WO2001062298A9 - Compositions and methods for treatment of angiogenesis in pathological lesions - Google Patents
Compositions and methods for treatment of angiogenesis in pathological lesionsInfo
- Publication number
- WO2001062298A9 WO2001062298A9 PCT/IB2001/000382 IB0100382W WO0162298A9 WO 2001062298 A9 WO2001062298 A9 WO 2001062298A9 IB 0100382 W IB0100382 W IB 0100382W WO 0162298 A9 WO0162298 A9 WO 0162298A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tumor
- fusion protein
- antibody
- scfv
- specific binding
- Prior art date
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
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Definitions
- biocidal or cytotoxic molecule examples include interleukin-2 (IL-2) , doxorubicin, interleukin-12 (IL-12), Interferon- ⁇ (IFN- ⁇ ), Tumor Necrosis Factor ⁇ (TNF ⁇ ) also, especially with the L19 antibody (see below) , tissue factor (preferably truncated) .
- IL-2 interleukin-2
- doxorubicin interleukin-12
- IFN- ⁇ Interferon- ⁇
- TNF ⁇ Tumor Necrosis Factor ⁇
- tissue factor preferably truncated
- the present invention diverges in a novel and unobvious way from the referenced prior art by conjugating IL-2 to an antibody directed to an extracellular matrix component, which component is present in angiogenesis in pathological lesions.
- an extracellular matrix component which component is present in angiogenesis in pathological lesions.
- the antibody has been directed against a cell- surface tumor marker.
- tumor cells present a great heterogeneity in expression of cell surface tumor markers, and may be down-regulated during therapies .
- T or NK cells receive one signal through receptor (s) (for instance T-cell receptor for T cells) specifically recognizing appropriate ligands at the tumor cell surface, and a second signal through IL-2 receptor chains by IL-2, also localized at the tumor cell surface (Lode et al . , 1999, PNAS USA, 96: 8591-8596 and references therein) .
- receptor for instance T-cell receptor for T cells
- the inventors constructed and expressed in mammalian cells an antibody-IL2 fusion protein, the antibody (L19, of which the sequence is disclosed in Pini et al . (1998) J. Biol . Chem . 273: 21769-21776) being directed against a component of the extracellular matrix present in angiogenesis in pathological lesions (in particular fibronectin ED-B) .
- L19 of which the sequence is disclosed in Pini et al . (1998) J. Biol . Chem . 273: 21769-21776) being directed against a component of the extracellular matrix present in angiogenesis in pathological lesions (in particular fibronectin ED-B) .
- In vivo biodistribution experiments in tumor bearing mice demonstrated accumulation of the fusion protein around new forming tumor blood vessels.
- the fusion protein was tested in therapeutic experiments in tumor bearing animals and surprisingly found to induce an antitumor effect and to be significantly more active in reducing tumor growth than an equimolar mixture of L19 and
- Tissue factor is a component of the blood coagulation cascade, normally present in a membrane-anchored form in the adventitia of blood vessels and therefore not accessible to other components of the blood coagulation cascade.
- tissue factor becomes accessible and, upon binding to Factor Vila, starts a series of biochemical processes which result in blood clot formation.
- the truncated form of TF (residues 1-219) is significantly less active in promoting blood coagulation and can therefore be injected systemically either alone, or bound to a monoclonal antibody.
- tissue factor delivered to the extracellular matrix of pathological lesions e.g. tumors
- tissue factor is surprisingly able to mediate a biocidal effect (e.g. on tumor cells), specifically infarction, especially when fused to an L19 antibody molecule (see below) .
- tissue factor preferably truncated as is known in the art
- tissue factor is provided as a conjugate or fusion with a specific binding member directed to a component of the extracellular matrix found in lesions of pathological angiogenesis, e.g. fibronectin ED-B or tenascin-C.
- IL-12 is a heterodimeric protein composed of a 40 kD (p40) subunit and a 35 kD (p35) subunit.
