) | 2016-08-22 | 2023-01-27 | シーエイチオー ファーマ インコーポレイテッド | Antibodies, Binding Fragments, and Methods of Use |
WO2018036852A1 (en) | 2016-08-25 | 2018-03-01 | F. Hoffmann-La Roche Ag | Intermittent dosing of an anti-csf-1r antibody in combination with macrophage activating agent |
WO2018045245A1 (en) | 2016-09-02 | 2018-03-08 | Sirenas Llc | Cyclic peptide analogs and conjugates thereof |
WO2018045379A1 (en) | 2016-09-02 | 2018-03-08 | Dana-Farber Cancer Institute, Inc. | Composition and methods of treating b cell disorders |
US20190233505A1 (en) | 2016-09-06 | 2019-08-01 | Dana-Farber Cancer Institute, Inc. | Methods of treating or preventing zika virus infection |
JP2019534858A (en) | 2016-09-09 | 2019-12-05 | ジェネンテック, インコーポレイテッド | Selective peptide inhibitor of FRIZZLED |
TW201825674A (en) | 2016-09-09 | 2018-07-16 | 美商艾斯合顧問有限公司 | Oncolytic virus expressing bispecific engager molecules |
EP3512885B1 (en) | 2016-09-16 | 2024-02-21 | Shanghai Henlius Biotech, Inc. | Anti-pd-1 antibodies |
SG10201607778XA (en) | 2016-09-16 | 2018-04-27 | Chugai Pharmaceutical Co Ltd | Anti-Dengue Virus Antibodies, Polypeptides Containing Variant Fc Regions, And Methods Of Use |
CN109689682B (en) | 2016-09-19 | 2022-11-29 | 豪夫迈·罗氏有限公司 | Complement factor-based affinity chromatography |
RU2759334C2 (en) * | 2016-09-21 | 2021-11-12 | Нексткьюр, Инк. | Antibodies against siglec-15 and their application methods |
AU2017339517B2 (en) | 2016-10-06 | 2024-03-14 | Foundation Medicine, Inc. | Therapeutic and diagnostic methods for cancer |
WO2018068201A1 (en) | 2016-10-11 | 2018-04-19 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against ctla-4 |
WO2018071504A2 (en) | 2016-10-14 | 2018-04-19 | Boehringer Ingelheim International Gmbh | Methods of treating diseases |
EP3532496A1 (en) | 2016-10-28 | 2019-09-04 | Banyan Biomarkers, Inc. | Antibodies to ubiquitin c-terminal hydrolase l1 (uch-l1) and glial fibrillary acidic protein (gfap) and related methods |
EP3532091A2 (en) | 2016-10-29 | 2019-09-04 | H. Hoffnabb-La Roche Ag | Anti-mic antibidies and methods of use |
PE20191131A1 (en) | 2016-11-03 | 2019-09-02 | Bristol Myers Squibb Co | ACTIVABLE CYTOTOXIC T LYMPHOCYTE 4 ANTI ANTIGEN (CTLA-4) ANTIBODIES AND THEIR USES |
CA3040812A1 (en) | 2016-11-04 | 2018-05-11 | Novimmune Sa | Anti-cd19 antibodies and methods of use thereof |
US11434301B2 (en) | 2016-11-11 | 2022-09-06 | The Regents Of The University Of California | Anti-CD46 antibodies and methods of use |
AU2017361081A1 (en) | 2016-11-15 | 2019-05-23 | Genentech, Inc. | Dosing for treatment with anti-CD20/anti-CD3 bispecific antibodies |
TW201829463A (en) | 2016-11-18 | 2018-08-16 | 瑞士商赫孚孟拉羅股份公司 | Anti-hla-g antibodies and use thereof |
US11279694B2 (en) | 2016-11-18 | 2022-03-22 | Sumitomo Dainippon Pharma Oncology, Inc. | Alvocidib prodrugs and their use as protein kinase inhibitors |
JP2019535731A (en) | 2016-11-21 | 2019-12-12 | オービーアイ ファーマ,インコーポレイテッド | Conjugated biological molecules, pharmaceutical compositions and methods |
AU2017361887B2 (en) | 2016-11-21 | 2019-08-15 | Cureab Gmbh | Anti-GP73 antibodies and immunoconjugates |
CA3045306A1 (en) | 2016-11-29 | 2018-06-07 | Boston Biomedical, Inc. | Naphthofuran derivatives, preparation, and methods of use thereof |
CR20230163A (en) | 2016-12-07 | 2023-07-06 | Genentech Inc | Anti-tau antibodies and methods of use |
AU2017373884A1 (en) | 2016-12-07 | 2019-05-30 | Ac Immune Sa | Anti-tau antibodies and methods of their use |
US10132797B2 (en) | 2016-12-19 | 2018-11-20 | Tolero Pharmaceuticals, Inc. | Profiling peptides and methods for sensitivity profiling |
JP7304287B2 (en) | 2016-12-22 | 2023-07-06 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Treatment of tumors with anti-CSF-1R antibodies in combination with anti-PD-L1 antibodies after unsuccessful anti-PD-L1/PD1 therapy |
US20180244785A1 (en) | 2017-01-09 | 2018-08-30 | Merrimack Pharmaceuticals, Inc. | Anti-fgfr antibodies and methods of use |
TW201831517A (en) | 2017-01-12 | 2018-09-01 | 美商優瑞科生物技術公司 | Constructs targeting histone h3 peptide/mhc complexes and uses thereof |
AR110873A1 (en) | 2017-02-10 | 2019-05-08 | Genentech Inc | ANTIBODIES AGAINST TRIPTASE, COMPOSITIONS OF THESE AND USES OF THESE |
WO2018152496A1 (en) | 2017-02-17 | 2018-08-23 | The Usa, As Represented By The Secretary, Dept. Of Health And Human Services | Compositions and methods for the diagnosis and treatment of zika virus infection |
TW201834697A (en) | 2017-02-28 | 2018-10-01 | 美商梅爾莎納醫療公司 | Combination therapies of her2-targeted antibody-drug conjugates |
TW201837467A (en) | 2017-03-01 | 2018-10-16 | 美商建南德克公司 | Diagnostic and therapeutic methods for cancer |
AU2018231127A1 (en) | 2017-03-09 | 2019-09-19 | Cytomx Therapeutics, Inc. | CD147 antibodies, activatable CD147 antibodies, and methods of making and use thereof |
GB201703876D0 (en) | 2017-03-10 | 2017-04-26 | Berlin-Chemie Ag | Pharmaceutical combinations |
AU2018235838B2 (en) | 2017-03-16 | 2023-12-14 | Alpine Immune Sciences, Inc. | CD80 variant immunomodulatory proteins and uses thereof |
EP3596116B1 (en) | 2017-03-16 | 2023-09-06 | Alpine Immune Sciences, Inc. | Pd-l1 variant immunomodulatory proteins and uses thereof |
US11732022B2 (en) | 2017-03-16 | 2023-08-22 | Alpine Immune Sciences, Inc. | PD-L2 variant immunomodulatory proteins and uses thereof |
CN110475790A (en) | 2017-03-24 | 2019-11-19 | 全药工业株式会社 | Anti- IgM/B cell surface antigen bispecific antibody |
CN110461877A (en) | 2017-03-27 | 2019-11-15 | 勃林格殷格翰国际有限公司 | The anti-antibody combined treatment of IL-36R |
WO2018183041A1 (en) | 2017-03-27 | 2018-10-04 | Immunomedics, Inc. | Treatment of trop-2 expressing triple negative breast cancer with sacituzumab govitecan and a rad51 inhibitor |
TW202400231A (en) | 2017-03-28 | 2024-01-01 | 美商建南德克公司 | Methods of treating neurodegenerative diseases |
CN110678753B (en) | 2017-03-30 | 2023-10-24 | 普莱戈斯瑞恩癌症有限责任公司 | Compositions and methods for treating lung cancer |
JP7071994B2 (en) | 2017-03-30 | 2022-05-19 | プロガストリン、エ、カンセル、エス、アー エル、エル | Compositions and Methods for Treating Prostate Cancer |
CN108588126B (en) | 2017-03-31 | 2020-04-10 | 北京百奥赛图基因生物技术有限公司 | Preparation method and application of humanized modified animal model of CD47 gene |
BR112019018767A2 (en) | 2017-04-03 | 2020-05-05 | Hoffmann La Roche | antibodies, bispecific antigen binding molecule, one or more isolated polynucleotides, one or more vectors, host cell, method for producing an antibody, pharmaceutical composition, uses, method for treating a disease in an individual and invention |
EP3606964A4 (en) | 2017-04-03 | 2020-12-09 | Immunomedics, Inc. | Subcutaneous administration of antibody-drug conjugates for cancer therapy |
BR112019021282A2 (en) | 2017-04-12 | 2020-05-19 | Magenta Therapeutics Inc | aryl hydrocarbon receptor antagonists and uses thereof |
KR102495650B1 (en) | 2017-04-12 | 2023-02-02 | 에프. 호프만-라 로슈 아게 | Methods for Labeling Aldehyde-Containing Target Molecules |
EP3615569A1 (en) | 2017-04-25 | 2020-03-04 | The U.S.A. As Represented By The Secretary, Department Of Health And Human Services | Antibodies and methods for the diagnosis and treatment of epstein barr virus infection |
WO2018200586A1 (en) | 2017-04-26 | 2018-11-01 | Eureka Therapeutics, Inc. | Constructs specifically recognizing glypican 3 and uses thereof |
US20220135670A1 (en) | 2017-04-27 | 2022-05-05 | Tesaro, Inc. | Antibody agents directed against lymphocyte activation gene-3 (lag-3) and uses thereof |
TW201842929A (en) | 2017-05-03 | 2018-12-16 | 美商必治妥美雅史谷比公司 | Stable formulations of fibronectin based scaffold domain proteins that bind to myostatin |
MX2019013137A (en) | 2017-05-05 | 2020-07-14 | Allakos Inc | Methods and compositions for treating allergic ocular diseases. |
KR102376863B1 (en) | 2017-05-12 | 2022-03-21 | 하푼 테라퓨틱스, 인크. | mesothelin binding protein |
JP2020520923A (en) | 2017-05-17 | 2020-07-16 | ボストン バイオメディカル, インコーポレイテッド | Methods for treating cancer |
WO2018215835A1 (en) | 2017-05-26 | 2018-11-29 | Novimmune Sa | Anti-cd47 x anti-mesothelin antibodies and methods of use thereof |
BR112019025188A2 (en) | 2017-06-01 | 2020-06-23 | Cytomx Therapeutics, Inc. | ACTIVABLE ANTI-PDL1 ANTIBODIES AND METHODS OF USE OF THE SAME |
US10793634B2 (en) | 2017-06-09 | 2020-10-06 | Boehringer Ingelheim International Gmbh | Anti-TrkB antibodies |
CN111094334A (en) | 2017-07-19 | 2020-05-01 | 美国卫生与公众服务部 | Antibodies and methods for diagnosis and treatment of hepatitis B virus infection |
JP2020530554A (en) | 2017-07-20 | 2020-10-22 | シートムエックス セラピューティクス,インコーポレイテッド | Methods and Uses for Qualitative and / or Quantitative Analysis of Activating Antibody Properties |
JP2020527351A (en) | 2017-07-21 | 2020-09-10 | ジェネンテック, インコーポレイテッド | Cancer treatment and diagnosis |
JP7418322B2 (en) | 2017-08-08 | 2024-01-19 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Obinutuzumab treatment of DLBCL patient subgroups |
CA3072267A1 (en) | 2017-08-09 | 2019-02-14 | University Of Saskatchewan | Her3 binding agents and uses thereof |
WO2019033043A2 (en) | 2017-08-11 | 2019-02-14 | Genentech, Inc. | Anti-cd8 antibodies and uses thereof |
US10759865B2 (en) | 2017-08-22 | 2020-09-01 | Eyal Levit | Treatment of diabetes mellitus |