- IL-12 is produced by macrophages and B lymphocytes and has been shown to have multiple effects on T cells and natural killer (NK) cells.
- NK natural killer
- Some of these IL-12 activities include the induction of interferon gamma in resting and activated T and NK cells, the enhancement of cytotoxic activity of NK and T cells, and the stimulation of resting T cell proliferation In the presence of a comitogen. Current evidence indicates that IL-12 is a key mediator of cellular immunity.
- the present inventors have found that when targeting the L19- interleukin-12 fusion protein to tumor vasculature in tumor bearing mice, they have observed increased levels of IFN- ⁇ in the blood. In contrast, no elevated levels of IFN- ⁇ could be detected with a non-targeted scFv-interleukin-12 fusion protein.
- Tumor Necrosis Factor ⁇ is a cytokine produced by many cell types, mainly activated monocytes and macrophages. It is expressed as a 26 kDa integral transmembrane precursor protein from which a mature protein of approximately 17kDa is released by proteolytic cleavage.
- the soluble bioactive TNF ⁇ is a homotrimer that interacts with two different cell surface receptors (Tartaglia L.A., et al J. Biol . Chem . , 268: 18542-18548, 1993) p55TNFR (50-60 kDa) and p75TNFR (75-80 kDa) .
- p75TNFR is species-specific; in fact, human TNF ⁇ does not bind to this mouse receptor.
- TNF ⁇ can induce hemorrhagic necrosis of transplanted solid tumors, in vivo (Carswell E.A., et al , Proc. Natl . Acad. Sci . USA, 72: 3666-3670, 1975), and can exert cytotoxic activity in vitro against some tumor cell lines (Helson L., et al , Nature, 258: 731-732. 1975).
- TNF ⁇ has a very rapid clearance from the bloodstream (plasma half-life generally less than 30 minutes) (Blick M.m et al . Cancer Res . , 47: 2989, 1987), which decreases the hematic concentration under therapeutic levels, very rapidly.
- TNF ⁇ tumor-derived factors that synergise with TNF ⁇
- endothelial cells of the growing tumor vasculature Clauss M., et al . J. Biol Chem. , 265:7078-7083, 1990a
- alterations of the hemostatic properties of proliferating endothelial cells in tumor angiogenesis Clauss., et al J. Exp. Med. , 172:1535-1545, 1990b.
- Indirect (host-mediated) effects of TNF ⁇ can contribute to tumor regression on animal models (Palladino Jr. M.A., et al . J Immunol . , 138:4023-4032, 1987).
- the inventors constructed and expressed on mammalian cells an antibody-murine TNF ⁇ ( TNF ⁇ ) fusion protein, the antibody L19 being directed against a component of the ECM present in angiogenesis in pathological lesions (in particular B-FN) .
- TNF ⁇ tumor-bearing mice
- B-FN pathological lesions
- Figure 2 shows biological activity of the IL2 portion of the fusion protein (O) and of IL2 contained in a mixture of equimolar concentrations of LI9 and IL2 (•) measured by CTLL cell proliferation.
- Figure 4 is a plot (versus time) of the volume of F9 murine teratocarcinoma tumors subcutaneously implanted in mice, which have been injected intravenously with 3 doses of either scFv(L19)-TF or scFv (Dl .3) -TF. The first injection (indicated by an arrow) was performed when tumors were small. Standard errors are indicated.
- Figure 5 is a plot (versus time) of the volume of C51 murine carcinoma tumors subcutaneously implanted in mice, which have been injected intravenously with 3 doses of either scFv(L19)- TF or scFv (Dl .3) -TF. The first injection (indicated by an arrow) was performed when tumors were small. Standard errors are indicated.
- Figure 8 illustrates the kinetic of doxorubicin release from scF (LI9) -doxorubicin conjugates, analysed by HPLC.
- Figure 9 illustrates the toxicity towards C51 murine carcinoma cells, mediated by doxorubicin released from a scFv(L19)- doxorubicin conjugate.
- Figure 10 is a plot (versus time) of the volume of F9 murine teratocarcinoma tumors subcutaneously implanted in mice, which have been injected intravenously with 5 doses of either scFv (L19) -doxorubicin [18 ⁇ g/injection] or phosphate buffered saline.
- the first injection (indicated by an arrow) was performed when tumors were small. Standard errors are indicated.
- Figure 19 illustrates vector pIS14 that encodes a fusion protein comprising the LI9 scFv and monomeric IFN- ⁇ .
- the present invention provides for treatment of lesions of pathological angiogenesis.
- the biocidal or cytotoxic molecule that exerts its effect on target cells by cellular interaction may interact directly with the target cells, may interact with a membrane-bound receptor on the target cell or perturb the electrochemical potential of the cell membrane.
- Molecules which interact with a membrane-bound receptor include chemokines, cytokines and hormones.
- Compounds which perturb the electrochemical potential of the cell membrane include hemolysin, ionophores, drugs acting on ion channels.
- the molecule is interleukin-2, tissue factor (preferably truncated) or doxorubicin.
- Other embodiments may employ interleukin 12, interferon-gamma, IP-10 and Tumor Necrosis Factor- ⁇ (TNF- ⁇ ) .
- the members of a specific binding pair may be naturally derived or wholly or partially synthetically produced.
- One member of the pair of molecules has an area on its surface, or a cavity, which specifically binds to and is therefore complementary to a particular spatial and polar organisation of the other member of the pair of molecules.
- the members of the pair have the property of binding specifically to each other.
- antibody should be construed as covering any specific binding member having an antibody antigen-binding domain binding domain with the required specificity.
- this term covers antibody fragments, derivatives, functional equivalents and homologues of antibodies, including any polypeptide comprising an immunoglobulin binding domain, whether natural or wholly or partially synthetic. Chimeric molecules comprising an immunoglobulin binding domain, or equivalent, fused to another polypeptide are therefore included. Cloning and expression of chimeric antibodies are described in EP-A-0120694 and EP-A-0125023.
- Antigen binding domain This describes the part of an antibody which comprises the area which specifically binds to and is complementary to part or all of an antigen. Where an antigen is large, an antibody may only bind to a particular part of the antigen, which part is termed an epitope.
- An antigen binding domain may be provided by one or more antibody variable domains (e.g. a so- called Fd antibody fragment consisting of a VH domain) .
- an antigen binding domain comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH) .
- a preferred such domain comprises the L19 antibody VH and VL domains. Modified forms of one or other of these domains may be employed in further embodiments, e.g. the LI9 VH or LI9 VL domain in which 1, 2, 3, 4 or 5 amino acid substitutions have been made in a CDR, e.g. CDR3, and/or FR, which specific binding members retain ability to bind fibronectin ED-B.
- a specific binding member employed in accordance with the present invention may comprise other amino acids, e.g. forming a peptide or polypeptide, such as a folded domain, or to impart to the molecule another functional characteristic in addition to ability to bind antigen.
- Specific binding members of the invention may carry a detectable label.
- the present invention also provides a recombinant host cell which comprises one or more constructs as above.
- a still further aspect provides a method comprising introducing such nucleic acid into a host cell.
- the introduction may employ any available technique.
- suitable techniques may include calcium phosphate transfection, DEAE- Dextran, electroporation, liposome-mediated transfection and transduction using retrovirus or other virus, e.g. vaccinia or, for insect cells, baculovirus.
- suitable techniques may include calcium chloride transformation, electroporation and transfection using bacteriophage .
- Suitable host cells include bacteria, mammalian cells, yeast and baculovirus systems.
- Mammalian cell lines available in the art for expression of a heterologous polypeptide include
- Specific binding members of the present invention may be administered to a patient in need of treatment via any suitable route, usually by injection into the bloodstream an/dor directly into the site to be treated, e.g. tumor.