MX2020002198A (en) | 2017-08-30 | 2020-07-20 | Cytomx Therapeutics Inc | Activatable anti-cd166 antibodies and methods of use thereof. |
WO2019055579A1 (en) | 2017-09-12 | 2019-03-21 | Tolero Pharmaceuticals, Inc. | Treatment regimen for cancers that are insensitive to bcl-2 inhibitors using the mcl-1 inhibitor alvocidib |
US20200297871A1 (en) | 2017-09-15 | 2020-09-24 | King's College London | Compositions and methods for enhancing gamma delta t cells in the gut |
WO2019075090A1 (en) | 2017-10-10 | 2019-04-18 | Tilos Therapeutics, Inc. | Anti-lap antibodies and uses thereof |
EP3694870A1 (en) | 2017-10-10 | 2020-08-19 | Alpine Immune Sciences, Inc. | Ctla-4 variant immunomodulatory proteins and uses thereof |
CN111372950A (en) | 2017-10-12 | 2020-07-03 | 免疫苏醒公司 | VEGFR-antibody light chain fusion proteins |
JP7438106B2 (en) | 2017-10-14 | 2024-02-26 | シートムエックス セラピューティクス,インコーポレイテッド | Antibodies, activatable antibodies, bispecific antibodies, and bispecific activatable antibodies and methods of use thereof |
LT3691692T (en) | 2017-10-14 | 2021-05-10 | Abbvie Inc. | Anti-cd71 activatable antibody drug conjugates and methods of use thereof |
EA202090974A1 (en) | 2017-10-18 | 2020-08-05 | Элпайн Иммьюн Сайенсиз, Инк. | VARIANT IMMUNOMODULATING PROTEINS OF ICOS LIGAND AND ACCOMPANYING COMPOSITIONS AND METHODS |
BR112020007321A2 (en) | 2017-10-20 | 2020-09-29 | F. Hoffmann-La Roche Ag | antibody conjugate, use, use of a stable isotope marker and kit |
CA3078676A1 (en) | 2017-10-30 | 2019-05-09 | F. Hoffmann-La Roche Ag | Method for in vivo generation of multispecific antibodies from monospecific antibodies |
AU2018358241A1 (en) | 2017-10-31 | 2020-05-07 | Edigene Biotechnology, Inc. | Compositions and methods for the expansion of hematopoietic stem and progenitor cells |
EP3703715A1 (en) | 2017-10-31 | 2020-09-09 | Magenta Therapeutics, Inc. | Compositions and methods for hematopoietic stem and progenitor cell transplant therapy |
PL3704146T3 (en) | 2017-11-01 | 2022-03-07 | F. Hoffmann-La Roche Ag | Trifab-contorsbody |
EP3704150A1 (en) | 2017-11-01 | 2020-09-09 | F. Hoffmann-La Roche AG | The compbody - a multivalent target binder |
CA3080904A1 (en) | 2017-11-01 | 2019-05-09 | Juno Therapeutics, Inc. | Antibodies and chimeric antigen receptors specific for b-cell maturation antigen |
JP2021502066A (en) | 2017-11-06 | 2021-01-28 | ジェネンテック, インコーポレイテッド | Cancer diagnosis and therapy |
PT3720879T (en) | 2017-12-05 | 2022-07-13 | Progastrine Et Cancers S A R L | Combination therapy between anti-progastrin antibody and immunotherapy to treat cancer |
WO2019123262A1 (en) | 2017-12-18 | 2019-06-27 | VIIV Healthcare UK (No.5) Limited | Antigen binding polypeptides |
US11802154B2 (en) | 2017-12-20 | 2023-10-31 | Alexion Pharmaceuticals, Inc. | Humanized anti-CD200 antibodies and uses thereof |
MX2020006119A (en) | 2017-12-21 | 2020-08-24 | Hoffmann La Roche | Antibodies binding to hla-a2/wt1. |
WO2019131988A1 (en) | 2017-12-28 | 2019-07-04 | Chugai Seiyaku Kabushiki Kaisha | Cytotoxicity-inducing therapeutic agent |
KR20200104333A (en) | 2017-12-28 | 2020-09-03 | 난징 레전드 바이오테크 씨오., 엘티디. | Single-domain antibodies to TIGIT and variants thereof |
CN111479588A (en) | 2017-12-29 | 2020-07-31 | 豪夫迈·罗氏有限公司 | Methods for improving VEGF receptor blocking selectivity of anti-VEGF antibodies |
CN111902411A (en) | 2018-01-03 | 2020-11-06 | 美真达治疗公司 | Compositions and methods for expanding hematopoietic stem and progenitor cells and treating inherited metabolic disorders |
EP3735467A4 (en) | 2018-01-05 | 2021-12-01 | Ottawa Hospital Research Institute | Modified vaccinia vectors |
US11713353B2 (en) | 2018-01-15 | 2023-08-01 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against PD-1 |
EP3740505A1 (en) | 2018-01-16 | 2020-11-25 | Lakepharma Inc. | Bispecific antibody that binds cd3 and another target |
AU2019218959A1 (en) | 2018-02-08 | 2020-09-03 | Genentech, Inc. | Bispecific antigen-binding molecules and methods of use |
TWI829667B (en) | 2018-02-09 | 2024-01-21 | 瑞士商赫孚孟拉羅股份公司 | Antibodies binding to gprc5d |
WO2019165434A1 (en) | 2018-02-26 | 2019-08-29 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2019173771A1 (en) | 2018-03-09 | 2019-09-12 | Cytomx Therapeutics, Inc. | Activatable cd147 antibodies and methods of making and use thereof |
BR112020014591A2 (en) | 2018-03-14 | 2020-12-01 | Beijing Xuanyi Pharmasciences Co., Ltd. | anticlaudin antibodies 18.2 |
US20200040103A1 (en) | 2018-03-14 | 2020-02-06 | Genentech, Inc. | Anti-klk5 antibodies and methods of use |
CA3093729A1 (en) | 2018-03-15 | 2019-09-19 | Chugai Seiyaku Kabushiki Kaisha | Anti-dengue virus antibodies having cross-reactivity to zika virus and methods of use |
CN112313248A (en) | 2018-03-29 | 2021-02-02 | 百时美施贵宝公司 | Method for purifying monomeric monoclonal antibodies |
AU2019245243A1 (en) | 2018-03-29 | 2020-09-03 | Genentech, Inc | Modulating lactogenic activity in mammalian cells |
EP3774917A4 (en) | 2018-03-30 | 2022-01-19 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies against lag-3 and uses thereof |
TW202011029A (en) | 2018-04-04 | 2020-03-16 | 美商建南德克公司 | Methods for detecting and quantifying FGF21 |
IT201800004253A1 (en) | 2018-04-05 | 2019-10-05 | Compositions and methods for the treatment of hereditary dominant catecholaminergic polymorphic ventricular tachycardia. | |
AU2019252941A1 (en) | 2018-04-13 | 2020-11-19 | Genentech, Inc. | Stable anti-CD79B immunoconjugate formulations |
AR114789A1 (en) | 2018-04-18 | 2020-10-14 | Hoffmann La Roche | ANTI-HLA-G ANTIBODIES AND THE USE OF THEM |
WO2019213416A1 (en) | 2018-05-02 | 2019-11-07 | The Usa, As Represented By The Secretary, Dept. Of Health And Human Services | Antibodies and methods for the diagnosis, prevention, and treatment of epstein barr virus infection |
JP2021524756A (en) | 2018-05-14 | 2021-09-16 | ウェアウルフ セラピューティクス, インコーポレイテッド | Activateable cytokine polypeptides and how to use them |
ES2955511T3 (en) | 2018-05-14 | 2023-12-04 | Werewolf Therapeutics Inc | Activatable interleukin 2 polypeptides and methods of use thereof |
EP3802609A2 (en) | 2018-05-24 | 2021-04-14 | Janssen Biotech, Inc. | Psma binding agents and uses thereof |
WO2019241758A1 (en) | 2018-06-15 | 2019-12-19 | Alpine Immune Sciences, Inc. | Pd-1 variant immunomodulatory proteins and uses thereof |
US11203645B2 (en) | 2018-06-27 | 2021-12-21 | Obi Pharma, Inc. | Glycosynthase variants for glycoprotein engineering and methods of use |
MX2020013885A (en) | 2018-06-29 | 2021-03-09 | Boehringer Ingelheim Int | Anti-cd40 antibodies for use in treating autoimmune disease. |
AU2019306628A1 (en) | 2018-07-20 | 2021-02-11 | Surface Oncology, Inc. | Anti-CD112R compositions and methods |
MA53333A (en) | 2018-07-31 | 2021-11-03 | Amgen Inc | PHARMACEUTICAL FORMULATIONS OF MASKED ANTIBODIES |
BR112021002130A2 (en) | 2018-08-08 | 2021-05-04 | Genentech, Inc. | liquid formulation, article of manufacture or kit and method for reducing oxidation of a polypeptide |
AU2019316575A1 (en) | 2018-08-10 | 2021-03-04 | Amgen Inc. | Method of preparing an antibody pharmaceutical formulation |
WO2020032230A1 (en) | 2018-08-10 | 2020-02-13 | 中外製薬株式会社 | Anti-cd137 antigen-binding molecule and utilization thereof |
EP3844189A1 (en) | 2018-08-31 | 2021-07-07 | Regeneron Pharmaceuticals, Inc. | Dosing strategy that mitigates cytokine release syndrome for cd3/c20 bispecific antibodies |
MA53493A (en) | 2018-08-31 | 2021-07-07 | Alx Oncology Inc | POLYPEPTIDES LURES |
SG11202102208WA (en) | 2018-09-04 | 2021-04-29 | Magenta Therapeutics Inc | Aryl hydrocarbon receptor antagonists and methods of use |
WO2020061210A1 (en) | 2018-09-18 | 2020-03-26 | Merrimack Pharmaceuticals, Inc. | Anti-tnfr2 antibodies and uses thereof |
AU2019342099A1 (en) | 2018-09-19 | 2021-04-08 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
EP4249917A3 (en) | 2018-09-21 | 2023-11-08 | F. Hoffmann-La Roche AG | Diagnostic methods for triple-negative breast cancer |
JP7425049B2 (en) | 2018-09-25 | 2024-01-30 | ハープーン セラピューティクス,インク. | DLL3 binding protein and method of use |
JP2022502088A (en) | 2018-09-27 | 2022-01-11 | エクシリオ デベロップメント, インコーポレイテッド | Masked cytokine polypeptide |
US20210380923A1 (en) | 2018-10-10 | 2021-12-09 | Boehringer Ingelheim International Gmbh | Method for membrane gas transfer in high density bioreactor culture |
JP2022504839A (en) | 2018-10-10 | 2022-01-13 | ティロス・セラピューティクス・インコーポレイテッド | Anti-LAP antibody mutants and their use |
WO2020080715A1 (en) | 2018-10-15 | 2020-04-23 | 연세대학교 산학협력단 | Productivity-enhanced antibody and method for producing same |
WO2020081493A1 (en) | 2018-10-16 | 2020-04-23 | Molecular Templates, Inc. | Pd-l1 binding proteins |
MX2021004348A (en) | 2018-10-18 | 2021-05-28 | Genentech Inc | Diagnostic and therapeutic methods for sarcomatoid kidney cancer. |
SG11202103124WA (en) | 2018-10-23 | 2021-04-29 | Glycardial Diagnostics S L | Antibodies specific for glycosylated apoj and uses thereof |
RU2724469C2 (en) | 2018-10-31 | 2020-06-23 | Закрытое Акционерное Общество "Биокад" | Monoclonal antibody which specifically binds to cd20 |
WO2020092881A1 (en) | 2018-11-02 | 2020-05-07 | Cytomx Therapeutics, Inc. | Activatable anti-cd166 antibodies and methods of use thereof |
HUP1800376A2 (en) | 2018-11-07 | 2020-05-28 | Richter Gedeon Nyrt | Method for modifying the glycosylation profile of a recombinant glycoprotein produced in cell culture |
EP3883610A4 (en) | 2018-11-20 | 2022-11-02 | Cornell University | Macrocyclic complexes of radionuclides and their use in radiotherapy of cancer |
JP2022510276A (en) | 2018-11-30 | 2022-01-26 | アルパイン イミューン サイエンシズ インコーポレイテッド | CD86 variant immunomodulatory protein and its use |
MX2021006544A (en) | 2018-12-04 | 2021-07-07 | Sumitomo Pharma Oncology Inc | Cdk9 inhibitors and polymorphs thereof for use as agents for treatment of cancer. |
AU2019394972A1 (en) | 2018-12-06 | 2021-06-03 | Cytomx Therapeutics, Inc. | Matrix metalloprotease-cleavable and serine or cysteine protease-cleavable substrates and methods of use thereof |
MX2021006573A (en) | 2018-12-06 | 2021-07-15 | Genentech Inc | Combination therapy of diffuse large b-cell lymphoma comprising an anti-cd79b immunoconjugates, an alkylating agent and an anti-cd20 antibody. |
WO2020123662A2 (en) | 2018-12-11 | 2020-06-18 | AdMIRx Inc. | Fusion protein constructs for complement associated disease |
EP3898667A2 (en) | 2018-12-20 | 2021-10-27 | F. Hoffmann-La Roche AG | Modified antibody fcs and methods of use |
CN113631714A (en) | 2018-12-21 | 2021-11-09 | 豪夫迈·罗氏有限公司 | Methods of producing polypeptides using apoptosis-resistant cell lines |
TWI829831B (en) | 2018-12-21 | 2024-01-21 | 瑞士商赫孚孟拉羅股份公司 | Antibodies binding to cd3 |
EP3902833A2 (en) | 2018-12-26 | 2021-11-03 | City of Hope | Activatable masked anti-ctla4 binding proteins |
WO2020154405A2 (en) | 2019-01-22 | 2020-07-30 | Genentech, Inc. | Immunoglobulin a antibodies and methods of production and use |
EP3914615A1 (en) | 2019-01-23 | 2021-12-01 | F. Hoffmann-La Roche AG | Methods of producing multimeric proteins in eukaryotic host cells |
JPWO2020153467A1 (en) | 2019-01-24 | 2021-12-02 | 中外製薬株式会社 | New cancer antigens and antibodies against those antigens |
PE20212198A1 (en) | 2019-01-29 | 2021-11-16 | Juno Therapeutics Inc | ANTIBODIES AND CHIMERIC RECEPTORS OF SPECIFIC ANTIGENS TO ORPHAN RECEPTOR 1, RECEPTOR TYROSINE KINASE TYPE (ROR1) |
US20220080053A1 (en) | 2019-02-07 | 2022-03-17 | Sanofi | Use of anti-ceacam5 immunoconjugates for treating lung cancer |
EP3693023A1 (en) | 2019-02-11 | 2020-08-12 | Sanofi | Use of anti-ceacam5 immunoconjugates for treating lung cancer |
CN113874394B (en) | 2019-02-20 | 2024-01-19 | 和铂抗体有限公司 | Antibodies to |
WO2020176672A1 (en) | 2019-02-26 | 2020-09-03 | Cytomx Therapeutics, Inc. | Combined therapies of activatable immune checkpoint inhibitors and conjugated activatable antibodies |
CN113710706A (en) | 2019-02-27 | 2021-11-26 | 豪夫迈·罗氏有限公司 | Administration for anti-TIGIT antibody and anti-CD 20 antibody or anti-CD 38 antibody treatment |
CA3131953A1 (en) | 2019-03-01 | 2020-09-10 | Merrimack Pharmaceuticals, Inc. | Anti-tnfr2 antibodies and uses thereof |
JP7420827B2 (en) | 2019-03-08 | 2024-01-23 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Anti-IL-36R antibody preparation |
MA55296A (en) | 2019-03-14 | 2022-03-23 | Hoffmann La Roche | CANCER TREATMENT WITH BISPECIFIC ANTIBODIES TO HER2XCD3 IN COMBINATION WITH AN ANTI-HER2 MAB |
WO2020191326A1 (en) | 2019-03-20 | 2020-09-24 | Sumitomo Dainippon Pharma Oncology, Inc. | Treatment of acute myeloid leukemia (aml) with venetoclax failure |
KR20220004979A (en) | 2019-03-27 | 2022-01-12 | 유엠씨 우트레크트 홀딩 비.브이. | Engineered IGA Antibodies and Methods of Use |
JP2022527493A (en) | 2019-03-29 | 2022-06-02 | ブリストル-マイヤーズ スクイブ カンパニー | How to measure the hydrophobicity of a chromatographic resin |
HUP1900112A1 (en) | 2019-04-04 | 2020-10-28 | Richter Gedeon Nyrt | Improvement of affinity chromatography of immunoglobulins by using pre-capture flocculation |
WO2020214963A1 (en) | 2019-04-18 | 2020-10-22 | Genentech, Inc. | Antibody potency assay |
TW202106876A (en) | 2019-04-19 | 2021-02-16 | 日商中外製藥股份有限公司 | Chimeric receptor recognizing modification site of antibody |
CN113747944A (en) | 2019-04-19 | 2021-12-03 | 詹森生物科技公司 | Methods of treating prostate cancer with anti-PSMA/CD 3 antibodies |
CN114364703A (en) | 2019-04-19 | 2022-04-15 | 豪夫迈·罗氏有限公司 | Anti-merk antibodies and methods of use thereof |
JOP20210300A1 (en) | 2019-05-09 | 2023-01-30 | Boehringer Ingelheim Int | Anti-sema3a antibodies and their uses for treating eye or ocular diseases |
JP2022536602A (en) | 2019-05-14 | 2022-08-18 | ジェネンテック, インコーポレイテッド | Methods of using anti-CD79B immunoconjugates to treat follicular lymphoma |
JP2022532217A (en) | 2019-05-14 | 2022-07-13 | ウェアウルフ セラピューティクス, インコーポレイテッド | Separation part and how to use it |
AR119264A1 (en) | 2019-06-05 | 2021-12-09 | Genentech Inc | METHOD FOR REUSE OF CHROMATOGRAPHY |
WO2020257525A1 (en) | 2019-06-20 | 2020-12-24 | Cspc Dophen Corporation | Modified il-2 proteins, peg conjugates, and uses thereof |
TW202115112A (en) | 2019-06-27 | 2021-04-16 | 德商百靈佳殷格翰國際股份有限公司 | Anti-angpt2 antibodies |
CN113950485A (en) | 2019-07-10 | 2022-01-18 | 中外制药株式会社 | Claudin-6 binding molecules and uses thereof |
JPWO2021010326A1 (en) | 2019-07-12 | 2021-01-21 | ||
AR119393A1 (en) | 2019-07-15 | 2021-12-15 | Hoffmann La Roche | ANTIBODIES THAT BIND NKG2D |
JP2022542863A (en) | 2019-07-24 | 2022-10-07 | ハー・ルンドベック・アクチエゼルスカベット | Anti-mGluR5 antibody and uses thereof |
CN112300279A (en) | 2019-07-26 | 2021-02-02 | 上海复宏汉霖生物技术股份有限公司 | Methods and compositions directed to anti-CD 73 antibodies and variants |
JP2022543551A (en) | 2019-07-31 | 2022-10-13 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Antibody that binds to GPRC5D |
JP2022543553A (en) | 2019-07-31 | 2022-10-13 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Antibody that binds to GPRC5D |
DE102019121007A1 (en) | 2019-08-02 | 2021-02-04 | Immatics Biotechnologies Gmbh | Antigen binding proteins that specifically bind to MAGE-A |
US20210032370A1 (en) | 2019-08-02 | 2021-02-04 | Immatics Biotechnologies Gmbh | Recruiting agent further binding an mhc molecule |
WO2021024020A1 (en) | 2019-08-06 | 2021-02-11 | Astellas Pharma Inc. | Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer |
TWI780464B (en) | 2019-08-06 | 2022-10-11 | 香港商新旭生技股份有限公司 | Antibodies that bind to pathological tau species and uses thereof |
MX2022002738A (en) | 2019-09-04 | 2022-06-27 | Genentech Inc | Cd8 binding agents and uses thereof. |
US20210130492A1 (en) | 2019-09-18 | 2021-05-06 | Genentech, Inc. | Anti-klk7 antibodies, anti-klk5 antibodies, multispecific anti-klk5/klk7 antibodies, and methods of use |
JP2022548310A (en) | 2019-09-23 | 2022-11-17 | シートムエックス セラピューティクス,インコーポレイテッド | Anti-CD47 antibodies, activatable anti-CD47 antibodies, and methods of use thereof |
TW202126685A (en) | 2019-09-24 | 2021-07-16 | 德商百靈佳殷格翰國際股份有限公司 | Anti-nrp1a antibodies and their uses for treating eye or ocular diseases |
CR20220127A (en) | 2019-09-27 | 2022-05-27 | Genentech Inc | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
CA3154710A1 (en) | 2019-10-04 | 2021-04-08 | TAE Life Sciences | Antibody compositions comprising fc mutations and site-specific conjugation properties |
JP7413519B2 (en) | 2019-10-18 | 2024-01-15 | ジェネンテック, インコーポレイテッド | Methods of using anti-CD79B immunoconjugates to treat diffuse large B-cell lymphoma |
US20220389103A1 (en) | 2019-11-06 | 2022-12-08 | Genentech, Inc. | Diagnostic and therapeutic methods for treatment of hematologic cancers |
MX2022005317A (en) | 2019-11-15 | 2022-05-26 | Hoffmann La Roche | Prevention of visible particle formation in aqueous protein solutions. |
WO2021113780A1 (en) | 2019-12-06 | 2021-06-10 | Juno Therapeutics, Inc. | Anti-idiotypic antibodies to gprc5d-targeted binding domains and related compositions and methods |
JP2023504740A (en) | 2019-12-06 | 2023-02-06 | ジュノー セラピューティクス インコーポレイテッド | Anti-idiotypic antibodies against BCMA target binding domains and related compositions and methods |
PE20221511A1 (en) | 2019-12-13 | 2022-10-04 | Genentech Inc | ANTI-LY6G6D ANTIBODIES AND METHODS OF USE |
PE20221282A1 (en) | 2019-12-18 | 2022-09-05 | Hoffmann La Roche | ANTIBODIES THAT BIND HLA-A2/MAGE-A4 |
KR20220118527A (en) | 2019-12-23 | 2022-08-25 | 제넨테크, 인크. | Apolipoprotein L1-specific antibodies and methods of use |
US20230058982A1 (en) | 2019-12-27 | 2023-02-23 | Chugai Seiyaku Kabushiki Kaisha | Anti-ctla-4 antibody and use thereof |
US20230057263A1 (en) | 2020-01-06 | 2023-02-23 | Cytomx Therapeutics, Inc. | Single-and multi-chain polypeptides that bind specifically to cd3 epsilon |
CN110818795B (en) | 2020-01-10 | 2020-04-24 | 上海复宏汉霖生物技术股份有限公司 | anti-TIGIT antibodies and methods of use |
EP4090365A1 (en) | 2020-01-15 | 2022-11-23 | Immatics Biotechnologies GmbH | Antigen binding proteins specifically binding prame |
WO2021194481A1 (en) | 2020-03-24 | 2021-09-30 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2022050954A1 (en) | 2020-09-04 | 2022-03-10 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
AU2021212193A1 (en) | 2020-01-31 | 2022-09-08 | Celgene Corporation | Anti-CD30 antibody-drug conjugates and their use for the treatment of non-Hodgkin lymphoma |
TW202144395A (en) | 2020-02-12 | 2021-12-01 | 日商中外製藥股份有限公司 | Anti-CD137 antigen-binding molecule for use in cancer treatment |