- the precise dose will depend upon a number of factors, the route of treatment, the size and location of the area to be treated (e.g. tumor), the precise nature of the antibody (e.g. whole antibody, scFv molecule) , and the nature of any detectable label or other molecule attached to the antibody.
- a typical antibody dose will be in the range 10-50 mg.
- Specific binding members of the present invention will usually be administered in the form of a pharmaceutical composition, which may comprise at least one component in addition to the specific binding member.
- the present invention provides a method comprising causing or allowing binding of a specific binding member as provided herein to an extracellular matrix component which is present in angiogenesis in pathological lesions.
- binding may take place in vivo, e.g. following administration of a specific binding member, or nucleic acid encoding a specific binding member.
- the forward BC666 primer (sequence : ctcgaattctcttcctcatcgggtagta gctcttccggctcatcgtccagcggcgcacctacttcaagttctaca) contained the EcoRI restriction enzyme sequence, a 45 bp encoding for by a 15 amino acids linker (Ser-Gly) 3 and 21 bases of the mature human IL2 sequence .
- CTCGAATTCtttgatttccaccttggtccc CTCGAATTCtttgatttccaccttggtccc
- Recombinant FN fragments containing the type III homology repeats 7B89 and ED-B were produced as described by
- mice Female athymic-nude mice (8-week-old nude/nude CD1 mice, females) were obtained from Harlan Italy (Correzzana, Milano, Italy) .
- F9 a mouse embryonal carcinoma, mouse T cells (CTLL-2) and mouse myeloma cells were purchased from ATCC (American Type Culture Collection, Rockville, MD, USA; N592, human Small Cell Lung Cancer (SCLC) cell line, was kindly provided by Dr. J.D. Minna (National Cancer Institute and Naval Hospital, Bethesda, Maryland); C51, a mouse colon adenocarcinoma cell line derived from BALB/c, was kindly provided by Dr. M.P. Colombo (21) .
- Tumor and organ specimens were processed for microautoradiography to assess the pattern of 125 I-L19-IL2 fusion protein distribution within the tumors or organs as described by Tarli et al . 1999 (12). Immunohistochemical procedures were carried out as reported by Castellani et al . 1994 (11) . The nonparametric Mann-Whitney test was used to assess the differences in tumor weights between the three different groups of animals (mice treated with L19-IL2 fusion protein, with mixture of L19+IL2 and PBS) .
- G418 resistant clones were screened for the antibody specificity of the supernatants for the ED-B sequence by ELISA as previously described. Supernatants of clones showing immunological specificity for the ED-B sequence were tested for IL2 biological activity.
- Fusion proteins comprising antibody fragments in scFv configuration, genetically fused to truncated tissue factor (scFv-TF) , were cloned and expressed.
- the primer TF-fostueco2 (5' -AGA GAA TTC TTA TTA CTT ATC GTC ATC GTC CTT GTA GTC AGG CCT TTC ACG-3' ) introduced to the 3 'end of the product of TF-fostuecol the rest of the FLAG-tag (DYKDDDDK) , a EcoRI restriction site and finally two stop codons .
- the enzymatic activity of the scFv-TF fusion protein was analyzed using the Spectrozyme FXa assay (American Diagnostica, Pfungstadt, Germany) as described by Ruf et al (1991) .
- the molar concentrations of doxorubicin and scFv(Ll9) were determined from their UV absorption at 496 and 280 nm, respectively, including a correction for the absorption of doxorubicin at 280 nm.
- the degree of conjugate coupling was calculated as (ScFv:doxo) molar ratio (MR) from the following formula:
- Antibody immunoreactivity after conjugation was measured by loading 200 ⁇ g of (L19-doxo) conjugate onto 200 ⁇ l of ED-B- Sepharose resin (capacity > 2 mg ED-B/ml resin) on a pasteur pipette, followed by absorbance measuring at 496 nm of the flow-through and eluate fractions.
- Immunoreactivity defined as the ratio between the absorbance values of the eluted fraction and the sum of the values of the eluted and the flow-through fractions, was 30%.
- mice were injected into the tail vein with 2.5 ⁇ g of IL12-L19 fusion protein every 48 hours.
- the control group received PBS injections according to the same schedule.
- animals were sacrificed, tumors were weighed and organs and tumors were placed in fixative for histological analysis.
- the scFv L19 which contained in its 5' end the genomic sequence of the signal secretion peptide as reported by Li et al (Protein Engineering, 10:731, 1996 or 1997), was amplified by PCR using T7 primer on the vector pcDNA3.1 (Invitrogen, Croningen, The Netherlands) and the BC 679 primer (sequence: CTCGAATTCtttgatttccaccttggtccc) containing 21bp of the 3' end of L19 and the EcoRI restriction enzyme sequence.
- the fused gene was sequenced, introduced into the vector pcDNA3.1 containing the Cytomegalovirus (CMV) promoter and expressed in p3Ul cells in the presence of G418 (750 ⁇ g/ml, Calbiochem, San Diego, CA) .
- CMV Cytomegalovirus
- G418 750 ⁇ g/ml, Calbiochem, San Diego, CA
- Clones of G418-resistant cells were screened for the secretion of L19-mTNF ⁇ fusion protein by ELISA using recombinant ED-B domain of human Fibronectin
- the fusion protein showed an apparent molecular mass of about 42 kDa, as expected. Both the immunological activity of the scFv LI9 component and the biological activity of the mTNF ⁇ component in the purified protein were tested.
- L19-mTNF ⁇ fusion protein was shown immunohistochemically to strongly stain blood vessels of glioblastoma tumor. Radioiodinated L19-mTNF ⁇ fusion protein was injected in the tail vein of mice with subcutaneously implanted F9 tumors, and L19-TNF ⁇ fusion protein distribution was obtained at different time points: 3, 6, 24 and 48 hours. As reported in Table I, 22% of the injected dose per gram of tissue (%ID/g) localised in the tumor 3 hours after injection and after 48 hours more than 9% ID/g was still in the tumor. The localisation of Ll9-mTNF ⁇ fusion protein in the tumoral neovasculature was confirmed by microradiographic analysis.
Abstract
Description
Claims
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JP2001561361A JP4917232B2 (en) | 2000-02-24 | 2001-02-22 | Compositions and methods for the treatment of angiogenesis in pathological lesions |
CA2399866A CA2399866C (en) | 2000-02-24 | 2001-02-22 | Compositions and methods for treatment of angiogenesis in pathological lesions |
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AU2001239470A AU2001239470A1 (en) | 2000-02-24 | 2001-02-22 | Compositions and methods for treatment of angiogenesis in pathological lesions |
US10/204,581 US8623373B2 (en) | 2000-02-24 | 2001-02-22 | Compositions and methods for treatment of angiogenesis in pathological lesions |
US12/835,854 US8784824B2 (en) | 2000-02-24 | 2010-07-14 | Compositions and methods for treatment of angiogenesis in pathological lesions |
US14/297,032 US20140348784A1 (en) | 2000-02-24 | 2014-06-05 | Compositions and methods for treatment of angiogenesis in pathological lesions |
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AU2001239470A1 (en) | 2001-09-03 |
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EP1719528A2 (en) | 2006-11-08 |
CA2399866C (en) | 2011-05-10 |
PT1257297E (en) | 2006-12-29 |
EP1719528B1 (en) | 2011-09-28 |
DE60121733T2 (en) | 2007-08-09 |
ES2269361T3 (en) | 2007-04-01 |
WO2001062298A2 (en) | 2001-08-30 |
US20100316602A1 (en) | 2010-12-16 |
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DK1257297T3 (en) | 2006-11-20 |
CY1112168T1 (en) | 2015-12-09 |
CA2399866A1 (en) | 2001-08-30 |
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