WO2021174045A1 (en) | 2020-02-28 | 2021-09-02 | Bristol-Myers Squibb Company | Radiolabeled fibronectin based scaffolds and antibodies and theranostic uses thereof |
IL295590A (en) | 2020-02-28 | 2022-10-01 | Genzyme Corp | Modified binding polypeptides for optimized drug conjugation |
GB202003632D0 (en) | 2020-03-12 | 2020-04-29 | Harbour Antibodies Bv | SARS-Cov-2 (SARS2, COVID-19) antibodies |
WO2021183849A1 (en) | 2020-03-13 | 2021-09-16 | Genentech, Inc. | Anti-interleukin-33 antibodies and uses thereof |
EP4121163A1 (en) | 2020-03-19 | 2023-01-25 | Genentech, Inc. | Isoform-selective anti-tgf-beta antibodies and methods of use |
JP2023518841A (en) | 2020-03-26 | 2023-05-08 | ジェネンテック, インコーポレイテッド | Modified mammalian cells with reduced host cell proteins |
CN115776987A (en) | 2020-03-31 | 2023-03-10 | 瑞佩尔托利免疫医药股份有限公司 | Barcoded exchangeable peptide-MHC multimer libraries |
CN115698717A (en) | 2020-04-03 | 2023-02-03 | 基因泰克公司 | Methods of treatment and diagnosis of cancer |
US20230272056A1 (en) | 2020-04-09 | 2023-08-31 | Merck Sharp & Dohme Llc | Affinity matured anti-lap antibodies and uses thereof |
MX2022012592A (en) | 2020-04-10 | 2022-12-07 | Cytomx Therapeutics Inc | Activatable cytokine constructs and related compositions and methods. |
WO2021214222A1 (en) | 2020-04-24 | 2021-10-28 | Sanofi | Antitumor combinations containing anti-ceacam5 antibody conjugates, trifluridine and tipiracil |
CN115427083A (en) | 2020-04-24 | 2022-12-02 | 赛诺菲 | Antitumor combination comprising anti-CEACAM 5 antibody conjugate and cetuximab |
EP4138926A1 (en) | 2020-04-24 | 2023-03-01 | Sanofi | Antitumor combinations containing anti-ceacam5 antibody conjugates and folfox |
TW202206111A (en) | 2020-04-24 | 2022-02-16 | 美商建南德克公司 | Methods of using anti-cd79b immunoconjugates |
AU2021261553A1 (en) | 2020-04-24 | 2023-01-05 | Sanofi | Antitumor combinations containing anti-CEACAM5 antibody conjugates and FOLFIFI |
EP4143345A1 (en) | 2020-04-28 | 2023-03-08 | Genentech, Inc. | Methods and compositions for non-small cell lung cancer immunotherapy |
EP4146797A1 (en) | 2020-05-06 | 2023-03-15 | Orchard Therapeutics (Europe) Limited | Treatment for neurodegenerative diseases |
JP2023520249A (en) | 2020-05-15 | 2023-05-16 | エフ. ホフマン-ラ ロシュ アーゲー | Method for preventing visible particle formation in parenteral protein solutions |
JP2023525898A (en) | 2020-05-19 | 2023-06-19 | エフ. ホフマン-ラ ロシュ アーゲー | Use of Chelating Agents to Prevent Formation of Visible Particles in Parenteral Protein Solutions |
GB202007842D0 (en) | 2020-05-26 | 2020-07-08 | Quell Therapeutics Ltd | Polypeptide useful in adoptive cell therapy |
CN115956087A (en) | 2020-05-26 | 2023-04-11 | 勃林格殷格翰国际有限公司 | anti-PD-1 antibodies |
MX2022015651A (en) | 2020-06-11 | 2023-01-16 | Genentech Inc | Nanolipoprotein-polypeptide conjugates and compositions, systems, and methods using same. |
EP4165415A1 (en) | 2020-06-12 | 2023-04-19 | Genentech, Inc. | Methods and compositions for cancer immunotherapy |
KR20230025691A (en) | 2020-06-16 | 2023-02-22 | 제넨테크, 인크. | Methods and compositions for treating triple negative breast cancer |
EP4168118A1 (en) | 2020-06-18 | 2023-04-26 | Genentech, Inc. | Treatment with anti-tigit antibodies and pd-1 axis binding antagonists |
AU2021291011A1 (en) | 2020-06-19 | 2023-01-05 | F. Hoffmann-La Roche Ag | Antibodies binding to CD3 and CD19 |
WO2021255146A1 (en) | 2020-06-19 | 2021-12-23 | F. Hoffmann-La Roche Ag | Antibodies binding to cd3 and cea |
WO2021255143A1 (en) | 2020-06-19 | 2021-12-23 | F. Hoffmann-La Roche Ag | Antibodies binding to cd3 and folr1 |
AU2021291407A1 (en) | 2020-06-19 | 2022-09-29 | F. Hoffmann-La Roche Ag | Antibodies binding to CD3 |
WO2021262783A1 (en) | 2020-06-24 | 2021-12-30 | Genentech, Inc. | Apoptosis resistant cell lines |
WO2022006562A1 (en) | 2020-07-03 | 2022-01-06 | Dana-Farber Cancer Institute, Inc. | Multispecific coronavirus antibodies |
WO2022008468A1 (en) | 2020-07-07 | 2022-01-13 | F. Hoffmann-La Roche Ag | Alternative surfactants as stabilizers for therapeutic protein formulations |
CA3182579A1 (en) | 2020-07-07 | 2022-01-13 | Ugur Sahin | Therapeutic rna for hpv-positive cancer |
JP2023540429A (en) | 2020-07-10 | 2023-09-25 | アンセルム(アンスティチュート・ナシオナル・ドゥ・ラ・サンテ・エ・ドゥ・ラ・ルシェルシュ・メディカル) | Methods and compositions for treating epilepsy |
WO2022015726A1 (en) | 2020-07-13 | 2022-01-20 | Genentech, Inc. | Cell-based methods for predicting polypeptide immunogenicity |
AU2021308653A1 (en) | 2020-07-17 | 2023-02-16 | Genentech, Inc. | Anti-Notch2 antibodies and methods of use |
CA3189732A1 (en) | 2020-07-20 | 2022-01-27 | Dana-Farber Cancer Institute, Inc. | Methods and compositions for treatment and prevention of coronavirus infection |
EP4192868A1 (en) | 2020-08-05 | 2023-06-14 | Juno Therapeutics, Inc. | Anti-idiotypic antibodies to ror1-targeted binding domains and related compositions and methods |
EP4192511A1 (en) | 2020-08-07 | 2023-06-14 | Fortis Therapeutics, Inc. | Immunoconjugates targeting cd46 and methods of use thereof |
CA3188426A1 (en) | 2020-08-07 | 2022-02-10 | Yichin Liu | Flt3 ligand fusion proteins and methods of use |
JP2023537683A (en) | 2020-08-07 | 2023-09-05 | ジェネンテック, インコーポレイテッド | T cell-based methods for predicting polypeptide immunogenicity |
US20230295258A1 (en) | 2020-08-11 | 2023-09-21 | Kanaph Therapeutics Inc. | Fusion protein comprising il-12 and anti-fap antibody, and use thereof |
GB202013477D0 (en) | 2020-08-27 | 2020-10-14 | Quell Therapeutics Ltd | Nucleic acid constructs for expressing polypeptides in cells |
KR20230056766A (en) | 2020-08-28 | 2023-04-27 | 제넨테크, 인크. | CRISPR/Cas9 multiple knockout of host cell proteins |
BR112023001733A2 (en) | 2020-09-04 | 2023-03-28 | Merck Patent Gmbh | ANTI-CEACAM5 AND CONJUGATE ANTIBODIES AND THEIR USES |
CN116406291A (en) | 2020-10-05 | 2023-07-07 | 基因泰克公司 | Administration of treatment with anti-FCRH 5/anti-CD 3 bispecific antibodies |
WO2022087154A1 (en) | 2020-10-20 | 2022-04-28 | Repertoire Immune Medicines, Inc. | Mhc class ii peptide multimers and uses thereof |
TW202233671A (en) | 2020-10-20 | 2022-09-01 | 美商建南德克公司 | Peg-conjugated anti-mertk antibodies and methods of use |
US20220162329A1 (en) | 2020-11-04 | 2022-05-26 | Genentech, Inc. | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies |
JP2023548064A (en) | 2020-11-04 | 2023-11-15 | ジェネンテック, インコーポレイテッド | Administration for treatment with anti-CD20/anti-CD3 bispecific antibody and anti-CD79B antibody drug conjugate |
EP4240766A2 (en) | 2020-11-04 | 2023-09-13 | Genentech, Inc. | Subcutaneous dosing of anti-cd20/anti-cd3 bispecific antibodies |
EP4240494A1 (en) | 2020-11-06 | 2023-09-13 | Novartis AG | Anti-cd19 agent and b cell targeting agent combination therapy for treating b cell malignancies |
WO2022135667A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
TW202245808A (en) | 2020-12-21 | 2022-12-01 | 德商拜恩迪克公司 | Therapeutic rna for treating cancer |
WO2022135666A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Treatment schedule for cytokine proteins |
WO2022140797A1 (en) | 2020-12-23 | 2022-06-30 | Immunowake Inc. | Immunocytokines and uses thereof |
WO2022159575A1 (en) | 2021-01-20 | 2022-07-28 | Bioentre Llc | Ctla4-binding proteins and methods of treating cancer |
AU2022213913A1 (en) | 2021-01-27 | 2023-08-17 | Innovent Biologics (Suzhou) Co., Ltd. | Single-domain antibody against cd16a and use thereof |
BR112023015097A2 (en) | 2021-01-28 | 2023-10-03 | Janssen Biotech Inc | PSMA-BINDING PROTEINS AND USES THEREOF |
JP2024509695A (en) | 2021-02-03 | 2024-03-05 | ジェネンテック, インコーポレイテッド | Multispecific binding proteolysis platform and methods of use |
EP4288457A2 (en) | 2021-02-05 | 2023-12-13 | Boehringer Ingelheim International GmbH | Anti-il1rap antibodies |
TW202317612A (en) | 2021-03-01 | 2023-05-01 | 美商艾希利歐發展股份有限公司 | Combination of ctla4 and pd1/pdl1 antibodies for treating cancer |
EP4301781A1 (en) | 2021-03-01 | 2024-01-10 | Xilio Development, Inc. | Combination of masked ctla4 and pd1/pdl1 antibodies for treating cancer |
IL305758A (en) | 2021-03-10 | 2023-11-01 | Immunowake Inc | Immunomodulatory molecules and uses thereof |
AR125074A1 (en) | 2021-03-12 | 2023-06-07 | Genentech Inc | ANTI-KLK7 ANTIBODIES, ANTI-KLK5 ANTIBODIES, ANTI-KLK5/KLK7 MULTI-SPECIFIC ANTIBODIES AND METHODS OF USE |
CA3211924A1 (en) | 2021-03-16 | 2022-09-22 | Sayantan Mitra | Masked activatable cytokine constructs and related compositions and methods |
AU2022241935A1 (en) | 2021-03-22 | 2023-09-28 | Novimmune S.A. | Bispecific antibodies targeting cd47 and pd-l1 and methods of use thereof |
WO2022200389A1 (en) | 2021-03-22 | 2022-09-29 | Novimmune S.A. | Bispecific antibodies targeting cd47 and pd-l1 and methods of use thereof |
JP2024511424A (en) | 2021-03-25 | 2024-03-13 | ダイナミキュア バイオテクノロジー エルエルシー | Anti-IGFBP7 construct and its use |
TW202304524A (en) | 2021-04-10 | 2023-02-01 | 美商普方生物製藥美國公司 | Folr1 binding agents, conjugates thereof and methods of using the same |
AR125344A1 (en) | 2021-04-15 | 2023-07-05 | Chugai Pharmaceutical Co Ltd | ANTI-C1S ANTIBODY |
TW202305122A (en) | 2021-04-19 | 2023-02-01 | 美商建南德克公司 | Modified mammalian cells |
EP4326768A1 (en) | 2021-04-23 | 2024-02-28 | Profoundbio Us Co. | Anti-cd70 antibodies, conjugates thereof and methods of using the same |
AU2021443863A1 (en) | 2021-04-30 | 2023-10-26 | F. Hoffmann-La Roche Ag | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibody |
EP4330282A1 (en) | 2021-04-30 | 2024-03-06 | F. Hoffmann-La Roche AG | Dosing for combination treatment with anti-cd20/anti-cd3 bispecific antibody and anti-cd79b antibody drug conjugate |
EP4334354A1 (en) | 2021-05-06 | 2024-03-13 | Dana-Farber Cancer Institute, Inc. | Antibodies against alk and methods of use thereof |
WO2022236047A1 (en) | 2021-05-07 | 2022-11-10 | Viela Bio, Inc. | Use of an anti-cd19 antibody to treat myasthenia gravis |
EP4342497A1 (en) | 2021-05-10 | 2024-03-27 | Kawasaki Institute of Industrial Promotion | Antibody having reduced binding affinity for antigen |
IL308351A (en) | 2021-05-12 | 2024-01-01 | Genentech Inc | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
KR20240010469A (en) | 2021-05-21 | 2024-01-23 | 제넨테크, 인크. | Modified cells for production of recombinant products of interest |
TW202306994A (en) | 2021-06-04 | 2023-02-16 | 日商中外製藥股份有限公司 | Anti-ddr2 antibodies and uses thereof |
WO2022261183A2 (en) | 2021-06-08 | 2022-12-15 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for treating and/or identifying an agent for treating intestinal cancers |
CN117412988A (en) | 2021-06-08 | 2024-01-16 | 修普霍斯生物科学有限公司 | antibody-NKG 2D ligand domain fusion proteins |
BR112023025884A2 (en) | 2021-06-08 | 2024-02-27 | Xyphos Biosciences Inc | NKG2D ANTIBODY LIGAND DOMAIN FUSION PROTEIN |
WO2022270612A1 (en) | 2021-06-25 | 2022-12-29 | 中外製薬株式会社 | Use of anti-ctla-4 antibody |
JP7472405B2 (en) | 2021-06-25 | 2024-04-22 | 中外製薬株式会社 | Anti-CTLA-4 antibody |
TW202320857A (en) | 2021-07-06 | 2023-06-01 | 美商普方生物製藥美國公司 | Linkers, drug linkers and conjugates thereof and methods of using the same |
AU2022312698A1 (en) | 2021-07-13 | 2024-01-25 | BioNTech SE | Multispecific binding agents against cd40 and cd137 in combination therapy for cancer |
AU2022317215A1 (en) | 2021-07-27 | 2024-02-29 | Astrazeneca Ab | Treatment of lupus |
WO2023012147A1 (en) | 2021-08-03 | 2023-02-09 | F. Hoffmann-La Roche Ag | Bispecific antibodies and methods of use |
WO2023019092A1 (en) | 2021-08-07 | 2023-02-16 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
WO2023017098A2 (en) | 2021-08-11 | 2023-02-16 | King's College London | Compositions and methods for improved treatment of disorders affecting the central nervous system |
WO2023028591A1 (en) | 2021-08-27 | 2023-03-02 | Genentech, Inc. | Methods of treating tau pathologies |
WO2023036982A1 (en) | 2021-09-10 | 2023-03-16 | Harbour Antibodies Bv | Anti-sars2-s antibodies |
GB202112935D0 (en) | 2021-09-10 | 2021-10-27 | Harbour Antibodies Bv | Sars-cov-2 (sars2, covid-19) heavy chain only antibodies |
TW202321308A (en) | 2021-09-30 | 2023-06-01 | 美商建南德克公司 | Methods for treatment of hematologic cancers using anti-tigit antibodies, anti-cd38 antibodies, and pd-1 axis binding antagonists |
TW202334187A (en) | 2021-10-08 | 2023-09-01 | 美商Cytomx生物製藥公司 | Activatable cytokine constructs and related compositions and methods |
CA3233707A1 (en) | 2021-10-08 | 2023-04-13 | Alexey Yevgenyevich Berezhnoy | Activatable cytokine constructs and combination methods |
TW202333802A (en) | 2021-10-11 | 2023-09-01 | 德商拜恩迪克公司 | Therapeutic rna for lung cancer |
TW202334186A (en) | 2021-10-13 | 2023-09-01 | 美商Cytomx生物製藥公司 | Trimeric activatable cytokine constructs and related compositions and methods |
TW202333797A (en) | 2021-11-05 | 2023-09-01 | 法商賽諾菲公司 | Antitumor combinations containing anti-ceacam5 antibody-drug conjugates and anti-vegfr-2 antibodies |
WO2023081471A1 (en) | 2021-11-05 | 2023-05-11 | Dana-Farber Cancer Institute, Inc. | Human broadly crossreactive influenza monoclonal antibodies and methods of use thereof |
WO2023097024A1 (en) | 2021-11-24 | 2023-06-01 | Dana-Farber Cancer Institute, Inc. | Antibodies against ctla-4 and methods of use thereof |
WO2023097119A2 (en) | 2021-11-29 | 2023-06-01 | Dana-Farber Cancer Institute, Inc. | Methods and compositions to modulate riok2 |
WO2023099682A1 (en) | 2021-12-02 | 2023-06-08 | Sanofi | Ceacam5 adc–anti-pd1/pd-l1 combination therapy |
TW202339804A (en) | 2021-12-02 | 2023-10-16 | 法商賽諾菲公司 | Cea assay for patient selection in cancer therapy |
AR127887A1 (en) | 2021-12-10 | 2024-03-06 | Hoffmann La Roche | ANTIBODIES THAT BIND CD3 AND PLAP |
WO2023114543A2 (en) | 2021-12-17 | 2023-06-22 | Dana-Farber Cancer Institute, Inc. | Platform for antibody discovery |
WO2023114544A1 (en) | 2021-12-17 | 2023-06-22 | Dana-Farber Cancer Institute, Inc. | Antibodies and uses thereof |
AR128065A1 (en) | 2021-12-22 | 2024-03-20 | Cdr Life Ag | ANTI-C3 ANTIBODIES AND ANTIGEN-BINDING FRAGMENTS THEREOF AND THEIR USES TO TREAT OPHTHALMIC OR EYE DISEASES |
GB2614309A (en) | 2021-12-24 | 2023-07-05 | Stratosvir Ltd | Improved vaccinia virus vectors |
WO2023131901A1 (en) | 2022-01-07 | 2023-07-13 | Johnson & Johnson Enterprise Innovation Inc. | Materials and methods of il-1beta binding proteins |
US20230322958A1 (en) | 2022-01-19 | 2023-10-12 | Genentech, Inc. | Anti-Notch2 Antibodies and Conjugates and Methods of Use |
WO2023150552A1 (en) | 2022-02-04 | 2023-08-10 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for treatment of neurological disorders |
TW202342520A (en) | 2022-02-18 | 2023-11-01 | 美商樂天醫藥生技股份有限公司 | Anti-programmed death-ligand 1 (pd-l1) antibody molecules, encoding polynucleotides, and methods of use |
EP4238988A1 (en) | 2022-03-01 | 2023-09-06 | Consejo Superior De Investigaciones Científicas | Antibodies against sars-cov-2 and uses thereof |
WO2023172883A1 (en) | 2022-03-07 | 2023-09-14 | Alpine Immune Sciences, Inc. | Immunomodulatory proteins of variant cd80 polypeptides, cell therapies thereof and related methods and uses |
WO2023172968A1 (en) | 2022-03-09 | 2023-09-14 | Merck Patent Gmbh | Anti-gd2 antibodies, immunoconjugates and therapeutic uses thereof |
WO2023170240A1 (en) | 2022-03-09 | 2023-09-14 | Merck Patent Gmbh | Anti-ceacam5 antibodies and conjugates and uses thereof |
WO2023178357A1 (en) | 2022-03-18 | 2023-09-21 | Evolveimmune Therapeutics, Inc. | Bispecific antibody fusion molecules and methods of use thereof |
WO2023175171A1 (en) | 2022-03-18 | 2023-09-21 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Bk polyomavirus antibodies and uses thereof |
TW202346365A (en) | 2022-03-23 | 2023-12-01 | 瑞士商赫孚孟拉羅股份公司 | Combination treatment of an anti-cd20/anti-cd3 bispecific antibody and chemotherapy |
WO2023183923A1 (en) | 2022-03-25 | 2023-09-28 | Cytomx Therapeutics, Inc. | Activatable dual-anchored masked molecules and methods of use thereof |
WO2023192606A2 (en) | 2022-04-01 | 2023-10-05 | Cytomx Therapeutics, Inc. | Cd3-binding proteins and methods of use thereof |
WO2023192973A1 (en) | 2022-04-01 | 2023-10-05 | Cytomx Therapeutics, Inc. | Activatable multispecific molecules and methods of use thereof |
WO2023191816A1 (en) | 2022-04-01 | 2023-10-05 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
US20230406930A1 (en) | 2022-04-13 | 2023-12-21 | Genentech, Inc. | Pharmaceutical compositions of therapeutic proteins and methods of use |
WO2023198727A1 (en) | 2022-04-13 | 2023-10-19 | F. Hoffmann-La Roche Ag | Pharmaceutical compositions of anti-cd20/anti-cd3 bispecific antibodies and methods of use |
WO2023215737A1 (en) | 2022-05-03 | 2023-11-09 | Genentech, Inc. | Anti-ly6e antibodies, immunoconjugates, and uses thereof |
WO2023215498A2 (en) | 2022-05-05 | 2023-11-09 | Modernatx, Inc. | Compositions and methods for cd28 antagonism |
WO2023219613A1 (en) | 2022-05-11 | 2023-11-16 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2023240058A2 (en) | 2022-06-07 | 2023-12-14 | Genentech, Inc. | Prognostic and therapeutic methods for cancer |
WO2023240287A1 (en) | 2022-06-10 | 2023-12-14 | Bioentre Llc | Combinations of ctla4 binding proteins and methods of treating cancer |
WO2023245105A1 (en) | 2022-06-17 | 2023-12-21 | Genentech, Inc. | Use of kosmotropes to enhance yield of an affinity chromatography purification step |
WO2024015897A1 (en) | 2022-07-13 | 2024-01-18 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2024020432A1 (en) | 2022-07-19 | 2024-01-25 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2024020564A1 (en) | 2022-07-22 | 2024-01-25 | Genentech, Inc. | Anti-steap1 antigen-binding molecules and uses thereof |
WO2024030847A1 (en) | 2022-08-01 | 2024-02-08 | Cytomx Therapeutics, Inc. | Protease-cleavable moieties and methods of use thereof |
WO2024030845A1 (en) | 2022-08-01 | 2024-02-08 | Cytomx Therapeutics, Inc. | Protease-cleavable moieties and methods of use thereof |
WO2024030850A1 (en) | 2022-08-01 | 2024-02-08 | Cytomx Therapeutics, Inc. | Protease-cleavable substrates and methods of use thereof |
WO2024030843A1 (en) | 2022-08-01 | 2024-02-08 | Cytomx Therapeutics, Inc. | Protease-cleavable moieties and methods of use thereof |
WO2024030858A1 (en) | 2022-08-01 | 2024-02-08 | Cytomx Therapeutics, Inc. | Protease-cleavable substrates and methods of use thereof |
WO2024039672A2 (en) | 2022-08-15 | 2024-02-22 | Dana-Farber Cancer Institute, Inc. | Antibodies against msln and methods of use thereof |
WO2024039670A1 (en) | 2022-08-15 | 2024-02-22 | Dana-Farber Cancer Institute, Inc. | Antibodies against cldn4 and methods of use thereof |
WO2024044779A2 (en) | 2022-08-26 | 2024-02-29 | Juno Therapeutics, Inc. | Antibodies and chimeric antigen receptors specific for delta-like ligand 3 (dll3) |
WO2024049949A1 (en) | 2022-09-01 | 2024-03-07 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
WO2024056902A2 (en) | 2022-09-16 | 2024-03-21 | Christopher Shaw | Compositions and methods for treating neurological diseases |
WO2024079078A1 (en) | 2022-10-10 | 2024-04-18 | Uniqure France | Methods and compositions for treating epilepsy |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5439665A (en) * | 1988-07-29 | 1995-08-08 | Immunomedics | Detection and treatment of infectious and inflammatory lesions |
US5595721A (en) * | 1993-09-16 | 1997-01-21 | Coulter Pharmaceutical, Inc. | Radioimmunotherapy of lymphoma using anti-CD20 |
US5736137A (en) * | 1992-11-13 | 1998-04-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US5843439A (en) * | 1992-11-13 | 1998-12-01 | Anderson; Darrell R. | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US6183744B1 (en) * | 1997-03-24 | 2001-02-06 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
US6306393B1 (en) * | 1997-03-24 | 2001-10-23 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
USRE38008E1 (en) * | 1986-10-09 | 2003-02-25 | Neorx Corporation | Methods for improved targeting of antibody, antibody fragments, hormones and other targeting agents, and conjugates thereof |
Family Cites Families (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
EP0173494A3 (en) * | 1984-08-27 | 1987-11-25 | The Board Of Trustees Of The Leland Stanford Junior University | Chimeric receptors by dna splicing and expression |
AU606320B2 (en) | 1985-11-01 | 1991-02-07 | International Genetic Engineering, Inc. | Modular assembly of antibody genes, antibodies prepared thereby and use |
US4831175A (en) | 1986-09-05 | 1989-05-16 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Backbone polysubstituted chelates for forming a metal chelate-protein conjugate |
US5246692A (en) | 1986-09-05 | 1993-09-21 | The United States Of America As Represented By The Secretary Of Health And Human Services | Backbone polysubstituted chelates for forming a metal chelate-protein conjugate |
US5099069A (en) | 1986-09-05 | 1992-03-24 | Gansow Otto A | Backbone polysubstituted chelates for forming a metal chelate-protein conjugate |
US6893625B1 (en) | 1986-10-27 | 2005-05-17 | Royalty Pharma Finance Trust | Chimeric antibody with specificity to human B cell surface antigen |
IL85035A0 (en) | 1987-01-08 | 1988-06-30 | Int Genetic Eng | Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same |
CA1341235C (en) | 1987-07-24 | 2001-05-22 | Randy R. Robinson | Modular assembly of antibody genes, antibodies prepared thereby and use |
US4975278A (en) | 1988-02-26 | 1990-12-04 | Bristol-Myers Company | Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells |
IL162181A (en) * | 1988-12-28 | 2006-04-10 | Pdl Biopharma Inc | A method of producing humanized immunoglubulin, and polynucleotides encoding the same |
US5460785A (en) | 1989-08-09 | 1995-10-24 | Rhomed Incorporated | Direct labeling of antibodies and other protein with metal ions |
SE8903003D0 (en) | 1989-09-12 | 1989-09-12 | Astra Ab | NOVEL MEDICAL USE |
US5124471A (en) | 1990-03-26 | 1992-06-23 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Bifunctional dtpa-type ligand |
WO1992007466A1 (en) | 1990-11-05 | 1992-05-14 | Bristol-Myers Squibb Company | Synergistic therapy with combinations of anti-tumor antibodies and biologically active agents |
DE4124248A1 (en) | 1991-07-22 | 1993-01-28 | Henkel Kgaa | METHOD FOR SELECTIVE FAT CLEAVING, SUITABLE LIPASE MIXTURE AND MICROORGANISM |
DE69233011T2 (en) | 1991-07-25 | 2003-11-06 | Idec Pharma Corp | RECOMBINANT ANTIBODIES FOR HUMAN THERAPY |
IE922437A1 (en) | 1991-07-25 | 1993-01-27 | Idec Pharma Corp | Recombinant antibodies for human therapy |
US5686072A (en) | 1992-06-17 | 1997-11-11 | Board Of Regents, The University Of Texas | Epitope-specific monoclonal antibodies and immunotoxins and uses thereof |
US7744877B2 (en) | 1992-11-13 | 2010-06-29 | Biogen Idec Inc. | Expression and use of anti-CD20 Antibodies |
US5648267A (en) | 1992-11-13 | 1997-07-15 | Idec Pharmaceuticals Corporation | Impaired dominant selectable marker sequence and intronic insertion strategies for enhancement of expression of gene product and expression vector systems comprising same |
EP1112084B2 (en) | 1998-08-11 | 2012-04-25 | Biogen Idec Inc. | Combination therapies for b-cell lymphomas comprising administration of anti-cd20 antibody |
MY155913A (en) | 1998-11-09 | 2015-12-15 | Biogen Inc | Chimeric anti-cd20 antibody treatment of patients receiving bmt or pbsc transpants |
WO2000027428A1 (en) | 1998-11-09 | 2000-05-18 | Idec Pharmaceuticals Corporation | Treatment of hematologic malignancies associated with circulating tumor cells using chimeric anti-cd20 antibody |
US8557244B1 (en) | 1999-08-11 | 2013-10-15 | Biogen Idec Inc. | Treatment of aggressive non-Hodgkins lymphoma with anti-CD20 antibody |
CN1437478A (en) | 2000-04-25 | 2003-08-20 | Idec药物公司 | Intrathecal administration of Rituximab for treatment of central nervous system lymphomas |
SI1558648T1 (en) | 2002-10-17 | 2012-05-31 | Genmab As | Human monoclonal antibodies against cd20 |
DE60332957D1 (en) | 2002-12-16 | 2010-07-22 | Genentech Inc | IMMUNOGLOBULIN VARIANTS AND ITS USES |
-
1993
- 1993-11-12 CA CA002149329A patent/CA2149329C/en not_active Expired - Lifetime
- 1993-11-12 AU AU56032/94A patent/AU688743B2/en not_active Expired
- 1993-11-12 DE DE69303494T patent/DE69303494T2/en not_active Expired - Lifetime
- 1993-11-12 AT AT94901444T patent/ATE139900T1/en active
- 1993-11-12 PL PL93309002A patent/PL174494B1/en unknown
- 1993-11-12 WO PCT/US1993/010953 patent/WO1994011026A2/en active IP Right Grant
- 1993-11-12 EP EP96200772A patent/EP0752248B1/en not_active Expired - Lifetime
- 1993-11-12 DK DK96200772T patent/DK0752248T3/en active
- 1993-11-12 NZ NZ258392A patent/NZ258392A/en not_active IP Right Cessation
- 1993-11-12 ES ES96200772T patent/ES2152483T3/en not_active Expired - Lifetime
- 1993-11-12 DE DE69329503T patent/DE69329503T2/en not_active Expired - Lifetime
- 1993-11-12 AT AT96200772T patent/ATE196606T1/en active
- 1993-11-12 RO RO95-00888A patent/RO118524B1/en unknown
- 1993-11-12 PT PT96200772T patent/PT752248E/en unknown
- 1993-11-12 PL PL93320658A patent/PL174721B1/en unknown
- 1993-11-12 MD MD95-0311A patent/MD1367C2/en unknown
- 1993-11-12 EP EP99123967A patent/EP1005870B1/en not_active Expired - Lifetime
- 1993-11-12 RU RU95112506A patent/RU2139731C1/en active
- 1993-11-12 EP EP94901444A patent/EP0669836B1/en not_active Expired - Lifetime
- 1993-11-12 JP JP06512376A patent/JP3095175B2/en not_active Expired - Lifetime
- 1993-11-12 DE DE200412000036 patent/DE122004000036I1/en active Pending
- 1993-11-12 ES ES94901444T patent/ES2091684T3/en not_active Expired - Lifetime
- 1993-11-12 DK DK94901444.3T patent/DK0669836T3/en active
-
1995
- 1995-05-12 NO NO19951903A patent/NO321137B1/en not_active IP Right Cessation
- 1995-05-12 FI FI952327A patent/FI112033B/en not_active IP Right Cessation
- 1995-06-05 BG BG99701A patent/BG62386B1/en unknown
- 1995-06-07 US US08/475,813 patent/US6682734B1/en not_active Expired - Lifetime
- 1995-06-07 US US08/476,275 patent/US5776456A/en not_active Expired - Lifetime
- 1995-06-07 US US08/478,967 patent/US5843439A/en not_active Expired - Lifetime
- 1995-06-07 US US08/475,815 patent/US6399061B1/en not_active Expired - Lifetime
-
1996
- 1996-08-07 GR GR960402096T patent/GR3020731T3/en unknown
- 1996-09-17 LV LVP-96-373A patent/LV11732B/en unknown
-
2000
- 2000-04-21 JP JP2000126317A patent/JP4091235B2/en not_active Expired - Lifetime
- 2000-12-19 GR GR20000402807T patent/GR3035119T3/en unknown
-
2001
- 2001-07-17 US US09/905,928 patent/US20030021781A1/en not_active Abandoned
- 2001-07-25 US US09/911,692 patent/US7381560B2/en not_active Expired - Fee Related
- 2001-07-25 US US09/911,703 patent/US7422739B2/en not_active Expired - Fee Related
-
2004
- 2004-07-16 LU LU91089C patent/LU91089I2/en unknown
- 2004-07-16 NL NL300156C patent/NL300156I2/en unknown
- 2004-10-04 US US10/956,039 patent/US20050186205A1/en not_active Abandoned
-
2006
- 2006-03-07 NO NO20061094A patent/NO326271B1/en not_active IP Right Cessation
- 2006-03-07 NO NO20061095A patent/NO329146B1/en not_active IP Right Cessation
- 2006-05-15 JP JP2006135870A patent/JP4203080B2/en not_active Expired - Lifetime
- 2006-09-18 NO NO2006011C patent/NO2006011I2/en unknown
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE38008E1 (en) * | 1986-10-09 | 2003-02-25 | Neorx Corporation | Methods for improved targeting of antibody, antibody fragments, hormones and other targeting agents, and conjugates thereof |
US5439665A (en) * | 1988-07-29 | 1995-08-08 | Immunomedics | Detection and treatment of infectious and inflammatory lesions |
US5736137A (en) * | 1992-11-13 | 1998-04-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US5843439A (en) * | 1992-11-13 | 1998-12-01 | Anderson; Darrell R. | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US6399061B1 (en) * | 1992-11-13 | 2002-06-04 | Idec Pharmaceutical Corporation | Chimeric and radiolabelled antibodies specific to human CD20 antigen and use thereof for treatment of B-cell lymphoma |
US6682734B1 (en) * | 1992-11-13 | 2004-01-27 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US5595721A (en) * | 1993-09-16 | 1997-01-21 | Coulter Pharmaceutical, Inc. | Radioimmunotherapy of lymphoma using anti-CD20 |
US6090365A (en) * | 1993-09-16 | 2000-07-18 | Coulter Pharmaceutical, Inc. | Radioimmunotherapy of lymphoma using anti-CD20 antibodies |
US6183744B1 (en) * | 1997-03-24 | 2001-02-06 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
US6306393B1 (en) * | 1997-03-24 | 2001-10-23 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
Cited By (126)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7744877B2 (en) | 1992-11-13 | 2010-06-29 | Biogen Idec Inc. | Expression and use of anti-CD20 Antibodies |
US20020197255A1 (en) * | 1992-11-13 | 2002-12-26 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabelled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US20030147885A1 (en) * | 1992-11-13 | 2003-08-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US20080089893A9 (en) * | 1992-11-13 | 2008-04-17 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabelled antibodies to human b lymphocyte restricted differentiation antigen for treatment of b cell lymphoma |
US7422739B2 (en) | 1992-11-13 | 2008-09-09 | Biogen Idec Inc. | Anti-CD20 antibodies |
US7381560B2 (en) | 1992-11-13 | 2008-06-03 | Biogen Idec Inc. | Expression and use of anti-CD20 antibodies |
US9296821B2 (en) | 1998-08-11 | 2016-03-29 | Biogen Inc. | Combination therapies for B-cell lymphomas comprising administration of anti-CD20 antibodies |
US10113000B2 (en) | 1998-08-11 | 2018-10-30 | Biogen Inc. | Combination therapies for B-cell lymphomas comprising administration of anti-CD20 antibody |
US20030206903A1 (en) * | 1998-08-11 | 2003-11-06 | Idec Pharmaceuticals Corporation | Combination therapies for B-cell lynphomas comprising administration of anti-CD20 antibody |
US20080038261A1 (en) * | 1998-08-11 | 2008-02-14 | Biogen Idec Inc. | Combination therapies for b-cell lymphomas comprising administration of anti-cd20 antibody |
US8329172B2 (en) | 1998-08-11 | 2012-12-11 | Biogen Idec | Combination therapies for B-cell lymphomas comprising administration of anti-CD20 antibody |
US20090074760A1 (en) * | 1998-11-09 | 2009-03-19 | Grillo-Lopez Antonio J | Use of chimeric anti-cd20 antibody as in vitro or in vivo purging agent in patients receiving bmt or pbsc transplant |
US7682612B1 (en) | 1998-11-09 | 2010-03-23 | Biogen Idec Inc. | Treatment of hematologic malignancies associated with circulating tumor cells using chimeric anti-CD20 antibody |
US20100080769A1 (en) * | 1998-11-09 | 2010-04-01 | Biogen Idec Inc. | Treatment of Chronic Lymphocytic Leukemia using Anti-CD20 Antibodies |
US8206711B2 (en) | 1998-11-09 | 2012-06-26 | Biogen Idec Inc. | Treatment of chronic lymphocytic leukemia using anti-CD20 antibodies |
US20110165159A1 (en) * | 1998-11-09 | 2011-07-07 | Biogen Idec Inc. | Use of chimeric anti-cd20 antibody as in vitro or in vivo purging agent in patients receiving bmt or pbsc transplant |
US7820161B1 (en) | 1999-05-07 | 2010-10-26 | Biogen Idec, Inc. | Treatment of autoimmune diseases |
US9993550B2 (en) | 1999-05-07 | 2018-06-12 | Genentech, Inc. | Treatment of pemphigus |
US20110008337A1 (en) * | 1999-05-07 | 2011-01-13 | Genetech, Inc. | Treatment of Autoimmune Diseases |
US20110008250A1 (en) * | 1999-05-07 | 2011-01-13 | Genentech, Inc. | Treatment of Autoimmune Diseases |
US20110008338A1 (en) * | 1999-05-07 | 2011-01-13 | Genentech, Inc. | Treatment of Autoimmune Diseases |
US8545843B2 (en) | 1999-05-07 | 2013-10-01 | Genentech, Inc. | Treatment of vasculitis |
US20110008336A1 (en) * | 1999-05-07 | 2011-01-13 | Genentech, Inc. | Treatment of Autoimmune Diseases |
US20100003252A1 (en) * | 1999-07-12 | 2010-01-07 | Genentech, Inc. | Blocking immune response to a graft |
US8557244B1 (en) | 1999-08-11 | 2013-10-15 | Biogen Idec Inc. | Treatment of aggressive non-Hodgkins lymphoma with anti-CD20 antibody |
US8821873B2 (en) | 1999-08-11 | 2014-09-02 | Biogen Idec Inc. | Treatment of diffuse large-cell lymphoma with anti-CD20 antibody |
US9504744B2 (en) | 1999-08-11 | 2016-11-29 | Biogen Inc. | Treatment of diffuse large-cell lymphoma with anti-CD20 antibody |
US10400043B2 (en) | 1999-08-11 | 2019-09-03 | Biogen, Inc. | Treatment of diffuse large-cell lymphoma with anti-CD20 antibody |
US20060073146A1 (en) * | 2000-02-16 | 2006-04-06 | Genentech, Inc. | Uses of agonists and antagonists to modulate activity of TNF-related molecules |
US20020058029A1 (en) * | 2000-09-18 | 2002-05-16 | Nabil Hanna | Combination therapy for treatment of autoimmune diseases using B cell depleting/immunoregulatory antibody combination |
US9005612B2 (en) | 2001-01-17 | 2015-04-14 | Emergent Product Development Seattle, Llc | Binding domain-immunoglobulin fusion proteins |
US8853366B2 (en) | 2001-01-17 | 2014-10-07 | Emergent Product Development Seattle, Llc | Binding domain-immunoglobulin fusion proteins |
US20050070689A1 (en) * | 2001-08-03 | 2005-03-31 | Genentech, Inc. | Taci and br3 polypeptides and uses thereof |
US8483729B2 (en) | 2001-09-05 | 2013-07-09 | Telecommunication Systems, Inc. | Inter-carrier messaging service providing phone number only experience |
US20080171036A1 (en) * | 2002-07-25 | 2008-07-17 | Anan Chuntharapai | Taci antibodies and uses thereof |
US20060034835A1 (en) * | 2002-12-16 | 2006-02-16 | Genentech, Inc. | Immunoglobulin variants and uses thereof |
US7799900B2 (en) | 2002-12-16 | 2010-09-21 | Genentech, Inc. | Immunoglobulin variants and uses thereof |
US20090155257A1 (en) * | 2002-12-16 | 2009-06-18 | Genentech, Inc. | Immunoglobulin variants and uses thereof |
US8562992B2 (en) | 2002-12-16 | 2013-10-22 | Genentech, Inc. | Immunoglobulin variants and uses thereof |
US20080213280A1 (en) * | 2003-04-09 | 2008-09-04 | Genentech, Inc. | Therapy of autoimmune disease in a patient with an inadequate response to a tnf-alpha inhibitor |
EP2062916A2 (en) | 2003-04-09 | 2009-05-27 | Genentech, Inc. | Therapy of autoimmune disease in a patient with an inadequate response to a TNF-Alpha inhibitor |
US7976838B2 (en) | 2003-04-09 | 2011-07-12 | Genentech, Inc. | Therapy of autoimmune disease in a patient with an inadequate response to a TNF-α inhibitor |
US7708994B2 (en) | 2003-04-09 | 2010-05-04 | Genentech, Inc. | Therapy of autoimmune disease in a patient with an inadequate response to a TNF-α inhibitor |
WO2004091657A2 (en) | 2003-04-09 | 2004-10-28 | Genentech, Inc. | Therapy of autoimmune disease in a patient with an inadequate response to a tnf-alpha inhibitor |
US20060240008A1 (en) * | 2003-04-09 | 2006-10-26 | Genentech, Inc. | Therapy of autoimmune disease in a patient with an inadequate response to a TNF-alpha inhibitor |
US20040202658A1 (en) * | 2003-04-09 | 2004-10-14 | Genentech, Inc. | Therapy of autoimmune disease in a patient with an inadequate response to TNF-alpha inhibitor |
US20050163775A1 (en) * | 2003-06-05 | 2005-07-28 | Genentech, Inc. | Combination therapy for B cell disorders |
EP2272868A2 (en) | 2003-06-05 | 2011-01-12 | Genentech, Inc. | Combination therapy for B cell disorders |
US20050095243A1 (en) * | 2003-06-05 | 2005-05-05 | Genentech, Inc. | Combination therapy for B cell disorders |
US20100143352A1 (en) * | 2003-06-05 | 2010-06-10 | Genentech, Inc. | Combination therapy for b cell disorders |
US20100279932A1 (en) * | 2003-07-26 | 2010-11-04 | Trubion Pharmaceuticals, Inc. | Binding constructs and methods for use thereof |
US20050032130A1 (en) * | 2003-07-29 | 2005-02-10 | Genentech, Inc. | Neutralizing antibody assay and uses therefor |
US20090136492A1 (en) * | 2003-08-29 | 2009-05-28 | Genentech, Inc. | Therapy of ocular disorders |
US20050053602A1 (en) * | 2003-08-29 | 2005-03-10 | Genentech, Inc. | Therapy of ocular disorders |
US9296820B2 (en) | 2003-11-05 | 2016-03-29 | Roche Glycart Ag | Polynucleotides encoding anti-CD20 antigen binding molecules with increased Fc receptor binding affinity and effector function |
US20090010921A1 (en) * | 2003-11-05 | 2009-01-08 | Glycart Biotechnology Ag | Antigen binding molecules with increased Fc receptor binding affinity and effector function |
US8883980B2 (en) | 2003-11-05 | 2014-11-11 | Roche Glycart Ag | Antigen binding molecules with increased Fc receptor binding affinity and effector function |
US20050191297A1 (en) * | 2003-12-19 | 2005-09-01 | Genentech, Inc. | Detection of CD20 in transplant rejection |
US20050186206A1 (en) * | 2003-12-19 | 2005-08-25 | Genentech, Inc. | Detection of CD20 in therapy of autoimmune diseases |
US20080075719A1 (en) * | 2004-04-16 | 2008-03-27 | Genentech, Inc. | Method for Augmenting B Cell Depletion |
US20050271658A1 (en) * | 2004-05-05 | 2005-12-08 | Genentech, Inc. | Preventing autoimmune disease |
US20060024295A1 (en) * | 2004-06-04 | 2006-02-02 | Genentech, Inc. | Method for treating lupus |
EP3130349A1 (en) | 2004-06-04 | 2017-02-15 | Genentech, Inc. | Method for treating multiple sclerosis |
US20100303810A1 (en) * | 2004-06-04 | 2010-12-02 | Genentech, Inc. | Method for treating lupus |
US20100233121A1 (en) * | 2004-06-04 | 2010-09-16 | Genentech, Inc. | Method for treating multiple sclerosis |
US20060051345A1 (en) * | 2004-06-04 | 2006-03-09 | Genentech, Inc. | Method for treating multiple sclerosis |
US20060062787A1 (en) * | 2004-07-22 | 2006-03-23 | Genentech, Inc. | Method for treating Sjogren's syndrome |
US20060110387A1 (en) * | 2004-10-05 | 2006-05-25 | Genentech, Inc. | Method for treating vasculitis |
US20070025987A1 (en) * | 2004-10-05 | 2007-02-01 | Genentech, Inc. | Method for Treating Vasculitis |
US20080299117A1 (en) * | 2005-01-13 | 2008-12-04 | Barron Hal V | Treatment Method |
US20060188495A1 (en) * | 2005-01-13 | 2006-08-24 | Genentech, Inc. | Treatment method |
US20080095771A1 (en) * | 2005-01-13 | 2008-04-24 | Genentech, Inc. | Treatment Method |
US20060246004A1 (en) * | 2005-02-07 | 2006-11-02 | Genentech, Inc. | Antibody variants and uses thereof |
US20060263355A1 (en) * | 2005-02-28 | 2006-11-23 | Joanne Quan | Treatment of bone disorders |
US20060233797A1 (en) * | 2005-04-15 | 2006-10-19 | Genentech, Inc. | Treatment of inflammatory bowel disease (IBD) |
US20070054656A1 (en) * | 2005-05-17 | 2007-03-08 | Chris Knotts | Inter-carrier digital message with user data payload service providing phone number only experience |
US20100015055A1 (en) * | 2005-05-20 | 2010-01-21 | Genentech, Inc. | Pretreatment of a biological sample from an autoimmune disease subject |
US20060263349A1 (en) * | 2005-05-20 | 2006-11-23 | Genentech, Inc. | Pretreatment of a biological sample from an autoimmune disease subject |
US7601335B2 (en) | 2005-05-20 | 2009-10-13 | Genentech, Inc. | Pretreatment of a biological sample from an autoimmune disease subject |
EP2415483A1 (en) | 2005-07-25 | 2012-02-08 | Emergent Product Development Seattle, LLC | Single dose use of cd20-specific binding molecules |
EP2298815A1 (en) | 2005-07-25 | 2011-03-23 | Trubion Pharmaceuticals, Inc. | B-cell reduction using CD37-specific and CD20-specific binding molecules |
US20080279850A1 (en) * | 2005-07-25 | 2008-11-13 | Trubion Pharmaceuticals, Inc. | B-Cell Reduction Using CD37-Specific and CD20-Specific Binding Molecules |
US20070059306A1 (en) * | 2005-07-25 | 2007-03-15 | Trubion Pharmaceuticals, Inc. | B-cell reduction using CD37-specific and CD20-specific binding molecules |
EP2586798A2 (en) | 2005-07-25 | 2013-05-01 | Emergent Product Development Seattle, LLC | B-cell reduction using CD37-specific and CD20-specific binding molecules |
US10143748B2 (en) | 2005-07-25 | 2018-12-04 | Aptevo Research And Development Llc | B-cell reduction using CD37-specific and CD20-specific binding molecules |
US10307481B2 (en) | 2005-07-25 | 2019-06-04 | Aptevo Research And Development Llc | CD37 immunotherapeutics and uses thereof |
US20090214539A1 (en) * | 2005-07-25 | 2009-08-27 | Trubion Pharmaceuticals, Inc. | B-cell reduction using cd37-specific and cd20-specific binding molecules |
EP2295080A2 (en) | 2005-07-25 | 2011-03-16 | Trubion Pharmaceuticals, Inc. | B-cell reduction using CD37-specific and CD20-specific binding molecules |
US10450379B2 (en) | 2005-11-15 | 2019-10-22 | Genetech, Inc. | Method for treating joint damage |
US10654940B2 (en) | 2005-11-15 | 2020-05-19 | Genentech, Inc. | Method for treating joint damage |
US20070212733A1 (en) * | 2005-11-23 | 2007-09-13 | Genentech, Inc. | Methods and compositions related to B cell assays |
US9726673B2 (en) | 2005-11-23 | 2017-08-08 | Genentech, Inc. | Methods and compositions related to B cell assays |
US20110033483A1 (en) * | 2006-06-12 | 2011-02-10 | Trubion Pharmaceuticals Inc. | Single-chain multivalent binding proteins with effector function |
US8409577B2 (en) | 2006-06-12 | 2013-04-02 | Emergent Product Development Seattle, Llc | Single chain multivalent binding proteins with effector function |
US20090175867A1 (en) * | 2006-06-12 | 2009-07-09 | Trubion Pharmaceuticals, Inc. | Single-Chain Multivalent Binding Proteins with Effector Function |
EP3597659A1 (en) | 2007-07-09 | 2020-01-22 | Genentech, Inc. | Prevention of disulfide bond reduction during recombinant production of polypeptides |
EP4335863A2 (en) | 2007-07-09 | 2024-03-13 | Genentech, Inc. | Prevention of disulfide bond reduction during recombinant production of polypeptides |
EP4245766A2 (en) | 2007-07-09 | 2023-09-20 | Genentech, Inc. | Prevention of disulfide bond reduction during recombinant production of polypeptides |
EP3327026A1 (en) | 2007-07-09 | 2018-05-30 | Genentech, Inc. | Prevention of disulfide bond reduction during recombinant production of polypeptides |
EP2586788A1 (en) | 2007-07-09 | 2013-05-01 | Genentech, Inc. | Prevention of disulfide bond reduction during recombinant production of polypeptides |
EP4219522A2 (en) | 2007-07-09 | 2023-08-02 | Genentech, Inc. | Prevention of disulfide bond reduction during recombinant production of polypeptides |
EP2233149A1 (en) | 2007-10-16 | 2010-09-29 | ZymoGenetics, Inc. | Combination of BLYS inhibition and anti-CD20 agents for treatment of autoimmune disease |
EP2077281A1 (en) | 2008-01-02 | 2009-07-08 | Bergen Teknologioverforing AS | Anti-CD20 antibodies or fragments thereof for the treatment of chronic fatigue syndrome |
US20090274692A1 (en) * | 2008-04-11 | 2009-11-05 | Trubion Pharmaceuticals, Inc. | Cd37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof |
US8333966B2 (en) | 2008-04-11 | 2012-12-18 | Emergent Product Development Seattle, Llc | CD37 immunotherapeutics and uses thereof |
US9101609B2 (en) | 2008-04-11 | 2015-08-11 | Emergent Product Development Seattle, Llc | CD37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof |
US9683047B2 (en) | 2008-09-16 | 2017-06-20 | Genentech, Inc. | Methods for treating progressive multiple sclerosis |
US20100158903A1 (en) * | 2008-09-16 | 2010-06-24 | Craig Smith | Methods for treating progressive multiple sclerosis |
EP3095463A2 (en) | 2008-09-16 | 2016-11-23 | F. Hoffmann-La Roche AG | Methods for treating progressive multiple sclerosis |
EP3747464A1 (en) | 2008-09-16 | 2020-12-09 | F. Hoffmann-La Roche AG | Methods for treating progessive multiple sclerosis using an anti-cd20 antibody |
US9994642B2 (en) | 2008-09-16 | 2018-06-12 | Genentech, Inc. | Methods for treating progressive multiple sclerosis |
WO2010075249A2 (en) | 2008-12-22 | 2010-07-01 | Genentech, Inc. | A method for treating rheumatoid arthritis with b-cell antagonists |
EP3760712A1 (en) | 2009-08-11 | 2021-01-06 | F. Hoffmann-La Roche AG | Production of proteins in glutamine-free cell culture media |
WO2011019619A1 (en) | 2009-08-11 | 2011-02-17 | Genentech, Inc. | Production of proteins in glutamine-free cell culture media |
US8512983B2 (en) | 2009-08-11 | 2013-08-20 | Martin Gawlitzek | Production of proteins in glutamine-free cell culture media |
US9714293B2 (en) | 2009-08-11 | 2017-07-25 | Genentech, Inc. | Production of proteins in glutamine-free cell culture media |
US10982003B2 (en) | 2009-08-11 | 2021-04-20 | Genentech, Inc. | Production of proteins in glutamine-free cell culture media |
US10377831B2 (en) | 2009-09-11 | 2019-08-13 | Genentech, Inc. | Highly concentrated pharmaceutical formulations |
US10280227B2 (en) | 2009-09-11 | 2019-05-07 | Genentech, Inc. | Highly concentrated pharmaceutical formulations |
US10752696B2 (en) | 2009-09-11 | 2020-08-25 | Genentech, Inc. | Highly concentrated pharmaceutical formulations |
WO2011100403A1 (en) | 2010-02-10 | 2011-08-18 | Immunogen, Inc | Cd20 antibodies and uses thereof |
US11584793B2 (en) | 2015-06-24 | 2023-02-21 | Hoffmann-La Roche Inc. | Anti-transferrin receptor antibodies with tailored affinity |
US11352426B2 (en) | 2015-09-21 | 2022-06-07 | Aptevo Research And Development Llc | CD3 binding polypeptides |
US10941205B2 (en) | 2015-10-02 | 2021-03-09 | Hoffmann-La Roche Inc. | Bispecific anti-human A-beta/human transferrin receptor antibodies and methods of use |
US11603411B2 (en) | 2015-10-02 | 2023-03-14 | Hoffmann-La Roche Inc. | Bispecific anti-human CD20/human transferrin receptor antibodies and methods of use |
WO2017055542A1 (en) | 2015-10-02 | 2017-04-06 | F. Hoffmann-La Roche Ag | Bispecific anti-human cd20/human transferrin receptor antibodies and methods of use |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7381560B2 (en) | Expression and use of anti-CD20 antibodies | |
US7744877B2 (en) | Expression and use of anti-CD20 Antibodies | |
US5736137A (en) | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma | |
Reff et al. | Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20 | |
US7837995B2 (en) | Immunotherapy of B-cell malignancies using anti-CD22 antibodies | |
EP0504327B1 (en) | Therapeutic uses of the hypervariable region of monoclonal antibody m195 and constructs thereof | |
AU2002237972B2 (en) | Use of CD23 antagonists for the treatment of neoplastic disorders | |
KR20030086992A (en) | Use of cd23 antagonists for the treatment of neoplastic disorders | |
Hornick | Engineering antibodies and antibody/cytokine fusion proteins for the treatment of human malignancies |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: IDEC PHARMACEUTICALS CORPORATION, CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ANDERSON, DARRELL R.;HANNA, NABIL;LEONARD, JOHN E.;AND OTHERS;REEL/FRAME:012565/0368;SIGNING DATES FROM 20010808 TO 20010816 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |