WO1998041562A1 - Non-antigenic branched polymer conjugates - Google Patents
Non-antigenic branched polymer conjugates Download PDFInfo
- Publication number
- WO1998041562A1 WO1998041562A1 PCT/US1998/004966 US9804966W WO9841562A1 WO 1998041562 A1 WO1998041562 A1 WO 1998041562A1 US 9804966 W US9804966 W US 9804966W WO 9841562 A1 WO9841562 A1 WO 9841562A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polymer
- group
- alkyl
- peg
- branched
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
- C07K17/02—Peptides being immobilised on, or in, an organic carrier
- C07K17/08—Peptides being immobilised on, or in, an organic carrier the carrier being a synthetic polymer
-
- 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
- A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/16—Masculine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
- C08G65/3322—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof acyclic
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/337—Polymers modified by chemical after-treatment with organic compounds containing other elements
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/338—Polymers modified by chemical after-treatment with inorganic and organic compounds
-
- 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
- C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
- C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
- C12N11/08—Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer
- C12N11/089—Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
Definitions
- the present invention relates to branched polymers which are useful in extending the in vivo circulating life of biologically active materials.
- the invention also relates to conjugates made with the polymers.
- one of the hydroxyl end-groups is converted into a reactive functional group. This process is frequently referred to as
- activation and the product is called an "activated poly(alkylene oxide)".
- Other substantially non-antigenic polymers are similarly “activated” or functionalized.
- the activated polymers are reacted with a therapeutic agent having nucleophilic functional groups that serve as attachment sites.
- nucleophilic functional group commonly used as an attachment site is the e-amino groups of lysines.
- Free carboxylic acid groups suitably activated carbonyl groups, oxidized carbohydrate moieties and mercapto groups have also been used as attachment sites.
- Insulin and hemoglobin were among the first therapeutic agents conjugated. These relatively large polypeptides contain several free e-amino attachment sites. A sufficient number of polymers could be attached to reduce immunogenicity and increase the circulating life without significant loss of biologic activity.
- Triazine is a toxic substance which is difficult to reduce to acceptable levels after conjugation.
- triazine is a planar group and can only be double-polymer substituted. The planar structure rigidly locks the two polymer chains in place. This limits the benefits of polymer conjugation to about the same as that obtained by increasing polymer chain length.
- non-triazine-based activated polymers would offer substantial benefits to the art.
- Prodrugs include chemical derivatives of a biologically-active parent compound which, upon administration, will eventually liberate the active parent compound in vivo.
- Use of prodrugs allows the artisan to modify the onset and/or duration of action of a biologically-active compound in vivo.
- Prodrugs are often biologically inert or substantially inactive forms of the parent or active compound. The rate of release of the active drug is influenced by several factors including the rate of hydrolysis of the linker which joins the parent biologically active compound to the prodrug carrier.
- prodrugs based on ester or phosphate linkages have been reported. In most cases, the particular type of ester linkage used to form the prodrug provides T ⁇ n for hydrolysis of up to several days in aqueous environments. Although one would expect a prodrug to have been formed, most of the conjugate is eliminated prior to sufficient hydrolysis being achieved in vivo. It would therefore be preferable to provide prodrugs which have a linkage which allows more rapid hydrolysis of the polymer-drug linkage in vivo so as to generate the parent drug compound more rapidly.
- branched, substantially non-antigenic polymers corresponding to the formula:
- (A) represents an activating functional group capable of undergoing nucleophilic substitution.
- (A) can be a group which is capable of bonding with biologically active nucleophiles or moieties capable of doing the same.
- (R) includes a poly(alkylene oxide) PAO such as a poly(ethylene glycol) (hereinafter: PEG).
- One preferred embodiment of the invention provides branched polymers containing a terminal carboxylic acid group which is useful in the formation of ester-based prodrugs.
- the branched polymers are of the formula:
- Another preferred embodiment of the invention includes branched polymers of the same formula set forth above, i.e.: (R) D L-A, except that (L) is selected form the group consisting of
- X is O, NQ, S, SO or SO 2 .
- Q is H, C,. registry alkyl, C,. g branched alkyl, C, ⁇ substituted alkyl, aryl or aralkyl; (m) is 0 or 1 ;
- (p) is a positive integer, preferably from about 1 to about 6; (R) and (n) are as defined above; and (A) is as defined above, including COOH as set forth in Formula (la).
- umbrella-like branched polymers of the present invention react with biologically active nucleophiles to form conjugates.
- the point of polymer attachment depends upon the functional group (A).
- (A) can be a succinimidyl succinate or carbonate and react with epsilon amino lysines.
- (A) can be a carboxylic acid which is capable of reacting with hydroxyl groups found on biologically-active nucleophiles to form ester-linked prodrugs.
- the branched polymers can also be activated to link with any primary or secondary amino group, mercapto group, carboxylic acid group, reactive carbonyl group or the like found on biologically-active materials. Other groups are apparent to those of ordinary skill in the art.
- the biologically active materials include proteins, peptides, enzymes, medicinal chemicals or organic moieties whether synthesized or isolated from nature.
- the methods include contacting a biologically active material containing a nucleophile capable of undergoing a substitution reaction with a branched polymer described above under conditions sufficient to effect attachment while maintaining at least a portion of the biological activity.
- the present invention also includes methods of treating various maladies and conditions.
- a mammal in need of treatment is administered an effective amount of a conjugate containing a biologically-active material such as a protein, enzyme or organic moiety and a branched polymer of the present invention.
- a biologically-active material such as a protein, enzyme or organic moiety
- a branched polymer of the present invention One of the chief advantages of the present invention is that the branching of the polymers imparts an umbrella-like three-dimensional protective covering to the materials they are conjugated with. This contrasts with the string-like structure of conventional polymer conjugates.
- the branching of the polymer chains from a common root allows dynamic, non-planar action in vivo.
- the branched polymers offer substantial benefits over straight-chained polymers of equivalent molecular weight.
- a second advantage of the branched polymers is that they provide the benefits associated with attaching several strands of polymers to a bioeffecting material but require substantially fewer conjugation sites.
- the advantages of the branched polymers are particularly dramatic for therapeutic agents having few available attachment sites. All the desired properties of polymer conjugation are realized and loss of bioactivity is minimized.
- the activated branched polymers of the present invention are preferably prepared from poly(alkylene oxides) (PAO's) that are water soluble at room temperatures.
- PAO's poly(alkylene oxides)
- alpha-substituted polyalkylene oxide derivatives such as methoxypoly (ethylene glycols) (mPEG) or other suitable alkyl substituted PAO derivatives such as those containing mono or bis terminal C t - C 4 groups.
- Straight-chained non-antigenic polymers such as monomethyl PEG homopolymers including mPEG-CH 2 -O-C-, mPEG-O-C-, and mPEG -O-CH 2 .CH 2 - II II
- (R) includes a water-soluble, substantially non-antigenic polymer
- (n) 2 o ⁇ ;
- (L) is an aliphatic linking moiety covalently linked to each (R) and
- (A) represents an activating functional group capable of undergoing nucleophilic substitution.
- Each (R) can be a water-soluble, substantially non-antigenic polymer chain.
- each chain has a molecular weight of between about 200 and about 80,000 daltons and preferably between about 2,000 and about 42,000 daltons. Molecular weights of about 5,000 to about 20,000 daltons are most preferred.
- Alternative polymeric substances include materials such as dextrans, polyvinyl pyrrolidones, polyacrylamides or other similar non-immunogenic polymers. Such polymers are also capable of being functionalized or activated for inclusion in the invention. The foregoing is merely illustrative and not intended to restrict the type of non-antigenic polymers suitable for use herein.
- (R) is a branched polymer for secondary and tertiary branching from a bioactive material.
- Bifunctional and hetero-bifunctional active polymer esters can also be used.
- the polymers of the present invention can also be copolymerized with bifunctional materials such as poly(alkylene glycol) diamines to form inte enetrating polymer networks suitable for use in permeable contact lenses, wound dressings, drug delivery devices and the like.
- the stearic limitations and water solubility of such branching will be readily recognized by one of ordinary skill in the art.
- the molecular weight of multiply branched polymers should not exceed 80,000 daltons.
- polymer chains As shown in Formula I, 2 or 3 polymer chains, designated (R) herein, are joined to the aliphatic linking moiety (L).
- Suitable aliphatics include substituted alkyl diamines and triamines, lysine esters and malonic ester derivatives.
- the linking moieties are preferably non-planar, so that the polymer chains are not rigidly fixed.
- the linking moiety (L) is also the means for attaching the multiple polymer chains or "branches" to (A), the moiety through which the polymer attaches to bio- effecting materials.
- (L) preferably includes a multiply-functionalized alkyl group containing up to 18, and more preferably, between 1-10 carbon atoms.
- a heteroatom such as nitrogen, oxygen or sulfur may be included within the alkyl chain.
- the alkyl chain may also be branched at a carbon or nitrogen atom.
- (L) is a single nitrogen atom.
- each (R) are preferably joined by a reaction between nucleophilic functional groups on both (R) and (L).
- Each (R) is suitably functionalized to undergo nucleophilic substitution and bond with (L).
- Such functionalization of polymers is readily apparent to those of ordinary skill in the art.
- linkages are contemplated between (R) and (L).
- Urethane (carbamate) linkages are preferred.
- the bond can be formed, for example, by reacting an amino group such as l,3-diamino-2-propanol with methoxypolyethylene glycol succinimidyl carbonate described in U.S. Patent No. 5,122,614, the disclosure of which is incorporated herein by reference.
- Amide linkages which can be formed by reacting an amino-terminated non-antigenic polymer such as methoxypolyethylene glycol-amine (mPEG amine) with an acyl chloride functional group.
- linkages between (R) and (L) include ether, amine, urea, and thio and thiol analogs thereof, as well as the thio and thiol analogs of the above- discussed urethane and amide linkages.
- the linkages are formed by methods well understood by those of ordinary skill in the art. Other suitable linkages and their formation can be determined by reference to the above-cited U.S. Patent No. 4,179,337.
- the moiety (A) of Formula I represents groups that "activate" the branched polymers of the present invention for conjugation with biologically active materials.
- (A) can be a moiety selected from:
- Functional groups capable of reacting with an amino group such as: a) carbonates such as the p-nitrophenyl, or succinimidyl; b) carbonyl imidazole; c) azlactones; d) cyclic imide thiones; or e) isocyanates or isothiocyanates.
- Functional groups capable of reacting with carboxylic acid groups and reactive carbonyl groups such as: a) primary amines; or b) hydrazine and hydrazide functional groups such as the acyl hydrazides, carbazates, semicarbamates, thiocarbazates, etc.
- Functional groups capable of reacting with mercapto or sulfhydryl groups such as phenyl glyoxals; see, for example, U.S. Patent No. 5,093,531, the disclosure of which is hereby incorporated by reference.
- IV. Functional groups capable of reacting with hydroxyl groups such as (carboxylic) acids, such as in Formula (la) or other nucleophiles capable of reacting with an electrophilic center.
- a non-limiting list includes, for example, hydroxyl, amino, carboxyl, thiol groups, active methylene and the like.
- the moiety (A) can also include a spacer moiety located proximal to the aliphatic linking moiety, (L).
- the spacer moiety may be a heteroalkyl, alkoxy, alkyl containing up to 18 carbon atoms or even an additional polymer chain.
- the spacer moieties can added using standard synthesis techniques. It is to be understood that those moieties selected for (A) can also react with other moieties besides biologically active nucleophiles.
- One preferred embodiment of the invention provides branched polymers containing a terminal carboxylic acid group which is useful in the formation of ester-based prodrugs.
- the branched polymers are of the formula:
- Some particularly preferred compounds within this aspect of the invention include: O
- X is O, NQ, S, SO or SO 2 .
- Q is H, C,_ 8 alkyl, C M branched alkyl, Cj.g substituted alkyl, aryl or aralkyl;
- (p) is 0 or an integer from about 1 to about 6; and R 2 ' represents the corresponding spacer moiety R 2 , described below, after undergoing the substitution reaction which results in the addition of the terminal carboxylic acid group.
- Another preferred embodiment of the invention includes branched polymers of the same formula set forth above, i.e. (I) and (la): (Rj consumerL-A, except that (L) is selected form the group consisting of
- Some particularly preferred compounds within this aspect of the invention include:
- (a) is an integer of from about 1 to about 5;
- (p) is a positive integer, preferably from about 1 to about 6;
- R 2 is a spacer moiety selected form the group consisting of: polymers, -CO-NH- (CH 2 -) d X 2 , -CO-NH- (CH 2 -CH 2 -O-) d X 2 , -CO-NH- ⁇ -X 2 and -C0-NH- ⁇ O ⁇ Y (O-CH 2 -CH 2 -) d X 2 where (d) is an integer between about 1 and about 18 inclusive and
- (X 2 ) is H, OH, NH 2 or COOH.
- the branched polymers are formed using conventional reaction techniques.
- the linking compound (L) has a number of nucleophilic functional groups which correspond to (n), (i.e. 2 or 3).
- a succinimidyl carbonate active ester of the branched polymer is prepared by contacting a branched polymer subunit (R n L, prepared as described above, with p-nitrophenyl chloroformate and thereafter with N-hydroxysuccinimide to form a succinimidyl carbonate.
- the hydroxy moiety can be reacted with bj ⁇ -succinimidyl carbonate directly.
- the polymer subunit (R) n L will include hydroxyl, amino, carboxyl and thiol groups, and the like, as well as amino or methylene hydrogens so that it can be attached to (A).
- the branched polymers can also be formed by reacting aliphatic linking compounds substituted with nucleophilic functional groups such as di- or tri-amino, mercapto alcohols or alkyl triols with an activated or functionalized polymer chain such as SC-PEG, PEG-NCO, PEG-NCS, SS-PEG, PEG-acids and acid derivatives.
- nucleophilic functional groups such as di- or tri-amino, mercapto alcohols or alkyl triols
- an activated or functionalized polymer chain such as SC-PEG, PEG-NCO, PEG-NCS, SS-PEG, PEG-acids and acid derivatives.
- synthesis include reacting a polymer functionalized with a nucleophilic moiety such as PEG-alcohol, PEG-amine or PEG-mercaptan with bifunctional molecules such as malonic acid derivatives or glyoxalic acid derivatives.
- a nucleophilic moiety such as PEG-alcohol, PEG-amine or PEG-mercaptan
- bifunctional molecules such as malonic acid derivatives or glyoxalic acid derivatives.
- Reaction with strong base converts the methylene linker into an anion that can be further fiinctionalized.
- the anion can be reacted with diethyloxalate to yield the corresponding ketoester.
- mPEG- FLAN mPEG-N-acyl-thiazolidine
- Branched polymers (III) and (IV) can then be activated.
- One manner of activation of (III) includes first functionalizing with compounds capable of activating the hydroxyl group such as p-nitrophenyl chloroformate to form a reactive p-nitrophenyl carbonate. The resulting p-nitrophenyl carbonate polymer can be directly reacted with a biologically active nucleophile.
- the p-nitrophenyl carbonate polymer can also serve as an intermediate. It can be reacted with a large excess of N-hydroxysuccinimide to form a succinimidyl carbonate-activated branched polymer. Other routes to succinimidyl carbonates are available and contemplated for use herein. Alternatively, a p-nitrophenyl carbonate polymer intermediate can be reacted with anhydrous hydrazine to form a carbazate branched polymer.
- Branched polymer (III) can also be activated by reacting it with an alkyl haloacetate in the presence of a base to form an intermediate alkyl ester of the corresponding polymeric carboxylic acid and thereafter reacting the intermediate alkyl ester with an acid such as trifluoroacetic acid to form the corresponding polymeric compound containing a terminal carboxylic acid.
- an alkyl haloacetate Preferably, tertiary alkyl haloacetates are used.
- the carboxylic acid derivative is formed by: i) contacting a branched polymer of the structure: (R) n L-A, wherein (R),(n), (L) and (A) are as defined herein, with an alkyl haloacetate in the presence of a base to form an alkyl ester of a branched non-antigenic polymer; and ii) reacting the alkyl ester with an acid to form the branched polymer containing a reactive carboxylic acid thereon.
- the molar ratio of the alkyl haloacetate to the branched polymer i.e. polyalkylene oxide, is greater than 1: 1.
- the reacting step ii) is carried out at a temperature of from about 0° to about 50°C and preferably at a temperature of from about 20 to about 30°C.
- the reacting step ii) can be carried out in the presence of water.
- X 3 is chlorine, bromine or iodine
- R 10 . ⁇ 2 are independently selected from the group alkyls, C ⁇ substituted alkyls or Cj.g branched alkyls and aryls are used.
- Preferred tertiary alkyl haloacetates include tertiary butyl haloacetates such as t-butyl bromoacetate or t-butyl chloroacetate.
- Suitable bases include potassium t-butoxide or butyl lithium, sodium amide and sodium hydride.
- Suitable acids include trifluoroacetic acid or sulfiiric, phosphoric and hydrochloric acids.
- Branched polymer (IV) can be activated by reacting it with a hydroxy acid such as lactic acid or glycolic acid to form the hydroxy amide. Thereafter, the hydroxy amide is functionalized in the same manner discussed above for (III).
- a hydroxy acid such as lactic acid or glycolic acid
- Branched polymer (Ilia) and (IVa) can then be activated in the same way as described above with regard to compounds (III) and (IV).
- m is zero (i.e. the carbonyl group is absent)
- synthesis of the branched polymer can be formed with a triamine (i.e. diethylenetriamine) being reacted with two equivalents of an acylating agent such as succinimidyl carbonate- activated PEG (SC-PEG), so that the terminal amino groups are fiinctionalized with the PEG.
- SC-PEG succinimidyl carbonate- activated PEG
- This intermediate which contains a secondary amine is then alkylated with ethyl bromoacetate or t-butyl bromoacetate to yield the branched polymer.
- synthesis of the branched polymer can be formed in a similar fashion.
- the terminal amines are functionalized with an activated PEG such as SC-PEG.
- the residual secondary amine is reacted with another acylating agent such as succinic anhydride under more forceful conditions so that the less reactive tertiary amine is acylated.
- Branched polymers corresponding to Formulas (II), (III), (Ilia), (IV), (IVa) and the like, can also be extended with a spacer moiety, designated herein as R 2 , between the aliphatic linking moiety and the group capable of undergoing nucleophilic substitution.
- R 2 a spacer moiety
- the polymer of Formula (III) with a spacer moiety is represented by Formula (V):
- Spacer moieties represented by (R 2 ) include but are not limited to: -CO-NH-(CH 2 -) d X 4 -CO-NH-(CH 2 -CH 2 -O-) d H
- the compounds of Formulas (Ilia) and (IVa) can also be converted into the corresponding R 2 spacer-containing compounds in the same manner as that set forth above.
- spacer moieties to a branched polymer
- R 2 can be joined to linker moieties (L) substituted with groups other than hydroxyl groups.
- L linker moieties
- suitable reagents such as substituted isocyanates or isothiocyanates and the like.
- terminal groups of the spacer moieties can be similarly functionalized to react with nucleophiles, i.e. attachment of a suitable (A) moiety, i.e. COOH or other "activated terminal group".
- the activated branched polymers can be purified by conventional methods and reacted with biologically active materials containing nucleophiles capable of bonding with the polymer while maintaining at least some of the activity associated with the material in unmodified form.
- nucleophiles conjugated with the branched polymers are described as "biologically active". The term, however, is not limited to physiological or pharmacological activities. For example, some nucleophile conjugates such as those containing enzymes, are able to catalyze reactions in organic solvents. Likewise, some inventive polymer conjugates containing proteins such as concanavalin A, immunoglobulin and the like are also useful as laboratory diagnostics. A key feature of all of the conjugates is that at least some portion of the activity associated with the unmodified bio-active material is maintained.
- the conjugates are biologically active and have numerous therapeutic applications.
- Mammals in need of treatment which includes a biologically active material can be treated by administering an effective amount of a polymer conjugate containing the desired bioactive material.
- mammals in need of enzyme replacement therapy or blood factors can be given branched polymer conjugates containing the desired material.
- Biologically active nucleophiles of interest of the present invention include, but are not limited to, proteins, peptides, polypeptides, enzymes, organic molecules of natural and synthetic origin such as medicinal chemicals and the like.
- Enzymes of interest include carbohydrate-specific enzymes, proteolytic enzymes, oxidoreductases, transferases, hydrolases, lyases, isomerases and ligases.
- examples of enzymes of interest include asparaginase, arginase, arginine deaminase, adenosine deaminase, superoxide dismutase, endotoxinases, catalases, chymotrypsin, lipases, uricases, adenosine diphosphatase, tyrosinases and bilirubin oxidase.
- Carbohydrate-specific enzymes of interest include glucose oxidases, glucodases, galactosidases, glucocerebrosidases, glucouronidases, etc.
- Proteins, polypeptides and peptides of interest include, but are not limited to, hemoglobin, both naturally occurring and recombinant mutant strains, serum proteins such as blood factors including Factors VII, VIII, and IX; immunoglobulins, cytokines such as interleukins, -, ⁇ - and ⁇ -interferons, colony stimulating factors including granulocyte colony stimulating factors, platelet derived growth factors and phospholipase-activating protein (PLAP).
- hemoglobin serum proteins
- cytokines such as interleukins, -, ⁇ - and ⁇ -interferons
- colony stimulating factors including granulocyte colony stimulating factors, platelet derived growth factors and phospholipase-activating protein (PLAP).
- PLAP phospholipase-activating protein
- proteins of general biological or therapeutic interest include insulin, plant proteins such as lectins and ricins, tumor necrosis factors and related alleles, growth factors such as tissue growth factors, such as TGF ⁇ 's or TGF ⁇ 's and epidermal growth factors, hormones, somatomedins, erythropoietin, pigmentary hormones, hypothalamic releasing factors, antidiuretic hormones, prolactin, chorionic gonadotropin, follicle- stimulating hormone, thyroid-stimulating hormone, tissue plasminogen activator, and the like.
- Immunoglobulins of interest include IgG, IgE, IgM, IgA, IgD and fragments thereof.
- Some proteins such as the interleukins, interferons and colony stimulating factors also exist in non-glycosylated form, usually as a result of using recombinant techniques.
- the non-glycosylated versions are also among the biologically active nucleophiles of the present invention.
- the biologically active nucleophiles of the present invention also include any portion of a polypeptide demonstrating in vivo bioactivity. This includes amino acid sequences, antisense moieties and the like, antibody fragments, single chain binding antigens, see, for example U.S. Patent No. 4,946,778, disclosure of which is incorporated herein by reference, binding molecules including fusions of antibodies or fragments, polyclonal antibodies, monoclonal antibodies, catalytic antibodies, nucleotides and oligonucleotides.
- proteins or portions thereof can be prepared or isolated by using techniques known to those of ordinary skill in the art such as tissue culture, extraction from animal sources, or by recombinant DNA methodologies.
- Transgenic sources of the proteins, polypeptides, amino acid sequences and the like are also contemplated. Such materials are obtained form transgenic animals, i.e., mice, pigs, cows, etc., wherein the proteins expressed in milk, blood or tissues. Transgenic insects and baculovirus expression systems are also contemplated as sources. Moreover, mutant versions of proteins, such as mutant TNF's and/or mutant interferons are also within the scope of the invention.
- allergen proteins such as ragweed, Antigen E, honeybee venom, mite allergen, and the like.
- Useful biologically active nucleophiles are not limited to proteins and peptides. Essentially any biologically-active compound is included within the scope of the present invention. The present invention is particularly well-suited for compounds which have few or even a single nucleophilic attachment site for polymer conjugation such as medicinal chemicals whether isolated from nature or synthesized. Chemotherapeutic molecules such as pharmaceutical chemicals i.e. anti-tumor agents such as paclitaxel, taxotere, related taxoteres, taxoid molecules, camptothecin, podophyllotoxin, anthracyclines, methotrexates, etc.
- pharmaceutical chemicals i.e. anti-tumor agents such as paclitaxel, taxotere, related taxoteres, taxoid molecules, camptothecin, podophyllotoxin, anthracyclines, methotrexates, etc.
- cardiovascular agents anti-neoplasties, anti-infectives, anti-anxiety agents, gastrointestinal agents, central nervous system-activating agents, analgesics, fertility or contraceptive agents, anti-inflammatory agents, steroidal agents, anti-urecemic agents, cardiovascular agents, vasodilating agents, vasoconstricting agents and the like.
- One or more of the activated branched polymers can be attached to a biologically active nucleophile by standard chemical reactions.
- the conjugate is represented by the formula:
- (L) is an aliphatic linking moiety
- (A 1 ) represents a linkage between (L) and the nucleophile
- (z) is an integer ⁇ 1 representing the number of polymers conjugated to the biologically active nucleophile.
- the upper limit for (z) will be determined by the number of available nucleophilic attachment sites and the degree of polymer attachment sought by the artisan.
- the degree of conjugation can be modified by varying the reaction stoichiometry using well-known techniques. More than one polymer conjugated to the nucleophile can be obtained by reacting a stoichiometric excess of the activated polymer with the nucleophile.
- the biologically active nucleophiles can be reacted with the activated branched polymers in an aqueous reaction medium which can be buffered, depending upon the pH requirements of the nucleophile.
- the optimum pH for the reaction is generally between about 6.5 and about 8.0 and preferably about 7.4 for proteinaceous/polypeptide materials. Organic/chemotherapeutic moieties can be reacted in non-aqueous systems.
- the optimum reaction conditions for the nucleophile's stability, reaction efficiency, etc. is within level of ordinary skill in the art.
- the preferred temperature range is between 4°C and 37°C.
- the temperature of the reaction medium cannot exceed the temperature at which the nucleophile may denature or decompose. It is preferred that the nucleophile be reacted with an excess of the activated branched polymer.
- the conjugate is recovered and purified such as by diafiltration, column chromatography, combinations thereof, or the like.
- the activated branched non-antigenic polymers of the present invention are a new and useful tool in the conjugation of biologically active materials, especially when they lack a sufficient number of suitable polymer attachment sites.
- This branched polymer was prepared by adding 100 mg (1.1 mmol) of 1, 3-diamino-2- propanol to a solution of 10.0 g (2 mmol) of SC-PEG in 50 mL of methylene chloride.
- Example 1 The compound of Example 1 was activated with p-nitrophenyl chloroformate.
- the U-PNP PEG of Example 2 was reacted with N- hydroxysuccinimide to form the succinimidyl carbonate ester of U-PEG.
- a solution containing 5.0 g (0.5 mmol) of the U-PNP PEG, 0.6 g (5 mmol) of N- hydroxysuccinimide and 0.13 g (1 mmol) of dusopropylethylamine in 40 ml of methylene chloride was refluxed for 18 hours. The solvent was then removed by distillation in vacuo, and the residue was recrystallized from 2-propanol to yield 4.2 g of the succinimidyl carbonate ester (82% yield).
- This branched polymer above was prepared by reacting U-PNP PEG (Ex. 2) with ethanolamine followed by p-nitrophenyl chloroformate.
- the NU-PEG-OH was prepared by reacting the above intermediate with p- nitrophenyl chloroformate.
- the intermediate was azeotropically dried by refluxing, 2.0 g (0.2 mmol) in 40 mL toluene for two hours, with the removal of 25 mL of solvent/water.
- the reaction mixture was cooled, followed by the addition of 0.3 mmol p-nitrophenyl chloroformate and 0.3 mmol pyridine, according to the procedure of Example 2.
- the resulting mixture was stirred for two hours at 45 °C, followed by stirring overnight at room temperature.
- the NU-PEG-OH was also recovered by the procedure in Example 2 to yield 1.5 g (71% yield).
- This branched polymer was prepared by reacting the U-PNP PEG of Example 2 with 2-(2-aminoethoxy) ethanol according to the procedure described in Example 4, (i.e., the amino alcohol was reacted with the p-nitrophenyl carbonate). The recrystallized product yield was 86%.
- EXAMPLE 6 XU-PNP-PEG
- Example 5 The compound of Example 5 was functionalized with p-nitrophenyl carbonate as in Examples 2 and 4. The recrystallized product yield was 83%
- succinimidyl carbonate derivative of compound prepared in Example 5 was prepared according to the process described in Example 3, by reacting N-hydroxysuccinimide with the p-nitrophenyl carbonate derivative of Example
- the branched polymer depicted above was prepared by reacting m-PNP PEG with lysine ethyl ester.
- a mixture of 5.0 g (1.0 mmol) of the polymer, 150 mg (0.6 mmol) of lysine dihydrochloride and 140 mg (1.8 mmol) of pyridine was refluxed for 18 hours.
- the solvent was removed by distillation in vacuo.
- the residue was recrystallized from 2-propanol to yield 4.5 g (88% yield) of product.
- reaction mixture was then filtered through CELITETM, followed by removal of the solvent by distillation in vacuo. The residue was recrystallized from 2- propanol to yield 48.2g (93% yield) of the product.
- EPO erythropoietin
- US-PEG US-PEG
- Conjugates of erythropoietin (EPO) with US-PEG were prepared by dialyzing two 3.0 mg EPO samples (human recombinant Chinese Hamster Ovary (CHO) cell culture) into 0.1 M phosphate buffer pH 7.0 solutions using a Centricon-10 (Amicon Corporation, Beverly, MA). The first EPO solution was combined with 1.954 mg (2-fold molar excess) of the US-PEG while the second EPO solution was combined with 3.908 mg (4-fold molar excess) of the US- PEG. The reaction mixtures were stirred for one hour at room temperature (about 22-25 °C).
- the excess polymer was removed by centrifugation and the reaction mixtures were dialyzed into 10 mM phosphate buffer, pH 8.0. Unreacted EPO was removed on an ion-exchange column (2-HD column, Sepracor). SDS-PAGE analysis confirmed that for both reaction mixtures, about two to three of the branched polymers were covalently bound to each protein molecule.
- the EPO activity of the conjugates was measured by colorometric assay with DA 1-K cells, a murine lymphoblastic cell line dependent on EL-3, GM-CSF and EPO for growth. The cells are grown in IMDM containing 5% FCS and incubated at
- Tumor Necrosis Factor was conjugated with the XUS-PEG of Example 7.
- the TNF was also conjugated with the linear SC PEG, methoxypoly(ethylene glycol) succinimidyl carbonate of U.S. Patent No. 5,122,614. Both conjugates were prepared by reacting a 500 micrograms of TNF, 2.0 mg/mL, with a 25-fold molar excess of the polymer. Each reaction was carried out for 140 minutes on ice.
- the ED S0 for the branched conjugate was 0.29 ng/mL for the concentration- response curve generated by dilutions of 0.1 micrograms/mL and 0.625 ng/mL for the concentration-response curve generated by dilutions of 0.01 micrograms/mL.
- the ED 50 for unmodified TNF of 0.01-0.02 ng/mL.
- the ED 50 for the linear succinimidyl carbonate conjugates ranged between 8 and 19 ng/mL.
- the resulting mixture was stirred at 40 °C overnight.
- the reaction mixture was filtered through a Celite pad followed by removal of the solvent by distillation in vacuo.
- the residue was recrystallized from 2-propanol to yield 0.98 g (97% recovery).
- the product contained 60% of the desired t-butyl ester as determined from ,3 C NMR.
- This branched polymer above was prepared by reacting US-PEG (Ex. 3) with methylparaaminobenzoate followed by selective hydrolysis to provide the branched polymer containing the terminal carboxylic acid.
- This branched polymer was formed by repeating Example 5 with the compound of Example 18.
- a mixture of 4.0 g (0.4 mmoles) of U-PEG carboxylic acid prepared in Example 15, 0.28 g (0.8 mmoles) of camptothecin, 0.10 g (0.8 mmoles) of diisopropylcarbodiimide and 0.10 g (0.8 mmoles) of 4-dimethylaminopyridine is added to 50 ml of anhydrous dichloromethane at 0°C. This mixture is allowed to warm up to room temperature, and stirring is continued for 18 hours, followed by removal of the solvent by distillation in vacuo. The residue is recrystallized from 2- propanol to yield 3.4 g of the title product.
- a mixture of 4.0 g (0.4 mmoles) of the compound of Example 19 U-PEG, 0.68 g (0.8 mmoles) of paclitaxel, 0.10 g (0.8 mmoles) of diisopropylcarbodiimide and 0.10 g (0.8 mmoles) of 4-dimethylaminopyridine is added to 50 ml of anhydrous dichloromethane at 0°C. This mixture is allowed to warm up to room temperature, and stirring is continued for 18 hours, followed by removal of the solvent by distillation. The residue is recrystallized from 2-propanol to yield 3.4 g of the titled product.
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002283939A CA2283939C (en) | 1997-03-20 | 1998-03-13 | Non-antigenic branched polymer conjugates |
DE69831402T DE69831402T2 (en) | 1997-03-20 | 1998-03-13 | NON-ACTING BRANCHED POLYMER CONJUGATES |
AT98910376T ATE303412T1 (en) | 1997-03-20 | 1998-03-13 | NON-ANTIGEN BRANCHED POLYMER CONJUGATES |
AU64630/98A AU743108B2 (en) | 1997-03-20 | 1998-03-13 | Non-antigenic branched polymer conjugates |
JP54063898A JP4612919B2 (en) | 1997-03-20 | 1998-03-13 | Non-antigenic branched polymer conjugate |
NZ337845A NZ337845A (en) | 1997-03-20 | 1998-03-13 | Non-antigenic branched polymer conjugates |
DK98910376T DK0973819T3 (en) | 1997-03-20 | 1998-03-13 | Non-antigenic branched polymer conjugates |
EP98910376A EP0973819B1 (en) | 1997-03-20 | 1998-03-13 | Non-antigenic branched polymer conjugates |
SI9830806T SI0973819T1 (en) | 1997-03-20 | 1998-03-13 | Non-antigenic branched polymer conjugates |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/821,055 US5919455A (en) | 1993-10-27 | 1997-03-20 | Non-antigenic branched polymer conjugates |
US08/821,055 | 1997-03-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998041562A1 true WO1998041562A1 (en) | 1998-09-24 |
Family
ID=25232381
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/004966 WO1998041562A1 (en) | 1997-03-20 | 1998-03-13 | Non-antigenic branched polymer conjugates |
Country Status (12)
Country | Link |
---|---|
US (3) | US5919455A (en) |
EP (1) | EP0973819B1 (en) |
JP (2) | JP4612919B2 (en) |
AT (1) | ATE303412T1 (en) |
AU (1) | AU743108B2 (en) |
CA (1) | CA2283939C (en) |
DE (1) | DE69831402T2 (en) |
DK (1) | DK0973819T3 (en) |
ES (1) | ES2249824T3 (en) |
NZ (1) | NZ337845A (en) |
SI (1) | SI0973819T1 (en) |
WO (1) | WO1998041562A1 (en) |
Cited By (114)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0841936A1 (en) * | 1995-07-31 | 1998-05-20 | Protein Delivery, Inc. | Conjugation-stabilized therapeutic agent compositions, delivery and diagnostic formulations |
EP0903152A2 (en) * | 1997-09-17 | 1999-03-24 | Mitsubishi Chemical Corporation | Bifunctional water-soluble polymer derivative and complex containing it |
KR100396983B1 (en) * | 2000-07-29 | 2003-09-02 | 이강춘 | Highly reactive branched polymer and proteins or peptides conjugated with the polymer |
JP2003530361A (en) * | 2000-04-07 | 2003-10-14 | アムジェン インコーポレーテッド | Novel chemically modified erythropoietin stimulating protein compositions and methods |
WO2004000366A1 (en) | 2002-06-21 | 2003-12-31 | Novo Nordisk Health Care Ag | Pegylated factor vii glycoforms |
WO2004061094A1 (en) | 2002-12-30 | 2004-07-22 | Gryphon Therapeutics, Inc. | Water-soluble thioester and selenoester compounds and methods for making and using the same |
WO2005028539A2 (en) * | 2003-09-17 | 2005-03-31 | Nektar Therapeutics Al, Corporation | Multi-arm polymer prodrugs |
WO2005047366A1 (en) * | 2003-11-06 | 2005-05-26 | Nektar Therapeutics Al, Corporation | Method of preparing carboxylic acid functionalized polymers |
EP1591467A1 (en) * | 2002-09-09 | 2005-11-02 | Nektar Therapeutics Al, Corporation | Conjugate between a polyethylene glycol having a terminal alkanal group and a human growth hormone |
EP1608688A2 (en) * | 2003-03-14 | 2005-12-28 | Neose Technologies, Inc. | Branched water-soluble polymers and their conjugates |
WO2006009901A2 (en) | 2004-06-18 | 2006-01-26 | Ambrx, Inc. | Novel antigen-binding polypeptides and their uses |
WO2006135930A2 (en) * | 2005-06-13 | 2006-12-21 | Nastech Pharmaceutical Company Inc. | Transmucosal delivery of peptide derivatives |
WO2006134173A2 (en) | 2005-06-17 | 2006-12-21 | Novo Nordisk Health Care Ag | Selective reduction and derivatization of engineered proteins comprising at least one non-native cysteine |
US7157546B2 (en) | 2002-09-09 | 2007-01-02 | Nektar Therapeutics Al, Corporation | Water-soluble polymer alkanals |
WO2008030558A2 (en) | 2006-09-08 | 2008-03-13 | Ambrx, Inc. | Modified human plasma polypeptide or fc scaffolds and their uses |
EP1982732A2 (en) | 2000-02-11 | 2008-10-22 | Maxygen Holdings Ltd. | Factor VII or VIIA-like molecules |
US7462627B2 (en) | 2006-02-09 | 2008-12-09 | Enzon Pharmaceuticals, Inc. | Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers |
WO2009067636A2 (en) | 2007-11-20 | 2009-05-28 | Ambrx, Inc. | Modified insulin polypeptides and their uses |
EP2080771A2 (en) | 2001-02-27 | 2009-07-22 | Maxygen Aps | New interferon beta-like molecules |
EP2133098A1 (en) | 2000-01-10 | 2009-12-16 | Maxygen Holdings Ltd | G-CSF conjugates |
WO2010011735A2 (en) | 2008-07-23 | 2010-01-28 | Ambrx, Inc. | Modified bovine g-csf polypeptides and their uses |
US7671067B2 (en) | 2006-02-09 | 2010-03-02 | Enzon Pharmaceuticals, Inc. | Treatment of non-hodgkin's lymphomas with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamtothecin |
US7736872B2 (en) | 2004-12-22 | 2010-06-15 | Ambrx, Inc. | Compositions of aminoacyl-TRNA synthetase and uses thereof |
EP2205281A1 (en) * | 2007-08-16 | 2010-07-14 | Pharmaessentia Corp. | Protein-polymer conjugates |
EP2213733A2 (en) | 2006-05-24 | 2010-08-04 | Novo Nordisk Health Care AG | Factor IX analogues having prolonged in vivo half life |
US7816320B2 (en) | 2004-12-22 | 2010-10-19 | Ambrx, Inc. | Formulations of human growth hormone comprising a non-naturally encoded amino acid at position 35 |
EP2263684A1 (en) | 2003-10-10 | 2010-12-22 | Novo Nordisk A/S | IL-21 derivatives |
US7872072B2 (en) | 2001-11-07 | 2011-01-18 | Nektar Therapeutics | Branched polymers and their conjugates |
EP2279756A2 (en) | 2005-04-05 | 2011-02-02 | Instituto di Ricerche di Biologia Molecolare p Angeletti S.P.A. | Method for shielding functional sites or epitopes on proteins |
EP2284191A2 (en) | 2004-12-22 | 2011-02-16 | Ambrx, Inc. | Process for the preparation of hGH |
US7928095B2 (en) | 2007-02-09 | 2011-04-19 | Enzon Pharmaceuticals, Inc. | Treatment of resistant or refractory cancers with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin |
US7947473B2 (en) | 2004-12-22 | 2011-05-24 | Ambrx, Inc. | Methods for expression and purification of pegylated recombinant human growth hormone containing a non-naturally encoded keto amino acid |
EP2327724A2 (en) | 2004-02-02 | 2011-06-01 | Ambrx, Inc. | Modified human growth hormone polypeptides and their uses |
US8012931B2 (en) | 2007-03-30 | 2011-09-06 | Ambrx, Inc. | Modified FGF-21 polypeptides and their uses |
WO2011107591A1 (en) | 2010-03-05 | 2011-09-09 | Rigshospitalet | Chimeric inhibitor molecules of complement activation |
WO2011143274A1 (en) | 2010-05-10 | 2011-11-17 | Perseid Therapeutics | Polypeptide inhibitors of vla4 |
US8076292B2 (en) | 2001-10-10 | 2011-12-13 | Novo Nordisk A/S | Factor VIII: remodeling and glycoconjugation of factor VIII |
US8093356B2 (en) | 2005-06-03 | 2012-01-10 | Ambrx, Inc. | Pegylated human interferon polypeptides |
US8114630B2 (en) | 2007-05-02 | 2012-02-14 | Ambrx, Inc. | Modified interferon beta polypeptides and their uses |
WO2012024452A2 (en) | 2010-08-17 | 2012-02-23 | Ambrx, Inc. | Modified relaxin polypeptides and their uses |
US8207112B2 (en) | 2007-08-29 | 2012-06-26 | Biogenerix Ag | Liquid formulation of G-CSF conjugate |
US8268967B2 (en) | 2004-09-10 | 2012-09-18 | Novo Nordisk A/S | Glycopegylated interferon α |
US8278418B2 (en) | 2008-09-26 | 2012-10-02 | Ambrx, Inc. | Modified animal erythropoietin polypeptides and their uses |
WO2013004607A1 (en) | 2011-07-01 | 2013-01-10 | Bayer Intellectual Property Gmbh | Relaxin fusion polypeptides and uses thereof |
WO2013006706A1 (en) | 2011-07-05 | 2013-01-10 | Bioasis Technologies Inc. | P97-antibody conjugates and methods of use |
US8354549B2 (en) | 2006-11-30 | 2013-01-15 | Nektar Therapeutics | Method for preparing a polymer conjugate |
EP2548967A2 (en) | 2006-09-21 | 2013-01-23 | The Regents of The University of California | Aldehyde tags, uses thereof in site-specific protein modification |
US8361961B2 (en) | 2004-01-08 | 2013-01-29 | Biogenerix Ag | O-linked glycosylation of peptides |
US8394365B2 (en) | 2003-09-17 | 2013-03-12 | Nektar Therapeutics | Multi-arm polymer prodrugs |
US8404809B2 (en) | 2005-05-25 | 2013-03-26 | Novo Nordisk A/S | Glycopegylated factor IX |
US8420792B2 (en) | 2006-09-08 | 2013-04-16 | Ambrx, Inc. | Suppressor tRNA transcription in vertebrate cells |
EP2633866A2 (en) | 2003-10-17 | 2013-09-04 | Novo Nordisk A/S | Combination therapy |
WO2013185115A1 (en) | 2012-06-08 | 2013-12-12 | Sutro Biopharma, Inc. | Antibodies comprising site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
US8632770B2 (en) | 2003-12-03 | 2014-01-21 | Novo Nordisk A/S | Glycopegylated factor IX |
US8633157B2 (en) | 2003-11-24 | 2014-01-21 | Novo Nordisk A/S | Glycopegylated erythropoietin |
US8637466B2 (en) | 2008-08-11 | 2014-01-28 | Nektar Therapeutics | Multi-arm polymeric alkanoate conjugates |
WO2014022515A1 (en) | 2012-07-31 | 2014-02-06 | Bioasis Technologies, Inc. | Dephosphorylated lysosomal storage disease proteins and methods of use thereof |
WO2014036492A1 (en) | 2012-08-31 | 2014-03-06 | Sutro Biopharma, Inc. | Modified amino acids comprising an azido group |
US8716240B2 (en) | 2001-10-10 | 2014-05-06 | Novo Nordisk A/S | Erythropoietin: remodeling and glycoconjugation of erythropoietin |
US8716239B2 (en) | 2001-10-10 | 2014-05-06 | Novo Nordisk A/S | Granulocyte colony stimulating factor: remodeling and glycoconjugation G-CSF |
US8791070B2 (en) | 2003-04-09 | 2014-07-29 | Novo Nordisk A/S | Glycopegylated factor IX |
US8791066B2 (en) | 2004-07-13 | 2014-07-29 | Novo Nordisk A/S | Branched PEG remodeling and glycosylation of glucagon-like peptide-1 [GLP-1] |
US8841439B2 (en) | 2005-11-03 | 2014-09-23 | Novo Nordisk A/S | Nucleotide sugar purification using membranes |
WO2014160438A1 (en) | 2013-03-13 | 2014-10-02 | Bioasis Technologies Inc. | Fragments of p97 and uses thereof |
US8853161B2 (en) | 2003-04-09 | 2014-10-07 | Novo Nordisk A/S | Glycopegylation methods and proteins/peptides produced by the methods |
EP2805964A1 (en) | 2009-12-21 | 2014-11-26 | Ambrx, Inc. | Modified bovine somatotropin polypeptides and their uses |
EP2805965A1 (en) | 2009-12-21 | 2014-11-26 | Ambrx, Inc. | Modified porcine somatotropin polypeptides and their uses |
US8906353B2 (en) | 2008-09-23 | 2014-12-09 | Nektar Therapeutics | Compositions and methods for achieving sustained therapeutic drug concentrations in a subject |
US8911967B2 (en) | 2005-08-19 | 2014-12-16 | Novo Nordisk A/S | One pot desialylation and glycopegylation of therapeutic peptides |
US8916360B2 (en) | 2003-11-24 | 2014-12-23 | Novo Nordisk A/S | Glycopegylated erythropoietin |
WO2015006555A2 (en) | 2013-07-10 | 2015-01-15 | Sutro Biopharma, Inc. | Antibodies comprising multiple site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
US8969532B2 (en) | 2006-10-03 | 2015-03-03 | Novo Nordisk A/S | Methods for the purification of polypeptide conjugates comprising polyalkylene oxide using hydrophobic interaction chromatography |
WO2015031673A2 (en) | 2013-08-28 | 2015-03-05 | Bioasis Technologies Inc. | Cns-targeted conjugates having modified fc regions and methods of use thereof |
US9005625B2 (en) | 2003-07-25 | 2015-04-14 | Novo Nordisk A/S | Antibody toxin conjugates |
WO2015054658A1 (en) | 2013-10-11 | 2015-04-16 | Sutro Biopharma, Inc. | Modified amino acids comprising tetrazine functional groups, methods of preparation, and methods of their use |
US9029331B2 (en) | 2005-01-10 | 2015-05-12 | Novo Nordisk A/S | Glycopegylated granulocyte colony stimulating factor |
WO2015081282A1 (en) | 2013-11-27 | 2015-06-04 | Redwood Bioscience, Inc. | Hydrazinyl-pyrrolo compounds and methods for producing a conjugate |
US9050304B2 (en) | 2007-04-03 | 2015-06-09 | Ratiopharm Gmbh | Methods of treatment using glycopegylated G-CSF |
US9121024B2 (en) | 2008-09-26 | 2015-09-01 | Ambrx, Inc. | Non-natural amino acid replication-dependent microorganisms and vaccines |
US9133495B2 (en) | 2006-09-08 | 2015-09-15 | Ambrx, Inc. | Hybrid suppressor tRNA for vertebrate cells |
US9150848B2 (en) | 2008-02-27 | 2015-10-06 | Novo Nordisk A/S | Conjugated factor VIII molecules |
US9175060B2 (en) | 2006-11-14 | 2015-11-03 | Shanghai Benemae Pharmaceutical Corporation | PEG modified exendin or exendin analog and compositions and use thereof |
US9187546B2 (en) | 2005-04-08 | 2015-11-17 | Novo Nordisk A/S | Compositions and methods for the preparation of protease resistant human growth hormone glycosylation mutants |
US9187532B2 (en) | 2006-07-21 | 2015-11-17 | Novo Nordisk A/S | Glycosylation of peptides via O-linked glycosylation sequences |
US9200049B2 (en) | 2004-10-29 | 2015-12-01 | Novo Nordisk A/S | Remodeling and glycopegylation of fibroblast growth factor (FGF) |
US9310374B2 (en) | 2012-11-16 | 2016-04-12 | Redwood Bioscience, Inc. | Hydrazinyl-indole compounds and methods for producing a conjugate |
US9434778B2 (en) | 2014-10-24 | 2016-09-06 | Bristol-Myers Squibb Company | Modified FGF-21 polypeptides comprising an internal deletion and uses thereof |
US9488660B2 (en) | 2005-11-16 | 2016-11-08 | Ambrx, Inc. | Methods and compositions comprising non-natural amino acids |
US9493499B2 (en) | 2007-06-12 | 2016-11-15 | Novo Nordisk A/S | Process for the production of purified cytidinemonophosphate-sialic acid-polyalkylene oxide (CMP-SA-PEG) as modified nucleotide sugars via anion exchange chromatography |
EP3103880A1 (en) | 2008-02-08 | 2016-12-14 | Ambrx, Inc. | Modified leptin polypeptides and their uses |
US9567386B2 (en) | 2010-08-17 | 2017-02-14 | Ambrx, Inc. | Therapeutic uses of modified relaxin polypeptides |
US9579390B2 (en) | 2012-11-12 | 2017-02-28 | Redwood Bioscience, Inc. | Compounds and methods for producing a conjugate |
EP3135690A1 (en) | 2012-06-26 | 2017-03-01 | Sutro Biopharma, Inc. | Modified fc proteins comprising site-specific non-natural amino acid residues, conjugates of the same, methods of their preparation and methods of their use |
US9605078B2 (en) | 2012-11-16 | 2017-03-28 | The Regents Of The University Of California | Pictet-Spengler ligation for protein chemical modification |
US10040761B2 (en) | 2010-06-25 | 2018-08-07 | Nof Corporation | Branched hetero polyethylene glycol and intermediate |
US10098865B2 (en) | 2010-12-22 | 2018-10-16 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
US10266578B2 (en) | 2017-02-08 | 2019-04-23 | Bristol-Myers Squibb Company | Modified relaxin polypeptides comprising a pharmacokinetic enhancer and uses thereof |
WO2019133399A1 (en) | 2017-12-26 | 2019-07-04 | Becton, Dickinson And Company | Deep ultraviolet-excitable water-solvated polymeric dyes |
WO2019191482A1 (en) | 2018-03-30 | 2019-10-03 | Becton, Dickinson And Company | Water-soluble polymeric dyes having pendant chromophores |
WO2020023300A1 (en) | 2018-07-22 | 2020-01-30 | Bioasis Technologies, Inc. | Treatment of lymmphatic metastases |
WO2020056066A1 (en) | 2018-09-11 | 2020-03-19 | Ambrx, Inc. | Interleukin-2 polypeptide conjugates and their uses |
WO2020082057A1 (en) | 2018-10-19 | 2020-04-23 | Ambrx, Inc. | Interleukin-10 polypeptide conjugates, dimers thereof, and their uses |
WO2020168017A1 (en) | 2019-02-12 | 2020-08-20 | Ambrx, Inc. | Compositions containing, methods and uses of antibody-tlr agonist conjugates |
US10894087B2 (en) | 2010-12-22 | 2021-01-19 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds |
WO2021183832A1 (en) | 2020-03-11 | 2021-09-16 | Ambrx, Inc. | Interleukin-2 polypeptide conjugates and methods of use thereof |
WO2021236526A1 (en) | 2020-05-18 | 2021-11-25 | Bioasis Technologies, Inc. | Compositions and methods for treating lewy body dementia |
WO2021255524A1 (en) | 2020-06-17 | 2021-12-23 | Bioasis Technologies, Inc. | Compositions and methods for treating frontotemporal dementia |
WO2022040596A1 (en) | 2020-08-20 | 2022-02-24 | Ambrx, Inc. | Antibody-tlr agonist conjugates, methods and uses thereof |
US11273202B2 (en) | 2010-09-23 | 2022-03-15 | Elanco Us Inc. | Formulations for bovine granulocyte colony stimulating factor and variants thereof |
WO2022212899A1 (en) | 2021-04-03 | 2022-10-06 | Ambrx, Inc. | Anti-her2 antibody-drug conjugates and uses thereof |
US11613607B2 (en) | 2016-10-07 | 2023-03-28 | Tokyo Institute Of Technology | Branched type hetero monodispersed polyethylene glycol, production method thereof, and conjugate thereof |
EP4155349A1 (en) | 2021-09-24 | 2023-03-29 | Becton, Dickinson and Company | Water-soluble yellow green absorbing dyes |
WO2024007016A2 (en) | 2022-07-01 | 2024-01-04 | Beckman Coulter, Inc. | Novel fluorescent dyes and polymers from dihydrophenanthrene derivatives |
WO2024044327A1 (en) | 2022-08-26 | 2024-02-29 | Beckman Coulter, Inc. | Dhnt monomers and polymer dyes with modified photophysical properties |
Families Citing this family (311)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6395888B1 (en) * | 1996-02-01 | 2002-05-28 | Gilead Sciences, Inc. | High affinity nucleic acid ligands of complement system proteins |
KR100361933B1 (en) * | 1993-09-08 | 2003-02-14 | 라 졸라 파마슈티칼 컴파니 | Chemically defined nonpolymeric bonds form the platform molecule and its conjugate |
US5919455A (en) * | 1993-10-27 | 1999-07-06 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
US5583114A (en) | 1994-07-27 | 1996-12-10 | Minnesota Mining And Manufacturing Company | Adhesive sealant composition |
GB9425138D0 (en) | 1994-12-12 | 1995-02-08 | Dynal As | Isolation of nucleic acid |
US5932462A (en) * | 1995-01-10 | 1999-08-03 | Shearwater Polymers, Inc. | Multiarmed, monofunctional, polymer for coupling to molecules and surfaces |
TW517067B (en) * | 1996-05-31 | 2003-01-11 | Hoffmann La Roche | Interferon conjugates |
KR100364938B1 (en) * | 1997-09-18 | 2002-12-18 | 에프. 호프만-라 로슈 아게 | Medicament containing interferon-alpha and amantadine for the treatment of chronic hepatitis c |
US6251382B1 (en) | 1998-04-17 | 2001-06-26 | Enzon, Inc. | Biodegradable high molecular weight polymeric linkers and their conjugates |
DK1087778T3 (en) * | 1998-06-08 | 2005-12-19 | Hoffmann La Roche | Use of PEG-IFN-alpha and ribavirin in the treatment of chronic hepatitis C |
PT1588716E (en) | 1998-08-06 | 2011-05-25 | Mountain View Pharmaceuticals | Peg-urate oxidase conjugates and use thereof |
CN1322243A (en) | 1998-08-06 | 2001-11-14 | 杜克大学 | Urate oxidase |
US6783965B1 (en) * | 2000-02-10 | 2004-08-31 | Mountain View Pharmaceuticals, Inc. | Aggregate-free urate oxidase for preparation of non-immunogenic polymer conjugates |
US20060188971A1 (en) * | 1998-08-06 | 2006-08-24 | Duke University | Urate oxidase |
US6458953B1 (en) * | 1998-12-09 | 2002-10-01 | La Jolla Pharmaceutical Company | Valency platform molecules comprising carbamate linkages |
CN1358171A (en) * | 1999-06-08 | 2002-07-10 | 拉卓拉药物公司 | Valency platform molecules comprising aminooxy groups |
US7169889B1 (en) * | 1999-06-19 | 2007-01-30 | Biocon Limited | Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin |
PE20010288A1 (en) | 1999-07-02 | 2001-03-07 | Hoffmann La Roche | ERYTHROPOYETIN DERIVATIVES |
CZ299516B6 (en) * | 1999-07-02 | 2008-08-20 | F. Hoffmann-La Roche Ag | Erythropoietin glycoprotein conjugate, process for its preparation and use and pharmaceutical composition containing thereof |
WO2001017614A2 (en) * | 1999-09-07 | 2001-03-15 | Conjuchem, Inc. | Methods and compositions containing succinimide or maleimide derivatives of antineoplastic agents |
US6723788B1 (en) | 1999-09-10 | 2004-04-20 | The Procter & Gamble Company | Enzyme inhibitors |
DE60044827D1 (en) | 1999-09-10 | 2010-09-23 | Procter & Gamble | POLYOXYALKYLENE CONJUGATES AS ENZYMINHIBITORS |
US6713454B1 (en) | 1999-09-13 | 2004-03-30 | Nobex Corporation | Prodrugs of etoposide and etoposide analogs |
CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
US6777387B2 (en) | 2000-03-31 | 2004-08-17 | Enzon Pharmaceuticals, Inc. | Terminally-branched polymeric linkers containing extension moieties and polymeric conjugates containing the same |
US6756037B2 (en) | 2000-03-31 | 2004-06-29 | Enzon, Inc. | Polymer conjugates of biologically active agents and extension moieties for facilitating conjugation of biologically active agents to polymeric terminal groups |
CN1434726A (en) | 2000-06-08 | 2003-08-06 | 拉卓拉药物公司 | Multivalent platform molecules comprising high molecular weight polyethylene oxide |
EP1307216A4 (en) * | 2000-07-12 | 2005-01-12 | Gryphon Therapeutics Inc | Polymer-modified bioactive synthetic chemokines, and methods for their manufacture and use |
AU7338501A (en) * | 2000-09-08 | 2002-03-22 | Gryphon Sciences | Polymer-modified synthetic proteins |
US7118737B2 (en) * | 2000-09-08 | 2006-10-10 | Amylin Pharmaceuticals, Inc. | Polymer-modified synthetic proteins |
ES2367891T3 (en) | 2000-09-29 | 2011-11-10 | Schering Corporation | INTERLEUCINA-10 PEGILADA. |
ES2382636T3 (en) | 2000-10-31 | 2012-06-12 | Surmodics Pharmaceuticals, Inc. | Method for producing compositions for improved administration of bioactive molecules |
WO2002039951A2 (en) * | 2000-11-15 | 2002-05-23 | Globe Immune, Inc. | Yeast-dentritic cell vaccines and uses thereof |
WO2002051428A1 (en) * | 2000-12-25 | 2002-07-04 | Shiseido Company, Ltd. | Sympathetic-activating perfume composition |
US6350756B1 (en) | 2001-01-18 | 2002-02-26 | California Pacific Medical Center | Camptothecin derivatives |
ATE471956T1 (en) * | 2001-01-30 | 2010-07-15 | Kyowa Hakko Kirin Co Ltd | BRANCHED POLYALKYLENE GLYCOLS |
EP1362053B1 (en) * | 2001-02-20 | 2007-11-14 | Enzon, Inc. | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
US6403604B1 (en) | 2001-03-01 | 2002-06-11 | California Pacific Medical Center | Nitrogen-based camptothecin derivatives |
US6855720B2 (en) | 2001-03-01 | 2005-02-15 | California Pacific Medical Center | Nitrogen-based camptothecin derivatives |
ATE439147T1 (en) * | 2001-03-23 | 2009-08-15 | Enzon Inc | PRODRUGS OF ANCIENT AROMATIC ACIDS CONTAINING SUBSTITUTED AROMATIC ACIDS |
US20030108585A1 (en) * | 2001-05-04 | 2003-06-12 | Roe R. Michael | Polymer conjugates of insecticidal peptides or nucleic acids or insecticides and methods of use thereof |
US20020187178A1 (en) * | 2001-05-04 | 2002-12-12 | Roe R. Michael | Polymer conjugates of insecticidal peptides or nucleic acids and methods of use thereof |
US6835802B2 (en) | 2001-06-04 | 2004-12-28 | Nobex Corporation | Methods of synthesizing substantially monodispersed mixtures of polymers having polyethylene glycol moieties |
US6828305B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of growth hormone drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
US6713452B2 (en) | 2001-06-04 | 2004-03-30 | Nobex Corporation | Mixtures of calcitonin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
US7713932B2 (en) | 2001-06-04 | 2010-05-11 | Biocon Limited | Calcitonin drug-oligomer conjugates, and uses thereof |
US6828297B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
US20040077835A1 (en) * | 2001-07-12 | 2004-04-22 | Robin Offord | Chemokine receptor modulators, production and use |
KR100761652B1 (en) * | 2001-08-25 | 2007-10-04 | 동아제약주식회사 | multi-branched polymer used in conjugating protein or peptide, and resulting conjugator |
US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
US7030082B2 (en) * | 2001-09-07 | 2006-04-18 | Nobex Corporation | Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith |
US6913903B2 (en) * | 2001-09-07 | 2005-07-05 | Nobex Corporation | Methods of synthesizing insulin polypeptide-oligomer conjugates, and proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
US7312192B2 (en) * | 2001-09-07 | 2007-12-25 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
US8008252B2 (en) | 2001-10-10 | 2011-08-30 | Novo Nordisk A/S | Factor VII: remodeling and glycoconjugation of Factor VII |
KR100508369B1 (en) * | 2001-10-31 | 2005-08-17 | 주식회사 바이오폴리메드 | Biocompatible polymers including peptide spacer |
DK1450822T3 (en) * | 2001-11-09 | 2010-04-19 | Enzon Inc | Polyalkylene oxide conjugates of thiol-containing medical preparations |
US20030171285A1 (en) * | 2001-11-20 | 2003-09-11 | Finn Rory F. | Chemically-modified human growth hormone conjugates |
RU2330067C2 (en) * | 2001-12-19 | 2008-07-27 | Дзе Юниверсити Оф Чикаго | Polynucleotide, coding chromo- or fluorescent mutant polypeptide, expression vector, cell, method of obtaining chromo- or fluorescent polypeptide, use of polypeptide and use of polynucleotide |
AU2003202026A1 (en) | 2002-01-16 | 2003-09-02 | Dynal Biotech Asa | Method for isolating nucleic acids and protein from a single sample |
EP1465933B1 (en) | 2002-01-16 | 2007-08-29 | Biocompatibles UK Limited | Polymer conjugates |
KR100888371B1 (en) | 2002-01-17 | 2009-03-13 | 동아제약주식회사 | Antivirus agent comprising bridged co-polymer derivatives and interferon complexes |
AU2003221291A1 (en) * | 2002-03-13 | 2003-09-22 | Beijing Jiankai Technology Co., Ltd. | Hydrophilic polymer derivate with y type branch and preparation method of it medical composite comprising above compound |
WO2003079980A2 (en) * | 2002-03-19 | 2003-10-02 | A & D Bioscience, Inc. | Caboxylic acid glycuronides, glycosamides and glycosides of quinolones, penicillins, analogs, and uses thereof |
WO2003078461A1 (en) * | 2002-03-20 | 2003-09-25 | Biopolymed Inc. | Preparation of g-csf stoichiometrically conjugated with biocompatible polymers at cystein residue |
EP1494706A4 (en) * | 2002-03-26 | 2006-10-25 | Biosynexus Inc | Antimicrobial polymer conjugates |
US20050233949A1 (en) * | 2002-04-12 | 2005-10-20 | Holick Michael F | Conjugates comprising cancer cell specific ligands, a sugar and cancer chemotherapeutic agents/boron neutron capture therapy agents, and uses thereof |
US20030215395A1 (en) * | 2002-05-14 | 2003-11-20 | Lei Yu | Controllably degradable polymeric biomolecule or drug carrier and method of synthesizing said carrier |
EP1534753B1 (en) * | 2002-05-28 | 2011-08-03 | UCB Pharma, S.A. | Peg positional isomer of an anti-tnfalpha antibody (cdp870) |
WO2003101998A1 (en) * | 2002-06-03 | 2003-12-11 | California Pacific Medical Center | Nitrogen-based homo-camptothecin derivatives |
US20040034050A1 (en) * | 2002-06-03 | 2004-02-19 | Yang Li-Xi | Homo-camptothecin derivatives |
DE60336555D1 (en) | 2002-06-21 | 2011-05-12 | Novo Nordisk Healthcare Ag | PEGYLATED GLYCO FORMS OF FACTOR VII |
US7122189B2 (en) * | 2002-08-13 | 2006-10-17 | Enzon, Inc. | Releasable polymeric conjugates based on aliphatic biodegradable linkers |
US7413738B2 (en) | 2002-08-13 | 2008-08-19 | Enzon Pharmaceuticals, Inc. | Releasable polymeric conjugates based on biodegradable linkers |
US7087229B2 (en) * | 2003-05-30 | 2006-08-08 | Enzon Pharmaceuticals, Inc. | Releasable polymeric conjugates based on aliphatic biodegradable linkers |
WO2004019860A2 (en) * | 2002-08-28 | 2004-03-11 | Pharmacia Corporation | Formulations of modified antibodies and methods of making the same |
AU2003265361A1 (en) * | 2002-08-28 | 2004-03-19 | Pharmacia Corporation | Stable ph optimized formulation of a modified antibody |
US7556813B2 (en) * | 2002-09-27 | 2009-07-07 | Trimeris, Inc. | Antiviral peptide-polymer conjugate comprising a polymer covalently attached to two or more synthetic HIV gp41 HR1 and/or HR2 peptides |
US8129330B2 (en) * | 2002-09-30 | 2012-03-06 | Mountain View Pharmaceuticals, Inc. | Polymer conjugates with decreased antigenicity, methods of preparation and uses thereof |
US20040062748A1 (en) * | 2002-09-30 | 2004-04-01 | Mountain View Pharmaceuticals, Inc. | Polymer conjugates with decreased antigenicity, methods of preparation and uses thereof |
PA8588901A1 (en) * | 2002-11-20 | 2005-02-04 | Pharmacia Corp | CONJUGATES OF N-TERMINAL HUMAN GROWTH HORMONE HORMONE AND PROCESS FOR PREPARATION |
GB0229287D0 (en) * | 2002-12-16 | 2003-01-22 | Dna Res Innovations Ltd | Polyfunctional reagents |
WO2004060300A2 (en) * | 2002-12-26 | 2004-07-22 | Mountain View Pharmaceuticals, Inc. | Polymer conjugates of cytokines, chemokines, growth factors, polypeptide hormones and antagonists thereof with preserved receptor-binding activity |
AU2003303635B2 (en) * | 2002-12-26 | 2009-07-23 | Mountain View Pharmaceuticals, Inc. | Polymer conjugates of interferon-beta with enhanced biological potency |
US20060014248A1 (en) * | 2003-01-06 | 2006-01-19 | Xencor, Inc. | TNF super family members with altered immunogenicity |
US7553930B2 (en) * | 2003-01-06 | 2009-06-30 | Xencor, Inc. | BAFF variants and methods thereof |
US20050130892A1 (en) * | 2003-03-07 | 2005-06-16 | Xencor, Inc. | BAFF variants and methods thereof |
US20050221443A1 (en) * | 2003-01-06 | 2005-10-06 | Xencor, Inc. | Tumor necrosis factor super family agonists |
US20040138154A1 (en) * | 2003-01-13 | 2004-07-15 | Lei Yu | Solid surface for biomolecule delivery and high-throughput assay |
US20070269891A9 (en) * | 2003-01-13 | 2007-11-22 | Yasunobu Tanaka | Solid surface with immobilized degradable cationic polymer for transfecting eukaryotic cells |
GB0301014D0 (en) * | 2003-01-16 | 2003-02-19 | Biocompatibles Ltd | Conjugation reactions |
US20060104968A1 (en) | 2003-03-05 | 2006-05-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases |
US20090123367A1 (en) * | 2003-03-05 | 2009-05-14 | Delfmems | Soluble Glycosaminoglycanases and Methods of Preparing and Using Soluble Glycosaminoglycanases |
EP2330213A1 (en) * | 2003-03-05 | 2011-06-08 | Halozyme, Inc. | Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof |
US7871607B2 (en) * | 2003-03-05 | 2011-01-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
US7332164B2 (en) * | 2003-03-21 | 2008-02-19 | Enzon Pharmaceuticals, Inc. | Heterobifunctional polymeric bioconjugates |
US7610156B2 (en) * | 2003-03-31 | 2009-10-27 | Xencor, Inc. | Methods for rational pegylation of proteins |
CA2520875A1 (en) * | 2003-03-31 | 2004-10-21 | Xencor, Inc. | Methods for rational pegylation of proteins |
US7642340B2 (en) | 2003-03-31 | 2010-01-05 | Xencor, Inc. | PEGylated TNF-α variant proteins |
AU2004229461A1 (en) | 2003-04-11 | 2004-10-28 | Pr Pharmaceuticals Inc. | Method for preparation of site-specific protein conjugates |
TW200510454A (en) | 2003-04-15 | 2005-03-16 | Smithkline Beecham Corp | Conjugates comprising human IL-18 and substitution mutants thereof |
US7189694B2 (en) * | 2003-04-18 | 2007-03-13 | University Of Florida Research Foundation, Inc. | Inhibitors of autophosphorylation protein kinases |
EP1624847B1 (en) | 2003-05-09 | 2012-01-04 | BioGeneriX AG | Compositions and methods for the preparation of human growth hormone glycosylation mutants |
EA010099B1 (en) * | 2003-05-12 | 2008-06-30 | Афимакс, Инк. | Novel peptides that bind to the erythropoietin receptor and methods for use thereof |
AU2004238869B2 (en) * | 2003-05-12 | 2009-06-25 | Affymax, Inc. | Novel poly(ethylene glycol) modified compounds and uses thereof |
BRPI0411166A (en) * | 2003-05-12 | 2006-07-18 | Affymax Inc | compound comprising a peptide moiety, a spacer moiety and a water soluble polymer moiety and a pharmaceutical composition comprising such a compound |
AP2042A (en) | 2003-05-12 | 2009-09-07 | Affymax Inc | Novel peptides that bind to the erythropoietin receptor |
US7947261B2 (en) * | 2003-05-23 | 2011-05-24 | Nektar Therapeutics | Conjugates formed from polymer derivatives having particular atom arrangements |
EA011351B1 (en) * | 2003-05-23 | 2009-02-27 | Нектар Терапеутикс Ал, Корпорейшн | Polymeric reagents, methods for production thereof, conjugates containing them and pharmaceutical compositions |
WO2005002625A2 (en) | 2003-06-26 | 2005-01-13 | Control Delivery Systems, Inc. | In-situ gelling drug delivery system |
CA2530113C (en) | 2003-06-26 | 2013-08-13 | Control Delivery Systems, Inc. | Bioerodible sustained release drug delivery systems |
JP4880461B2 (en) | 2003-08-13 | 2012-02-22 | バイオコン・リミテッド | Microparticulate fatty acid salt solid formulation for therapeutics |
CA2903196A1 (en) * | 2003-08-27 | 2005-03-10 | Ophthotech Corporation | Combination therapy for the treatment of ocular neovascular disorders |
AU2004279895A1 (en) | 2003-10-10 | 2005-04-21 | Xencor, Inc | Protein based TNF-alpha variants for the treatment of TNF-alpha related disorders |
ES2445948T3 (en) * | 2003-11-24 | 2014-03-06 | Ratiopharm Gmbh | Glycopegylated Erythropoietin |
JP2007515410A (en) * | 2003-12-03 | 2007-06-14 | ネオス テクノロジーズ インコーポレイテッド | GlycoPEGylated follicle stimulating hormone |
US7956032B2 (en) | 2003-12-03 | 2011-06-07 | Novo Nordisk A/S | Glycopegylated granulocyte colony stimulating factor |
EP1711825A4 (en) * | 2004-01-07 | 2008-01-23 | Ambit Biosciences Corp | Conjugated small molecules |
US20070105770A1 (en) * | 2004-01-21 | 2007-05-10 | Novo Nordisk A/S | Transglutaminase mediated conjugation of peptides |
EP1720892B1 (en) * | 2004-01-26 | 2013-07-24 | BioGeneriX AG | Branched polymer-modified sugars and nucleotides |
EP1708752B1 (en) * | 2004-01-27 | 2012-02-22 | University Of Southern California | Polymer-bound antibody cancer therapeutic agent |
US7803931B2 (en) | 2004-02-12 | 2010-09-28 | Archemix Corp. | Aptamer therapeutics useful in the treatment of complement-related disorders |
WO2005084303A2 (en) * | 2004-03-01 | 2005-09-15 | Enzon Pharmaceuticals, Inc. | Interferon-beta polymer conjugates |
US9085659B2 (en) * | 2004-05-03 | 2015-07-21 | Nektar Therapeutics | Polymer derivatives comprising an imide branching point |
EP1765411B2 (en) * | 2004-06-30 | 2017-10-11 | Nektar Therapeutics | Polymer-factor ix moiety conjugates |
AU2014280936B2 (en) * | 2004-06-30 | 2016-12-15 | Nektar Therapeutics | Polymer-factor ix moiety conjugates |
RU2393168C2 (en) | 2004-07-19 | 2010-06-27 | Биокон Лимитед | Insulin-oligomer conjugates, preparations and use thereof |
US9216161B2 (en) | 2004-08-13 | 2015-12-22 | Healthpartners Research Foundation | Methods of treating Huntington's disease comprising administering metal chelators to the upper one-third of the nasal cavity |
US7618615B2 (en) | 2004-08-13 | 2009-11-17 | Healthpartners Research Foundation | Methods for providing neuroprotection for the animal central nervous system against neurodegeneration caused by ischemia |
US7358223B2 (en) * | 2004-10-04 | 2008-04-15 | Nitto Denko Corporation | Biodegradable cationic polymers |
WO2006062685A2 (en) * | 2004-11-11 | 2006-06-15 | Affymax, Inc. | Novel peptides that bind to the erythropoietin receptor |
AU2005310189A1 (en) * | 2004-11-11 | 2006-06-08 | Affymax, Inc. | Novel peptides that bind to the erythropoietin receptor |
PT1835938E (en) | 2004-12-27 | 2013-11-06 | Baxter Int | Polymer-von willebrand factor-conjugates |
US7365127B2 (en) | 2005-02-04 | 2008-04-29 | Enzon Pharmaceuticals, Inc. | Process for the preparation of polymer conjugates |
WO2006086617A2 (en) * | 2005-02-10 | 2006-08-17 | Emory University | Polyethylene oxide polymers including anti-inflammatory glycodendrons |
WO2006102659A2 (en) * | 2005-03-23 | 2006-09-28 | Nektar Therapeutics Al, Corporation | CONJUGATES OF AN hGH MOIETY AND A POLYMER |
US8188224B2 (en) | 2005-04-11 | 2012-05-29 | Savient Pharmaceuticals, Inc. | Variant forms of urate oxidase and use thereof |
US8148123B2 (en) * | 2005-04-11 | 2012-04-03 | Savient Pharmaceuticals, Inc. | Methods for lowering elevated uric acid levels using intravenous injections of PEG-uricase |
CZ2007700A3 (en) * | 2005-04-11 | 2008-02-27 | Savient Pharmaceuticals, Inc. | Variant form of urate oxidase and use thereof |
US20080159976A1 (en) * | 2005-04-11 | 2008-07-03 | Jacob Hartman | Methods for lowering elevated uric acid levels using intravenous injections of PEG-uricase |
US7833979B2 (en) * | 2005-04-22 | 2010-11-16 | Amgen Inc. | Toxin peptide therapeutic agents |
JP2008545665A (en) * | 2005-05-23 | 2008-12-18 | ユニベルシテ ドゥ ジュネーブ | Injectable superparamagnetic nanoparticles for hyperthermic treatment and use to form hyperthermic implants |
EP1888098A2 (en) | 2005-05-25 | 2008-02-20 | Neose Technologies, Inc. | Glycopegylated erythropoietin formulations |
US8324159B2 (en) * | 2005-06-03 | 2012-12-04 | Affymax, Inc. | Erythropoietin receptor peptide formulations and uses |
US7550433B2 (en) * | 2005-06-03 | 2009-06-23 | Affymax, Inc. | Erythropoietin receptor peptide formulations and uses |
US7919461B2 (en) | 2005-06-03 | 2011-04-05 | Affymax, Inc. | Erythropoietin receptor peptide formulations and uses |
TW200722104A (en) * | 2005-06-20 | 2007-06-16 | Pepgen Corp | Low-toxicity, long-circulating human interferon-α analogs |
US7695710B2 (en) * | 2005-06-20 | 2010-04-13 | Pepgen Corporation | Antitumor and antiviral combination therapies using low-toxicity, long-circulating human interferon-alpha analogs |
ATE524509T1 (en) * | 2005-07-18 | 2011-09-15 | Nektar Therapeutics | BRANCHED FUNCTIONALIZED POLYMERS USING BRANCHED POLYOLS AS CORE |
KR100735784B1 (en) * | 2005-07-20 | 2007-07-06 | 재단법인 목암생명공학연구소 | Mutant of granulocyte-colony stimulating factorG-CSF and chemically conjugated polypeptide thereof |
US8008453B2 (en) | 2005-08-12 | 2011-08-30 | Amgen Inc. | Modified Fc molecules |
JP4808453B2 (en) * | 2005-08-26 | 2011-11-02 | 株式会社荏原製作所 | Polishing method and polishing apparatus |
CA2620638A1 (en) * | 2005-08-30 | 2007-03-08 | Novo Nordisk Health Care Ag | Liquid formulations of pegylated growth hormone |
US7875602B2 (en) * | 2005-10-21 | 2011-01-25 | Sutter West Bay Hospitals | Camptothecin derivatives as chemoradiosensitizing agents |
US7811555B2 (en) * | 2005-12-30 | 2010-10-12 | Cordis Corporation | Tri-branched biologically active copolymer |
US8133707B2 (en) * | 2006-01-17 | 2012-03-13 | Enzon Pharmaceuticals, Inc. | Methods of preparing activated polymers having alpha nitrogen groups |
EP1984009B1 (en) | 2006-01-18 | 2012-10-24 | Qps, Llc | Pharmaceutical compositions with enhanced stability |
US20140113860A1 (en) | 2006-02-03 | 2014-04-24 | Prolor Biotech Ltd. | Long-acting polypeptides and methods of producing and administering same |
US8048849B2 (en) | 2006-02-03 | 2011-11-01 | Modigene, Inc. | Long-acting polypeptides and methods of producing same |
US9458444B2 (en) | 2006-02-03 | 2016-10-04 | Opko Biologics Ltd. | Long-acting coagulation factors and methods of producing same |
US9249407B2 (en) | 2006-02-03 | 2016-02-02 | Opko Biologics Ltd. | Long-acting coagulation factors and methods of producing same |
US10351615B2 (en) | 2006-02-03 | 2019-07-16 | Opko Biologics Ltd. | Methods of treatment with long-acting growth hormone |
US10221228B2 (en) | 2006-02-03 | 2019-03-05 | Opko Biologics Ltd. | Long-acting polypeptides and methods of producing and administering same |
US8946155B2 (en) | 2006-02-03 | 2015-02-03 | Opko Biologics Ltd. | Long-acting polypeptides and methods of producing and administering same |
US20150038413A1 (en) | 2006-02-03 | 2015-02-05 | Opko Biologics Ltd. | Long-acting polypeptides and methods of producing and administering same |
CN101500614B (en) * | 2006-02-28 | 2011-08-10 | 雷迪实验室(欧洲)有限公司 | Method for making polyethylene glycol carbonates |
NZ571791A (en) | 2006-03-08 | 2012-03-30 | Archemix Llc | Complement binding aptamers and anti-C5 agents useful in the treatment of ocular disorders |
EP2010222A1 (en) | 2006-03-31 | 2009-01-07 | Baxter International Inc. | Pegylated factor viii |
US7645860B2 (en) | 2006-03-31 | 2010-01-12 | Baxter Healthcare S.A. | Factor VIII polymer conjugates |
US7700541B2 (en) * | 2006-04-06 | 2010-04-20 | Nitto Denko Corporation | Biodegradable cationic polymers |
CN101622270B (en) * | 2006-04-12 | 2014-01-01 | 萨文特医药公司 | Method for purification of proteins with cationic surfactant |
EP2395099A3 (en) | 2006-05-02 | 2012-05-16 | Allozyne, Inc. | Amino acid substituted molecules |
US20080096819A1 (en) * | 2006-05-02 | 2008-04-24 | Allozyne, Inc. | Amino acid substituted molecules |
WO2007146835A2 (en) * | 2006-06-09 | 2007-12-21 | Enzon Pharmaceuticals, Inc. | Indenoisoquinoline-releasable polymer conjugates |
JP5308333B2 (en) * | 2006-06-30 | 2013-10-09 | シグマ−タウ レア ディジージズ エスィアー | Recombinant host producing L-asparaginase II |
US9175061B2 (en) | 2006-07-07 | 2015-11-03 | Novo Nordisk Health Care Ag | Protein conjugates and methods for their preparation |
BRPI0719446A2 (en) | 2006-09-28 | 2013-12-10 | Schering Corp | Use of pegylated IL-10 to treat cancer |
CA2665480C (en) | 2006-10-04 | 2019-11-12 | Shawn Defrees | Glycerol linked pegylated sugars and glycopeptides |
US20090252703A1 (en) * | 2006-10-19 | 2009-10-08 | Gegg Jr Colin V | Use of alcohol co-solvents to improve pegylation reaction yields |
EP2081602A2 (en) | 2006-10-25 | 2009-07-29 | Amgen Inc. | Toxin peptide therapeutic agents |
WO2008055666A1 (en) * | 2006-11-07 | 2008-05-15 | Dsm Ip Assets B.V. | Carbamate, thiocarbamate or carbamide comprising a biomolecular moiety |
US8507653B2 (en) * | 2006-12-27 | 2013-08-13 | Nektar Therapeutics | Factor IX moiety-polymer conjugates having a releasable linkage |
CN101678119B (en) * | 2006-12-27 | 2014-02-12 | 尼克塔治疗公司 | Von willebrand factor- and factor VIII-polymer conjugates having releasable linkage |
EP2117528A4 (en) * | 2006-12-29 | 2013-01-02 | Sigma Tau Rare Diseases S A | Use of adenosine deaminase for treating pulmonary disease |
US7625898B2 (en) | 2007-01-16 | 2009-12-01 | Enzon Pharmaceuticals, Inc. | Posaconazole polymer conjugates and methods of treatment using posaconazole and polymer conjugates thereof |
EP2118127A4 (en) * | 2007-01-31 | 2010-12-01 | Affymax Inc | Nitrogen-based linkers for attaching modifying groups to polypeptides and other macromolecules |
EP2129231A4 (en) * | 2007-02-01 | 2015-01-21 | Nat Res Council Canada | Formulations of lipophilic bioactive molecules |
ES2507508T3 (en) * | 2007-04-20 | 2014-10-15 | Sigma-Tau Rare Diseases S.A. | Enzymatic anti-cancer therapy |
CN101688244B (en) * | 2007-04-20 | 2013-05-08 | 希格马托罕见疾病公司 | Stable recombinant adenosine deaminase |
EP2738257A1 (en) | 2007-05-22 | 2014-06-04 | Amgen Inc. | Compositions and methods for producing bioactive fusion proteins |
US20080312174A1 (en) * | 2007-06-05 | 2008-12-18 | Nitto Denko Corporation | Water soluble crosslinked polymers |
US9707274B2 (en) | 2007-06-08 | 2017-07-18 | Healthpartners Research & Education | Methods for preventing and treating post-traumatic stress disorder (PTSD) |
EP2175878A4 (en) * | 2007-07-11 | 2014-12-03 | Belrose Pharma Inc | Polymeric drug delivery system containing a multi-substituted aromatic moiety |
CA2707840A1 (en) * | 2007-08-20 | 2009-02-26 | Allozyne, Inc. | Amino acid substituted molecules |
KR101234540B1 (en) | 2007-10-16 | 2013-02-19 | 바이오콘 리미티드 | An orally administerable solid pharmaceutical composition and a process thereof |
TWI395593B (en) | 2008-03-06 | 2013-05-11 | Halozyme Inc | In vivo temporal control of activatable matrix-degrading enzymes |
WO2009128917A2 (en) | 2008-04-14 | 2009-10-22 | Halozyme, Inc. | Modified hyaluronidases and uses in treating hyaluronan-associated diseases and conditions |
TWI394580B (en) | 2008-04-28 | 2013-05-01 | Halozyme Inc | Super fast-acting insulin compositions |
US8476404B1 (en) * | 2008-07-04 | 2013-07-02 | Bhalchandra Shripad Lele | Selectively functionalized polyhydric compounds |
JP5675606B2 (en) | 2008-07-08 | 2015-02-25 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | Novel inhibitor of signal transduction transcription factor (STAT) proliferation and activation |
EA020347B1 (en) * | 2008-07-31 | 2014-10-30 | Фармаиссэншиа Корп. | Peptide-polymer conjugates |
EP2157432A1 (en) * | 2008-08-15 | 2010-02-24 | Qiagen GmbH | Method for analysing a complex sample by mass spectrometry |
EA022752B1 (en) | 2008-12-09 | 2016-02-29 | Галозим, Инк. | Extended soluble ph20 polypeptides and uses thereof |
CN102256625B (en) | 2008-12-17 | 2013-11-20 | 默沙东公司 | Mono- and di-peg il-10 production |
CN101870728A (en) | 2009-04-23 | 2010-10-27 | 派格生物医药(苏州)有限公司 | Novel Exendin variant and conjugate thereof |
BRPI1010775A2 (en) | 2009-06-09 | 2016-03-22 | Prolong Pharmaceuticals Llc | composition, method for preparing a composition, and use of a composition. |
SG176897A1 (en) | 2009-06-25 | 2012-01-30 | Savient Pharmaceuticals Inc | Methods and kits for predicting infusion reaction risk and antibody-mediated loss of response by monitoring serum uric acid during pegylated uricase therapy |
WO2011003633A1 (en) | 2009-07-06 | 2011-01-13 | Alize Pharma Ii | Pegylated l-asparaginase |
US9663778B2 (en) | 2009-07-09 | 2017-05-30 | OPKO Biologies Ltd. | Long-acting coagulation factors and methods of producing same |
AU2010280688A1 (en) | 2009-08-05 | 2012-02-23 | Allergan, Inc. | Controlled release formulations of lipocalin muteins |
EA026112B1 (en) | 2009-09-17 | 2017-03-31 | Бакстер Хелскэа, С.А. | Stable composition comprising hyaluronidase and immunoglobulin, and methods of use thereof |
US20110081398A1 (en) * | 2009-10-01 | 2011-04-07 | Tyco Healthcare Group Lp | Multi-mechanism surgical compositions |
US20110081701A1 (en) * | 2009-10-02 | 2011-04-07 | Timothy Sargeant | Surgical compositions |
US8968785B2 (en) * | 2009-10-02 | 2015-03-03 | Covidien Lp | Surgical compositions |
WO2011162831A2 (en) * | 2010-06-24 | 2011-12-29 | Vasculogics, Inc. | Compositions and methods for treatment of thrombosis and prolonging survival of stored platelets |
JP5825507B2 (en) * | 2010-06-25 | 2015-12-02 | 日油株式会社 | Branched heteropolyethylene glycol |
ES2661089T3 (en) | 2010-07-20 | 2018-03-27 | Halozyme Inc. | Methods of treatment or prevention of adverse side effects associated with the administration of an anti-hyaluronan agent |
IT1403458B1 (en) | 2010-12-28 | 2013-10-17 | Scarpa Calzaturificio Spa | SKI BOOT |
EP2672958A1 (en) | 2011-02-08 | 2013-12-18 | Halozyme, Inc. | Composition and lipid formulation of a hyaluronan-degrading enzyme and the use thereof for treatment of benign prostatic hyperplasia |
TW201300407A (en) | 2011-03-16 | 2013-01-01 | Amgen Inc | Potent and selective inhibitors of Nav1.3 and Nav1.7 |
US10166295B2 (en) | 2011-06-02 | 2019-01-01 | Opko Biologics Ltd. | Pegylated OXM variants |
CA2839512C (en) | 2011-06-17 | 2018-01-02 | Halozyme, Inc. | Continuous subcutaneous insulin infusion methods with a hyaluronan-degrading enzyme |
US20130011378A1 (en) | 2011-06-17 | 2013-01-10 | Tzung-Horng Yang | Stable formulations of a hyaluronan-degrading enzyme |
US20130090294A1 (en) | 2011-06-28 | 2013-04-11 | Alternative Innovative Technologies Llc | Novel methods of use of hsp70 for increased performance or treatment of hsp70 related disorders |
JP5252036B2 (en) * | 2011-06-28 | 2013-07-31 | 大日本印刷株式会社 | Substrate having a hydrophilic layer |
US9034318B2 (en) | 2011-08-30 | 2015-05-19 | The Regents Of The University Of Colorado, A Body Corporate | Chemically modified cystathionine beta-synthase enzyme for treatment of homocystinuria |
US20130071394A1 (en) | 2011-09-16 | 2013-03-21 | John K. Troyer | Compositions and combinations of organophosphorus bioscavengers and hyaluronan-degrading enzymes, and methods of use |
RU2014114849A (en) | 2011-10-14 | 2015-11-20 | Алтернатив Инновейтив Текнолоджиз Ллц | Degradation-resistant derivatives of proteins of heat shock-70 (btsh70) and methods of their application (options) |
WO2013063155A2 (en) | 2011-10-24 | 2013-05-02 | Halozyme, Inc. | Companion diagnostic for anti-hyaluronan agent therapy and methods of use thereof |
RU2685867C2 (en) | 2011-12-15 | 2019-04-23 | Алтернатив Инновейтив Текнолоджиз Ллц | Hybrid proteins and protein conjugates based on heat shock protein-70 (hsp70) and methods for use thereof (versions) |
DK2797622T3 (en) | 2011-12-30 | 2017-01-16 | Halozyme Inc | PH20 polypeptide variants, formulations and uses thereof |
KR101809858B1 (en) | 2012-04-04 | 2017-12-15 | 할로자임, 아이엔씨 | Combination therapy with an anti-hyaluronan agent and a tumor-targeted taxane |
US9522945B2 (en) | 2012-04-19 | 2016-12-20 | Opko Biologics Ltd. | Long-acting oxyntomodulin variants and methods of producing same |
AU2013273135B2 (en) | 2012-06-04 | 2017-12-07 | Opko Biologics Ltd. | Pegylated OXM variants |
US9278124B2 (en) | 2012-10-16 | 2016-03-08 | Halozyme, Inc. | Hypoxia and hyaluronan and markers thereof for diagnosis and monitoring of diseases and conditions and related methods |
CN114317505A (en) | 2012-11-20 | 2022-04-12 | 奥普科生物制品有限公司 | Method for increasing the hydrodynamic volume of a polypeptide by attachment to a gonadotrophin carboxy terminal peptide |
US20160067347A1 (en) | 2012-12-20 | 2016-03-10 | Amgen Inc. | Apj receptor agonists and uses thereof |
WO2014110867A1 (en) * | 2013-01-17 | 2014-07-24 | 厦门赛诺邦格生物科技有限公司 | Monofunctional branched polyethyleneglycol and bio-related substance modified by same |
WO2014114262A1 (en) * | 2013-01-28 | 2014-07-31 | 天津键凯科技有限公司 | Water soluble polymer-amino acid oligopeptide-medicine combination, preparation method therefore, and use thereof |
US9700633B2 (en) | 2013-01-28 | 2017-07-11 | Jenkem Technology Co., Ltd., Tianjin Branch | Conjugates of water soluble polymer-amino acid oligopeptide-drug, preparation method and use thereof |
US9675678B2 (en) | 2013-01-29 | 2017-06-13 | The Regents Of The University Of Colorado, A Body Corporate | Compositions and methods for treatment of homocystinuria |
US10279012B2 (en) | 2013-03-11 | 2019-05-07 | Healthpartners Research & Education | Methods of treating and preventing social communication disorder in patients by intranasal administration of insulin |
TW201446792A (en) | 2013-03-12 | 2014-12-16 | Amgen Inc | Potent and selective inhibitors of Nav1.7 |
CN106913865A (en) | 2013-04-18 | 2017-07-04 | 阿尔莫生物科技股份有限公司 | The method that disease and illness are treated using interleukin 10 |
US10364451B2 (en) | 2013-05-30 | 2019-07-30 | Duke University | Polymer conjugates having reduced antigenicity and methods of using the same |
US10392611B2 (en) | 2013-05-30 | 2019-08-27 | Duke University | Polymer conjugates having reduced antigenicity and methods of using the same |
WO2014204816A2 (en) | 2013-06-17 | 2014-12-24 | Armo Biosciences, Inc. | Method for assessing protein identity and stability |
TW201534726A (en) | 2013-07-03 | 2015-09-16 | Halozyme Inc | Thermally stable PH20 hyaluronidase variants and uses thereof |
EA201690212A8 (en) | 2013-07-12 | 2016-08-31 | Офтотек Корпорейшн | METHODS OF TREATMENT OR PREVENTION OF OPHTHALMIC PATHOLOGICAL CONDITIONS |
WO2015031316A1 (en) | 2013-08-30 | 2015-03-05 | Armo Biosciences, Inc. | Methods of using interleukin-10 for treating diseases and disorders |
KR20240034882A (en) | 2013-10-15 | 2024-03-14 | 씨젠 인크. | Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics |
US20150158926A1 (en) | 2013-10-21 | 2015-06-11 | Opko Biologics, Ltd. | Long-acting polypeptides and methods of producing and administering same |
CA2928710A1 (en) | 2013-11-11 | 2015-05-14 | Armo Biosciences, Inc. | Methods of using interleukin-10 for treating diseases and disorders |
ITTV20130205A1 (en) | 2013-12-06 | 2015-06-07 | Scarpa Calzaturificio Spa | SKI BOOT |
ITTV20130204A1 (en) | 2013-12-06 | 2015-06-07 | Scarpa Calzaturificio Spa | SKI BOOT |
US10314911B2 (en) | 2014-04-08 | 2019-06-11 | Healthpartners Research & Education | Methods for protecting and treating traumatic brain injury, concussion and brain inflammation with intranasal insulin |
US10293043B2 (en) | 2014-06-02 | 2019-05-21 | Armo Biosciences, Inc. | Methods of lowering serum cholesterol |
ES2950789T3 (en) | 2014-06-10 | 2023-10-13 | Amgen Inc | Apelin polypeptides |
HUE043847T2 (en) | 2014-08-28 | 2019-09-30 | Halozyme Inc | Combination therapy with a hyaluronan-degrading enzyme and an immune checkpoint inhibitor |
US10350270B2 (en) | 2014-10-14 | 2019-07-16 | Armo Biosciences, Inc. | Interleukin-15 compositions and uses thereof |
CN108064282A (en) | 2014-10-14 | 2018-05-22 | 哈洛齐梅公司 | Adenosine deaminase -2 (ADA2), its variant composition and use its method |
KR20170084033A (en) | 2014-10-22 | 2017-07-19 | 아르모 바이오사이언시스 인코포레이티드 | Methods of using interleukin-10 for treating diseases and disorders |
MX2017004488A (en) | 2014-10-23 | 2017-07-17 | Ngm Biopharmaceuticals Inc | Pharmaceutical compositions comprising peptide variants and methods of use thereof. |
WO2016073825A1 (en) | 2014-11-06 | 2016-05-12 | Pharmaessentia Corporation | Dosage regimen for pegylated interferon |
US10618970B2 (en) | 2015-02-03 | 2020-04-14 | Armo Biosciences, Inc. | Method of treating cancer with IL-10 and antibodies that induce ADCC |
WO2016154530A1 (en) | 2015-03-26 | 2016-09-29 | Duke University | Targeted therapeutic agents comprising multivalent protein-biopolymer fusions |
KR20180020141A (en) | 2015-05-28 | 2018-02-27 | 아르모 바이오사이언시스 인코포레이티드 | PEGylated interleukin-10 for cancer treatment |
EP3302528A1 (en) | 2015-05-29 | 2018-04-11 | Armo Biosciences, Inc. | Methods of using interleukin-10 for treating diseases and disorders |
AU2016273045B2 (en) | 2015-05-29 | 2020-11-26 | Opko Biologics Ltd. | Pegylated oxyntomodulin variants |
SI3307296T1 (en) | 2015-06-15 | 2022-04-29 | The Board of Trustees of the Leland Stanford Junior University Office of the General Counsel | Timp2 for use in treating aging-associated conditions |
CN113289009A (en) | 2015-06-19 | 2021-08-24 | Opko生物科学有限公司 | Long-acting coagulation factor and production method thereof |
CN108463244B (en) | 2015-08-04 | 2022-05-27 | 杜克大学 | Gene-encoded intrinsically disordered stealth polymers for delivery and methods of use thereof |
AU2016312510A1 (en) | 2015-08-25 | 2018-03-08 | Armo Biosciences, Inc. | Methods of using Interleukin-10 for treating diseases and disorders |
AU2016353988B2 (en) | 2015-11-09 | 2019-09-26 | Ngm Biopharmaceuticals, Inc. | Methods for treatment of bile acid-related disorders |
PT3373922T (en) | 2015-11-09 | 2022-03-28 | Univ Colorado Regents | Compositions and methods for treatment of homocystinuria |
US11793880B2 (en) | 2015-12-04 | 2023-10-24 | Seagen Inc. | Conjugates of quaternized tubulysin compounds |
SG10202010590UA (en) | 2015-12-04 | 2020-12-30 | Seattle Genetics Inc | Conjugates of quaternized tubulysin compounds |
US11752213B2 (en) | 2015-12-21 | 2023-09-12 | Duke University | Surfaces having reduced non-specific binding and antigenicity |
WO2017112826A2 (en) * | 2015-12-21 | 2017-06-29 | Duke University | Polymer conjugates having reduced antigenicity and methods of using the same |
ITUB20160158A1 (en) | 2016-01-15 | 2017-07-15 | Scarpa Calzaturificio Spa | SKI BOOT |
WO2017160599A1 (en) | 2016-03-14 | 2017-09-21 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Use of cd300b antagonists to treat sepsis and septic shock |
MA43835A (en) | 2016-03-25 | 2018-11-28 | Seattle Genetics Inc | PROCESS FOR THE PREPARATION OF PEGYLATED MEDICINAL PRODUCTS AND THEIR INTERMEDIARIES |
US10421785B2 (en) | 2016-04-11 | 2019-09-24 | Bar-Ilan University | Delta receptor agonist peptides and use thereof |
US11467156B2 (en) | 2016-06-01 | 2022-10-11 | Duke University | Nonfouling biosensors |
US20190160152A1 (en) | 2016-06-09 | 2019-05-30 | Opko Biologics Ltd. | Long-acting oxyntomodulin formulation and methods of producing and administering same |
RU2019110848A (en) | 2016-09-14 | 2020-10-15 | Дьюк Юниверсити | NANOPARTICLES BASED ON TRIBLOC POLYPEPTIDES FOR DELIVERY OF HYDROPHILIC MEDICINES |
US11155584B2 (en) | 2016-09-23 | 2021-10-26 | Duke University | Unstructured non-repetitive polypeptides having LCST behavior |
KR20220147721A (en) | 2016-11-14 | 2022-11-03 | 항저우 디에이씨 바이오테크 씨오, 엘티디 | Conjugation linkers, cell binding molecule-drug conjugates containing the likers, methods of making and uses such conjugates with the linkers |
US11135307B2 (en) | 2016-11-23 | 2021-10-05 | Mersana Therapeutics, Inc. | Peptide-containing linkers for antibody-drug conjugates |
WO2018132732A1 (en) | 2017-01-12 | 2018-07-19 | Duke University | Genetically encoded lipid-polypeptide hybrid biomaterials that exhibit temperature triggered hierarchical self-assembly |
JP2020512312A (en) | 2017-03-24 | 2020-04-23 | シアトル ジェネティックス, インコーポレイテッド | Process for the preparation of glucuronide drug-linker and its intermediates |
JP6935059B2 (en) | 2017-03-30 | 2021-09-15 | 日油株式会社 | A method for purifying polyethylene glycol having one carboxyl group |
MX2019012347A (en) | 2017-04-17 | 2020-01-15 | Univ Colorado Regents | Optimization of enzyme replacement therapy for treatment of homocystinuria. |
US11554097B2 (en) | 2017-05-15 | 2023-01-17 | Duke University | Recombinant production of hybrid lipid-biopolymer materials that self-assemble and encapsulate agents |
JP7091373B2 (en) | 2017-06-22 | 2022-06-27 | カタリスト・バイオサイエンシーズ・インコーポレイテッド | Modified Membrane Serine Protease 1 (MTSP-1) Polypeptide and Usage |
EP3658168A4 (en) | 2017-06-30 | 2021-07-14 | Duke University | Order and disorder as a design principle for stimuli-responsive biopolymer networks |
US20200353050A1 (en) | 2017-11-10 | 2020-11-12 | Armo Biosciences, Inc. | Compositions and methods of use of interleukin-10 in combination with immune check-point pathway inhibitors |
WO2019211842A1 (en) | 2018-04-30 | 2019-11-07 | Opko Biologics Ltd. | Long-acting human growth hormone-antagonists and methods of producing the same |
WO2019222435A1 (en) | 2018-05-16 | 2019-11-21 | Halozyme, Inc. | Methods of selecting subjects for combination cancer therapy with a polymer-conjugated soluble ph20 |
US20210347842A1 (en) | 2018-06-19 | 2021-11-11 | Eli Lilly And Company | Compositions and methods of use of il-10 agents in conjunction with chimeric antigen receptor cell therapy |
EP3829622A4 (en) | 2018-08-02 | 2022-05-11 | Duke University | Dual agonist fusion proteins |
CN110964116A (en) | 2018-09-26 | 2020-04-07 | 北京辅仁瑞辉生物医药研究院有限公司 | GLP1-Fc fusion proteins and conjugates thereof |
US11613744B2 (en) | 2018-12-28 | 2023-03-28 | Vertex Pharmaceuticals Incorporated | Modified urokinase-type plasminogen activator polypeptides and methods of use |
AU2019413431A1 (en) | 2018-12-28 | 2021-07-08 | Vertex Pharmaceuticals Incorporated | Modified urokinase-type plasminogen activator polypeptides and methods of use |
CN113710692A (en) | 2019-02-11 | 2021-11-26 | Opko生物科学有限公司 | Long-acting GLP-2 analogs |
US10882954B2 (en) | 2019-04-11 | 2021-01-05 | Sunbio Inc. | Tertiary alkoxy polyethylene glycol and derivatives thereof |
CN112175088B (en) | 2019-07-02 | 2023-03-28 | 江苏晟斯生物制药有限公司 | FIX fusion proteins, conjugates and uses thereof |
US11512314B2 (en) | 2019-07-12 | 2022-11-29 | Duke University | Amphiphilic polynucleotides |
MX2022002337A (en) | 2019-08-27 | 2022-06-08 | Tonix Pharma Ltd | Modified tff2 polypeptides. |
EP3954393A1 (en) | 2020-08-13 | 2022-02-16 | Bioasis Technologies Inc. | Combination therapies for delivery across the blood brain barrier |
WO2022211829A1 (en) | 2021-03-30 | 2022-10-06 | Jazz Pharmaceuticals Ireland Ltd. | Dosing of recombinant l-asparaginase |
WO2024015529A2 (en) | 2022-07-14 | 2024-01-18 | Jazz Pharmaceuticals Ireland Ltd. | Combination therapies involving l-asparaginase |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5219564A (en) * | 1990-07-06 | 1993-06-15 | Enzon, Inc. | Poly(alkylene oxide) amino acid copolymers and drug carriers and charged copolymers based thereon |
US5283317A (en) * | 1987-08-03 | 1994-02-01 | Ddi Pharmaceuticals, Inc. | Intermediates for conjugation of polypeptides with high molecular weight polyalkylene glycols |
US5321095A (en) * | 1993-02-02 | 1994-06-14 | Enzon, Inc. | Azlactone activated polyalkylene oxides |
US5324844A (en) * | 1989-04-19 | 1994-06-28 | Enzon, Inc. | Active carbonates of polyalkylene oxides for modification of polypeptides |
Family Cites Families (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4179337A (en) * | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
IL47468A (en) * | 1975-06-12 | 1979-05-31 | Rehovot Res Prod | Process for the cross-linking of proteins using water soluble cross-linking agents |
IT1107772B (en) * | 1977-08-22 | 1985-11-25 | Cancer Res Inst Royal | PROCEDURE FOR THE PRODUCTION OF MACROMOLECULAR COMPLEXES PRODUCT OBTAINED AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT AS AN ACTIVE INGREDIENT |
US5217564A (en) * | 1980-04-10 | 1993-06-08 | Massachusetts Institute Of Technology | Method of producing sheets of crystalline material and devices made therefrom |
US4766106A (en) * | 1985-06-26 | 1988-08-23 | Cetus Corporation | Solubilization of proteins for pharmaceutical compositions using polymer conjugation |
US4680338A (en) * | 1985-10-17 | 1987-07-14 | Immunomedics, Inc. | Bifunctional linker |
US4889916A (en) * | 1985-11-19 | 1989-12-26 | The Johns Hopkins University | Protein label and drug delivery system |
JP2514950B2 (en) * | 1986-03-10 | 1996-07-10 | エフ・ホフマン―ラ ロシユ アーゲー | Chemically modified protein, its production method and intermediate |
US4846548A (en) | 1987-05-06 | 1989-07-11 | St&E, Inc. | Fiber optic which is an inherent chemical sensor |
US5229490A (en) * | 1987-05-06 | 1993-07-20 | The Rockefeller University | Multiple antigen peptide system |
US4904582A (en) * | 1987-06-11 | 1990-02-27 | Synthetic Genetics | Novel amphiphilic nucleic acid conjugates |
US5214131A (en) * | 1988-05-06 | 1993-05-25 | Sumitomo Pharmaceuticals Company, Limited | Polyethylene glycol derivatives, modified peptides and production thereof |
JP2958019B2 (en) * | 1988-05-06 | 1999-10-06 | 住友製薬株式会社 | Polyethylene glycol derivative, modified peptide and method for producing the same |
US5091176A (en) * | 1988-11-02 | 1992-02-25 | W. R. Grace & Co.-Conn. | Polymer-modified peptide drugs having enhanced biological and pharmacological activities |
US5122614A (en) * | 1989-04-19 | 1992-06-16 | Enzon, Inc. | Active carbonates of polyalkylene oxides for modification of polypeptides |
ES2247656T3 (en) | 1989-04-19 | 2006-03-01 | Enzon, Inc. | A PROCESS TO FORM A MODIFIED POLYPEPTIDE THAT INCLUDES A POLYPEPTIDE AND A POLYCHYLENE OXIDE. |
GB8918589D0 (en) * | 1989-08-15 | 1989-09-27 | Graham Neil B | Polymeric compositions |
US5091542A (en) * | 1990-03-09 | 1992-02-25 | Hybritech Incorporated | Tris-maleimido compounds as intermediates in trifunctional antibody synthesis |
JP3051145B2 (en) * | 1990-08-28 | 2000-06-12 | 住友製薬株式会社 | Novel polyethylene glycol derivative modified peptide |
US5545698A (en) * | 1990-08-31 | 1996-08-13 | University Of Minnesota | Polyethylene glycol derivatives for solid-phase applications |
US5462990A (en) * | 1990-10-15 | 1995-10-31 | Board Of Regents, The University Of Texas System | Multifunctional organic polymers |
US5252714A (en) * | 1990-11-28 | 1993-10-12 | The University Of Alabama In Huntsville | Preparation and use of polyethylene glycol propionaldehyde |
US5595732A (en) * | 1991-03-25 | 1997-01-21 | Hoffmann-La Roche Inc. | Polyethylene-protein conjugates |
US5281698A (en) * | 1991-07-23 | 1994-01-25 | Cetus Oncology Corporation | Preparation of an activated polymer ester for protein conjugation |
NZ244778A (en) * | 1991-10-21 | 1994-03-25 | Ortho Pharma Corp | Peg imidates and protein derivatives thereof |
WO1993024476A1 (en) * | 1992-06-04 | 1993-12-09 | Clover Consolidated, Limited | Water-soluble polymeric carriers for drug delivery |
US5514379A (en) * | 1992-08-07 | 1996-05-07 | The General Hospital Corporation | Hydrogel compositions and methods of use |
US5382657A (en) * | 1992-08-26 | 1995-01-17 | Hoffmann-La Roche Inc. | Peg-interferon conjugates |
US5298643A (en) * | 1992-12-22 | 1994-03-29 | Enzon, Inc. | Aryl imidate activated polyalkylene oxides |
US5349001A (en) * | 1993-01-19 | 1994-09-20 | Enzon, Inc. | Cyclic imide thione activated polyalkylene oxides |
US5543158A (en) * | 1993-07-23 | 1996-08-06 | Massachusetts Institute Of Technology | Biodegradable injectable nanoparticles |
US5643575A (en) * | 1993-10-27 | 1997-07-01 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
US5919455A (en) * | 1993-10-27 | 1999-07-06 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
US5605976A (en) * | 1995-05-15 | 1997-02-25 | Enzon, Inc. | Method of preparing polyalkylene oxide carboxylic acids |
US5443953A (en) * | 1993-12-08 | 1995-08-22 | Immunomedics, Inc. | Preparation and use of immunoconjugates |
US5730990A (en) * | 1994-06-24 | 1998-03-24 | Enzon, Inc. | Non-antigenic amine derived polymers and polymer conjugates |
US5932462A (en) * | 1995-01-10 | 1999-08-03 | Shearwater Polymers, Inc. | Multiarmed, monofunctional, polymer for coupling to molecules and surfaces |
US5756593A (en) * | 1995-05-15 | 1998-05-26 | Enzon, Inc. | Method of preparing polyalkyene oxide carboxylic acids |
TW517067B (en) * | 1996-05-31 | 2003-01-11 | Hoffmann La Roche | Interferon conjugates |
-
1997
- 1997-03-20 US US08/821,055 patent/US5919455A/en not_active Expired - Lifetime
-
1998
- 1998-03-13 DK DK98910376T patent/DK0973819T3/en active
- 1998-03-13 AU AU64630/98A patent/AU743108B2/en not_active Expired
- 1998-03-13 JP JP54063898A patent/JP4612919B2/en not_active Expired - Lifetime
- 1998-03-13 SI SI9830806T patent/SI0973819T1/en unknown
- 1998-03-13 CA CA002283939A patent/CA2283939C/en not_active Expired - Lifetime
- 1998-03-13 ES ES98910376T patent/ES2249824T3/en not_active Expired - Lifetime
- 1998-03-13 DE DE69831402T patent/DE69831402T2/en not_active Expired - Lifetime
- 1998-03-13 AT AT98910376T patent/ATE303412T1/en active
- 1998-03-13 NZ NZ337845A patent/NZ337845A/en not_active IP Right Cessation
- 1998-03-13 EP EP98910376A patent/EP0973819B1/en not_active Expired - Lifetime
- 1998-03-13 WO PCT/US1998/004966 patent/WO1998041562A1/en active IP Right Grant
- 1998-12-29 US US09/222,463 patent/US6113906A/en not_active Expired - Lifetime
-
2000
- 2000-04-07 US US09/545,066 patent/US6566506B2/en not_active Expired - Fee Related
-
2010
- 2010-02-05 JP JP2010024340A patent/JP4961025B2/en not_active Expired - Lifetime
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5283317A (en) * | 1987-08-03 | 1994-02-01 | Ddi Pharmaceuticals, Inc. | Intermediates for conjugation of polypeptides with high molecular weight polyalkylene glycols |
US5324844A (en) * | 1989-04-19 | 1994-06-28 | Enzon, Inc. | Active carbonates of polyalkylene oxides for modification of polypeptides |
US5219564A (en) * | 1990-07-06 | 1993-06-15 | Enzon, Inc. | Poly(alkylene oxide) amino acid copolymers and drug carriers and charged copolymers based thereon |
US5321095A (en) * | 1993-02-02 | 1994-06-14 | Enzon, Inc. | Azlactone activated polyalkylene oxides |
Cited By (226)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0841936A4 (en) * | 1995-07-31 | 2001-09-26 | Nobex Corp | Conjugation-stabilized therapeutic agent compositions, delivery and diagnostic formulations |
EP0841936A1 (en) * | 1995-07-31 | 1998-05-20 | Protein Delivery, Inc. | Conjugation-stabilized therapeutic agent compositions, delivery and diagnostic formulations |
EP1352662A1 (en) * | 1997-09-17 | 2003-10-15 | Mitsubishi Chemical Corporation | Conjugates of an antibody and a water-soluble polymer used in immunoliposomes |
EP0903152A3 (en) * | 1997-09-17 | 1999-07-07 | Mitsubishi Chemical Corporation | Bifunctional water-soluble polymer derivative and complex containing it |
EP0903152A2 (en) * | 1997-09-17 | 1999-03-24 | Mitsubishi Chemical Corporation | Bifunctional water-soluble polymer derivative and complex containing it |
EP2133098A1 (en) | 2000-01-10 | 2009-12-16 | Maxygen Holdings Ltd | G-CSF conjugates |
EP1982732A2 (en) | 2000-02-11 | 2008-10-22 | Maxygen Holdings Ltd. | Factor VII or VIIA-like molecules |
EP2319541A1 (en) | 2000-02-11 | 2011-05-11 | Bayer HealthCare LLC | Factor VII or VIIA-like conjugates |
JP2003530361A (en) * | 2000-04-07 | 2003-10-14 | アムジェン インコーポレーテッド | Novel chemically modified erythropoietin stimulating protein compositions and methods |
KR100396983B1 (en) * | 2000-07-29 | 2003-09-02 | 이강춘 | Highly reactive branched polymer and proteins or peptides conjugated with the polymer |
EP2080771A2 (en) | 2001-02-27 | 2009-07-22 | Maxygen Aps | New interferon beta-like molecules |
US8716240B2 (en) | 2001-10-10 | 2014-05-06 | Novo Nordisk A/S | Erythropoietin: remodeling and glycoconjugation of erythropoietin |
US8716239B2 (en) | 2001-10-10 | 2014-05-06 | Novo Nordisk A/S | Granulocyte colony stimulating factor: remodeling and glycoconjugation G-CSF |
US8076292B2 (en) | 2001-10-10 | 2011-12-13 | Novo Nordisk A/S | Factor VIII: remodeling and glycoconjugation of factor VIII |
US8809453B2 (en) | 2001-11-07 | 2014-08-19 | Nektar Therapeutics | Branched polymers |
US8440816B2 (en) | 2001-11-07 | 2013-05-14 | Nektar Therapeutics | Branched polymers |
US9187569B2 (en) | 2001-11-07 | 2015-11-17 | Nektar Therapeutics | Branched polymers |
US8273833B2 (en) | 2001-11-07 | 2012-09-25 | Nektar Therapeutics | Branched Polymers |
US7872072B2 (en) | 2001-11-07 | 2011-01-18 | Nektar Therapeutics | Branched polymers and their conjugates |
WO2004000366A1 (en) | 2002-06-21 | 2003-12-31 | Novo Nordisk Health Care Ag | Pegylated factor vii glycoforms |
US8853325B2 (en) | 2002-09-09 | 2014-10-07 | Nektar Therapeutics | Water-soluble polymer alkanals |
US7157546B2 (en) | 2002-09-09 | 2007-01-02 | Nektar Therapeutics Al, Corporation | Water-soluble polymer alkanals |
EP1591467A1 (en) * | 2002-09-09 | 2005-11-02 | Nektar Therapeutics Al, Corporation | Conjugate between a polyethylene glycol having a terminal alkanal group and a human growth hormone |
US8076412B2 (en) | 2002-09-09 | 2011-12-13 | Nektar Therapeutics | Water-soluble polymer alkanals |
US7838595B2 (en) | 2002-09-09 | 2010-11-23 | Nektar Therapeutics | Water-soluble polymer alkanals |
WO2004061094A1 (en) | 2002-12-30 | 2004-07-22 | Gryphon Therapeutics, Inc. | Water-soluble thioester and selenoester compounds and methods for making and using the same |
US8034900B2 (en) | 2002-12-30 | 2011-10-11 | Amylin Pharmaceuticals, Inc. | Water-soluble thioester and selenoester compounds and methods for making and using the same |
US8247381B2 (en) | 2003-03-14 | 2012-08-21 | Biogenerix Ag | Branched water-soluble polymers and their conjugates |
EP1608688A4 (en) * | 2003-03-14 | 2010-06-30 | Biogenerix Ag | Branched water-soluble polymers and their conjugates |
EP1608688A2 (en) * | 2003-03-14 | 2005-12-28 | Neose Technologies, Inc. | Branched water-soluble polymers and their conjugates |
US8853161B2 (en) | 2003-04-09 | 2014-10-07 | Novo Nordisk A/S | Glycopegylation methods and proteins/peptides produced by the methods |
US8791070B2 (en) | 2003-04-09 | 2014-07-29 | Novo Nordisk A/S | Glycopegylated factor IX |
US9005625B2 (en) | 2003-07-25 | 2015-04-14 | Novo Nordisk A/S | Antibody toxin conjugates |
US8263062B2 (en) | 2003-09-17 | 2012-09-11 | Nektar Therapeutics | Multi-arm polymer prodrugs |
US8318145B2 (en) | 2003-09-17 | 2012-11-27 | Nektar Therapeutics | Multi-arm polymer prodrugs |
WO2005028539A2 (en) * | 2003-09-17 | 2005-03-31 | Nektar Therapeutics Al, Corporation | Multi-arm polymer prodrugs |
US8771662B2 (en) | 2003-09-17 | 2014-07-08 | Nektar Therapeutics | Multi-arm polymer prodrugs |
US10463659B2 (en) | 2003-09-17 | 2019-11-05 | Nektar Therapeutics | Multi-arm polymer prodrugs |
US7744861B2 (en) | 2003-09-17 | 2010-06-29 | Nektar Therapeutics | Multi-arm polymer prodrugs |
US9333200B2 (en) | 2003-09-17 | 2016-05-10 | Nektar Therapeutics | Multi-arm polymer prodrugs |
CN1852740B (en) * | 2003-09-17 | 2011-05-11 | 耐科塔医药公司 | Multi-arm polymer prodrugs |
US8394365B2 (en) | 2003-09-17 | 2013-03-12 | Nektar Therapeutics | Multi-arm polymer prodrugs |
WO2005028539A3 (en) * | 2003-09-17 | 2005-11-24 | Nektar Therapeutics Al Corp | Multi-arm polymer prodrugs |
US9808533B2 (en) | 2003-09-17 | 2017-11-07 | Nektar Therapeutics | Multi-arm polymer prodrugs |
EP2263684A1 (en) | 2003-10-10 | 2010-12-22 | Novo Nordisk A/S | IL-21 derivatives |
EP2641611A2 (en) | 2003-10-17 | 2013-09-25 | Novo Nordisk A/S | Combination therapy |
EP2633866A2 (en) | 2003-10-17 | 2013-09-04 | Novo Nordisk A/S | Combination therapy |
US10011682B2 (en) | 2003-11-06 | 2018-07-03 | Nektar Therapeutics | Method of preparing carboxylic acid functionalized polymers |
WO2005047366A1 (en) * | 2003-11-06 | 2005-05-26 | Nektar Therapeutics Al, Corporation | Method of preparing carboxylic acid functionalized polymers |
US8067505B2 (en) | 2003-11-06 | 2011-11-29 | Nektar Therapeutics | Method of preparing carboxylic acid functionalized polymers |
US11111335B2 (en) | 2003-11-06 | 2021-09-07 | Nektar Therapeutics | Method of preparing carboxylic acid functionalized polymers |
US8633157B2 (en) | 2003-11-24 | 2014-01-21 | Novo Nordisk A/S | Glycopegylated erythropoietin |
US8916360B2 (en) | 2003-11-24 | 2014-12-23 | Novo Nordisk A/S | Glycopegylated erythropoietin |
US8632770B2 (en) | 2003-12-03 | 2014-01-21 | Novo Nordisk A/S | Glycopegylated factor IX |
US8361961B2 (en) | 2004-01-08 | 2013-01-29 | Biogenerix Ag | O-linked glycosylation of peptides |
US8907064B2 (en) | 2004-02-02 | 2014-12-09 | Ambrx, Inc. | Modified human four helical bundle polypeptides and their uses |
US9260472B2 (en) | 2004-02-02 | 2016-02-16 | Ambrx, Inc. | Modified human four helical bundle polypeptides and their uses |
US8097702B2 (en) | 2004-02-02 | 2012-01-17 | Ambrx, Inc. | Modified human interferon polypeptides with at least one non-naturally encoded amino acid and their uses |
EP2327724A2 (en) | 2004-02-02 | 2011-06-01 | Ambrx, Inc. | Modified human growth hormone polypeptides and their uses |
US8906676B2 (en) | 2004-02-02 | 2014-12-09 | Ambrx, Inc. | Modified human four helical bundle polypeptides and their uses |
US8232371B2 (en) | 2004-02-02 | 2012-07-31 | Ambrx, Inc. | Modified human interferon polypeptides and their uses |
WO2006009901A2 (en) | 2004-06-18 | 2006-01-26 | Ambrx, Inc. | Novel antigen-binding polypeptides and their uses |
US9175083B2 (en) | 2004-06-18 | 2015-11-03 | Ambrx, Inc. | Antigen-binding polypeptides and their uses |
US8791066B2 (en) | 2004-07-13 | 2014-07-29 | Novo Nordisk A/S | Branched PEG remodeling and glycosylation of glucagon-like peptide-1 [GLP-1] |
US8268967B2 (en) | 2004-09-10 | 2012-09-18 | Novo Nordisk A/S | Glycopegylated interferon α |
US10874714B2 (en) | 2004-10-29 | 2020-12-29 | 89Bio Ltd. | Method of treating fibroblast growth factor 21 (FGF-21) deficiency |
US9200049B2 (en) | 2004-10-29 | 2015-12-01 | Novo Nordisk A/S | Remodeling and glycopegylation of fibroblast growth factor (FGF) |
US7947473B2 (en) | 2004-12-22 | 2011-05-24 | Ambrx, Inc. | Methods for expression and purification of pegylated recombinant human growth hormone containing a non-naturally encoded keto amino acid |
US7816320B2 (en) | 2004-12-22 | 2010-10-19 | Ambrx, Inc. | Formulations of human growth hormone comprising a non-naturally encoded amino acid at position 35 |
US8143216B2 (en) | 2004-12-22 | 2012-03-27 | Ambrx, Inc. | Modified human growth hormone |
US8163695B2 (en) | 2004-12-22 | 2012-04-24 | Ambrx | Formulations of human growth hormone comprising a non-naturally encoded amino acid |
US8178108B2 (en) | 2004-12-22 | 2012-05-15 | Ambrx, Inc. | Methods for expression and purification of recombinant human growth hormone |
US8178494B2 (en) | 2004-12-22 | 2012-05-15 | Ambrx, Inc. | Modified human growth hormone formulations with an increased serum half-life |
US7838265B2 (en) | 2004-12-22 | 2010-11-23 | Ambrx, Inc. | Compositions of aminoacyl-tRNA synthetase and uses thereof |
US7939496B2 (en) | 2004-12-22 | 2011-05-10 | Ambrx, Inc. | Modified human growth horomone polypeptides and their uses |
US8080391B2 (en) | 2004-12-22 | 2011-12-20 | Ambrx, Inc. | Process of producing non-naturally encoded amino acid containing high conjugated to a water soluble polymer |
US7959926B2 (en) | 2004-12-22 | 2011-06-14 | Ambrx, Inc. | Methods for expression and purification of recombinant human growth hormone mutants |
US7846689B2 (en) | 2004-12-22 | 2010-12-07 | Ambrx, Inc. | Compositions of aminoacyl-tRNA synthetase and uses thereof |
US7858344B2 (en) | 2004-12-22 | 2010-12-28 | Ambrx, Inc. | Compositions of aminoacyl-tRNA synthetase and uses thereof |
US7736872B2 (en) | 2004-12-22 | 2010-06-15 | Ambrx, Inc. | Compositions of aminoacyl-TRNA synthetase and uses thereof |
EP2284191A2 (en) | 2004-12-22 | 2011-02-16 | Ambrx, Inc. | Process for the preparation of hGH |
US7883866B2 (en) | 2004-12-22 | 2011-02-08 | Ambrx, Inc. | Compositions of aminoacyl-tRNA synthetase and uses thereof |
US7829310B2 (en) | 2004-12-22 | 2010-11-09 | Ambrx, Inc. | Compositions of aminoacyl-tRNA synthetase and uses thereof |
US9029331B2 (en) | 2005-01-10 | 2015-05-12 | Novo Nordisk A/S | Glycopegylated granulocyte colony stimulating factor |
EP2279756A2 (en) | 2005-04-05 | 2011-02-02 | Instituto di Ricerche di Biologia Molecolare p Angeletti S.P.A. | Method for shielding functional sites or epitopes on proteins |
EP2314320A2 (en) | 2005-04-05 | 2011-04-27 | Istituto di Richerche di Biologia Molecolare P. Angeletti S.p.A. | Method for shielding functional sites or epitopes on proteins |
US9187546B2 (en) | 2005-04-08 | 2015-11-17 | Novo Nordisk A/S | Compositions and methods for the preparation of protease resistant human growth hormone glycosylation mutants |
US8404809B2 (en) | 2005-05-25 | 2013-03-26 | Novo Nordisk A/S | Glycopegylated factor IX |
US8093356B2 (en) | 2005-06-03 | 2012-01-10 | Ambrx, Inc. | Pegylated human interferon polypeptides |
WO2006135930A3 (en) * | 2005-06-13 | 2007-05-31 | Nastech Pharm Co | Transmucosal delivery of peptide derivatives |
WO2006135930A2 (en) * | 2005-06-13 | 2006-12-21 | Nastech Pharmaceutical Company Inc. | Transmucosal delivery of peptide derivatives |
EP2360170A2 (en) | 2005-06-17 | 2011-08-24 | Novo Nordisk Health Care AG | Selective reduction and derivatization of engineered proteins comprinsing at least one non-native cysteine |
WO2006134173A2 (en) | 2005-06-17 | 2006-12-21 | Novo Nordisk Health Care Ag | Selective reduction and derivatization of engineered proteins comprising at least one non-native cysteine |
US8911967B2 (en) | 2005-08-19 | 2014-12-16 | Novo Nordisk A/S | One pot desialylation and glycopegylation of therapeutic peptides |
US8841439B2 (en) | 2005-11-03 | 2014-09-23 | Novo Nordisk A/S | Nucleotide sugar purification using membranes |
US9488660B2 (en) | 2005-11-16 | 2016-11-08 | Ambrx, Inc. | Methods and compositions comprising non-natural amino acids |
US8048891B2 (en) | 2006-02-09 | 2011-11-01 | Enzon Pharmaceuticals, Inc. | Treatment of non-hodgkin's lymphomas with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin |
US8299089B2 (en) | 2006-02-09 | 2012-10-30 | Enzon Pharmaceuticals, Inc. | Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers |
US7723351B2 (en) | 2006-02-09 | 2010-05-25 | Enzon Pharmaceuticals, Inc. | Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers |
US7671067B2 (en) | 2006-02-09 | 2010-03-02 | Enzon Pharmaceuticals, Inc. | Treatment of non-hodgkin's lymphomas with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamtothecin |
US7462627B2 (en) | 2006-02-09 | 2008-12-09 | Enzon Pharmaceuticals, Inc. | Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers |
EP2213733A2 (en) | 2006-05-24 | 2010-08-04 | Novo Nordisk Health Care AG | Factor IX analogues having prolonged in vivo half life |
US9187532B2 (en) | 2006-07-21 | 2015-11-17 | Novo Nordisk A/S | Glycosylation of peptides via O-linked glycosylation sequences |
US8022186B2 (en) | 2006-09-08 | 2011-09-20 | Ambrx, Inc. | Modified human plasma polypeptide or Fc scaffolds and their uses |
US8053560B2 (en) | 2006-09-08 | 2011-11-08 | Ambrx, Inc. | Modified human plasma polypeptide or Fc scaffolds and their uses |
US9133495B2 (en) | 2006-09-08 | 2015-09-15 | Ambrx, Inc. | Hybrid suppressor tRNA for vertebrate cells |
US7919591B2 (en) | 2006-09-08 | 2011-04-05 | Ambrx, Inc. | Modified human plasma polypeptide or Fc scaffolds and their uses |
US8618257B2 (en) | 2006-09-08 | 2013-12-31 | Ambrx, Inc. | Modified human plasma polypeptide or Fc scaffolds and their uses |
WO2008030558A2 (en) | 2006-09-08 | 2008-03-13 | Ambrx, Inc. | Modified human plasma polypeptide or fc scaffolds and their uses |
US8420792B2 (en) | 2006-09-08 | 2013-04-16 | Ambrx, Inc. | Suppressor tRNA transcription in vertebrate cells |
EP2548967A2 (en) | 2006-09-21 | 2013-01-23 | The Regents of The University of California | Aldehyde tags, uses thereof in site-specific protein modification |
US8969532B2 (en) | 2006-10-03 | 2015-03-03 | Novo Nordisk A/S | Methods for the purification of polypeptide conjugates comprising polyalkylene oxide using hydrophobic interaction chromatography |
US9175060B2 (en) | 2006-11-14 | 2015-11-03 | Shanghai Benemae Pharmaceutical Corporation | PEG modified exendin or exendin analog and compositions and use thereof |
US8354549B2 (en) | 2006-11-30 | 2013-01-15 | Nektar Therapeutics | Method for preparing a polymer conjugate |
US8541608B2 (en) | 2006-11-30 | 2013-09-24 | Nektar Therapeutics | Method for preparing a polymer conjugate |
US8937180B2 (en) | 2006-11-30 | 2015-01-20 | Nektar Therapeutics | Method for preparing a polymer conjugate |
US7928095B2 (en) | 2007-02-09 | 2011-04-19 | Enzon Pharmaceuticals, Inc. | Treatment of resistant or refractory cancers with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin |
US9079971B2 (en) | 2007-03-30 | 2015-07-14 | Ambrx, Inc. | Modified FGF-21 polypeptides comprising non-naturally occurring amino acids |
US8383365B2 (en) | 2007-03-30 | 2013-02-26 | Ambrx, Inc. | Methods of making FGF-21 mutants comprising non-naturally encoded phenylalanine derivatives |
US9517273B2 (en) | 2007-03-30 | 2016-12-13 | Ambrx, Inc. | Methods of treatment using modified FGF-21 polypeptides comprising non-naturally occurring amino acids |
US10961291B2 (en) | 2007-03-30 | 2021-03-30 | Ambrx, Inc. | Modified FGF-21 polypeptides and their uses |
US10377805B2 (en) | 2007-03-30 | 2019-08-13 | Ambrx, Inc. | Modified FGF-21 polypeptides comprising non-naturally encoding amino acids and their uses |
US9975936B2 (en) | 2007-03-30 | 2018-05-22 | Ambrx, Inc. | Nucleic acids encoding modified FGF-21 polypeptides comprising non-naturally occurring amino acids |
US8012931B2 (en) | 2007-03-30 | 2011-09-06 | Ambrx, Inc. | Modified FGF-21 polypeptides and their uses |
US9050304B2 (en) | 2007-04-03 | 2015-06-09 | Ratiopharm Gmbh | Methods of treatment using glycopegylated G-CSF |
US8114630B2 (en) | 2007-05-02 | 2012-02-14 | Ambrx, Inc. | Modified interferon beta polypeptides and their uses |
US9493499B2 (en) | 2007-06-12 | 2016-11-15 | Novo Nordisk A/S | Process for the production of purified cytidinemonophosphate-sialic acid-polyalkylene oxide (CMP-SA-PEG) as modified nucleotide sugars via anion exchange chromatography |
EP2205281A1 (en) * | 2007-08-16 | 2010-07-14 | Pharmaessentia Corp. | Protein-polymer conjugates |
EP2205281A4 (en) * | 2007-08-16 | 2014-10-08 | Pharmaessentia Corp | Protein-polymer conjugates |
EP4129343A1 (en) * | 2007-08-16 | 2023-02-08 | PharmaEssentia Corp. | Protein-polymer conjugates |
US8207112B2 (en) | 2007-08-29 | 2012-06-26 | Biogenerix Ag | Liquid formulation of G-CSF conjugate |
US8946148B2 (en) | 2007-11-20 | 2015-02-03 | Ambrx, Inc. | Modified insulin polypeptides and their uses |
WO2009067636A2 (en) | 2007-11-20 | 2009-05-28 | Ambrx, Inc. | Modified insulin polypeptides and their uses |
EP2930182A1 (en) | 2007-11-20 | 2015-10-14 | Ambrx, Inc. | Modified insulin polypeptides and their uses |
EP3103880A1 (en) | 2008-02-08 | 2016-12-14 | Ambrx, Inc. | Modified leptin polypeptides and their uses |
US9938333B2 (en) | 2008-02-08 | 2018-04-10 | Ambrx, Inc. | Modified leptin polypeptides and their uses |
US9150848B2 (en) | 2008-02-27 | 2015-10-06 | Novo Nordisk A/S | Conjugated factor VIII molecules |
EP3225248A1 (en) | 2008-07-23 | 2017-10-04 | Ambrx, Inc. | Modified bovine g-csf polypeptides and their uses |
US10138283B2 (en) | 2008-07-23 | 2018-11-27 | Ambrx, Inc. | Modified bovine G-CSF polypeptides and their uses |
WO2010011735A2 (en) | 2008-07-23 | 2010-01-28 | Ambrx, Inc. | Modified bovine g-csf polypeptides and their uses |
US10039737B2 (en) | 2008-08-11 | 2018-08-07 | Nektar Therapeutics | Multi-arm polymeric alkanoate conjugates |
US8962566B2 (en) | 2008-08-11 | 2015-02-24 | Nektar Therapeutics | Multi-arm polymeric alkanoate conjugates |
US9220790B2 (en) | 2008-08-11 | 2015-12-29 | Naktar Therapeutics | Multi-arm polymeric alkanoate conjugates |
US9504755B2 (en) | 2008-08-11 | 2016-11-29 | Nektar Therapeutics | Multi-arm polymeric alkanoate conjugates |
US8637466B2 (en) | 2008-08-11 | 2014-01-28 | Nektar Therapeutics | Multi-arm polymeric alkanoate conjugates |
US11672776B2 (en) | 2008-08-11 | 2023-06-13 | Nektar Therapeutics | Multi-arm polymeric alkanoate conjugates |
US9801873B2 (en) | 2008-09-23 | 2017-10-31 | Nektar Therapeutics | Methods for treating humans having brain cancer |
US8906353B2 (en) | 2008-09-23 | 2014-12-09 | Nektar Therapeutics | Compositions and methods for achieving sustained therapeutic drug concentrations in a subject |
US10525051B2 (en) | 2008-09-23 | 2020-01-07 | Nektar Therapeutics | Compositions and methods for achieving sustained therapeutic drug concentrations in a subject |
US9644014B2 (en) | 2008-09-26 | 2017-05-09 | Ambrx, Inc. | Modified animal erythropoietin polypeptides and their uses |
EP3216800A1 (en) | 2008-09-26 | 2017-09-13 | Ambrx, Inc. | Modified animal erythropoietin polypeptides and their uses |
US8278418B2 (en) | 2008-09-26 | 2012-10-02 | Ambrx, Inc. | Modified animal erythropoietin polypeptides and their uses |
US10428333B2 (en) | 2008-09-26 | 2019-10-01 | Ambrx Inc. | Non-natural amino acid replication-dependent microorganisms and vaccines |
US9121024B2 (en) | 2008-09-26 | 2015-09-01 | Ambrx, Inc. | Non-natural amino acid replication-dependent microorganisms and vaccines |
US9121025B2 (en) | 2008-09-26 | 2015-09-01 | Ambrx, Inc. | Non-natural amino acid replication-dependent microorganisms and vaccines |
US9156899B2 (en) | 2008-09-26 | 2015-10-13 | Eli Lilly And Company | Modified animal erythropoietin polypeptides and their uses |
EP2805964A1 (en) | 2009-12-21 | 2014-11-26 | Ambrx, Inc. | Modified bovine somatotropin polypeptides and their uses |
EP2805965A1 (en) | 2009-12-21 | 2014-11-26 | Ambrx, Inc. | Modified porcine somatotropin polypeptides and their uses |
EP3815708A1 (en) | 2010-03-05 | 2021-05-05 | Omeros Corporation | Chimeric inhibitor molecules of complement activation |
WO2011107591A1 (en) | 2010-03-05 | 2011-09-09 | Rigshospitalet | Chimeric inhibitor molecules of complement activation |
WO2011143274A1 (en) | 2010-05-10 | 2011-11-17 | Perseid Therapeutics | Polypeptide inhibitors of vla4 |
US10040761B2 (en) | 2010-06-25 | 2018-08-07 | Nof Corporation | Branched hetero polyethylene glycol and intermediate |
US10494340B2 (en) | 2010-06-25 | 2019-12-03 | Nof Corporation | Branched hetero polyethylene glycol and intermediate |
US10751391B2 (en) | 2010-08-17 | 2020-08-25 | Ambrx, Inc. | Methods of treatment using modified relaxin polypeptides comprising a non-naturally encoded amino acid |
US11311605B2 (en) | 2010-08-17 | 2022-04-26 | Ambrx, Inc. | Methods of treating heart failure and fibrotic disorders using modified relaxin polypeptides |
EP4302783A2 (en) | 2010-08-17 | 2024-01-10 | Ambrx, Inc. | Modified relaxin polypeptides and their uses |
US8735539B2 (en) | 2010-08-17 | 2014-05-27 | Ambrx, Inc. | Relaxin polypeptides comprising non-naturally encoded amino acids |
US9567386B2 (en) | 2010-08-17 | 2017-02-14 | Ambrx, Inc. | Therapeutic uses of modified relaxin polypeptides |
US10702588B2 (en) | 2010-08-17 | 2020-07-07 | Ambrx, Inc. | Modified relaxin polypeptides comprising a non-naturally encoded amino acid in the A chain |
WO2012024452A2 (en) | 2010-08-17 | 2012-02-23 | Ambrx, Inc. | Modified relaxin polypeptides and their uses |
US11439710B2 (en) | 2010-08-17 | 2022-09-13 | Ambrx, Inc. | Nucleic acids encoding modified relaxin polypeptides |
US9452222B2 (en) | 2010-08-17 | 2016-09-27 | Ambrx, Inc. | Nucleic acids encoding modified relaxin polypeptides |
US11786578B2 (en) | 2010-08-17 | 2023-10-17 | Ambrx, Inc. | Modified relaxin polypeptides and their uses |
US9962450B2 (en) | 2010-08-17 | 2018-05-08 | Ambrx, Inc. | Method of treating heart failure with modified relaxin polypeptides |
US10253083B2 (en) | 2010-08-17 | 2019-04-09 | Ambrx, Inc. | Therapeutic uses of modified relaxin polypeptides |
US11273202B2 (en) | 2010-09-23 | 2022-03-15 | Elanco Us Inc. | Formulations for bovine granulocyte colony stimulating factor and variants thereof |
US10098865B2 (en) | 2010-12-22 | 2018-10-16 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
US11813241B2 (en) | 2010-12-22 | 2023-11-14 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
US10894087B2 (en) | 2010-12-22 | 2021-01-19 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds |
WO2013004607A1 (en) | 2011-07-01 | 2013-01-10 | Bayer Intellectual Property Gmbh | Relaxin fusion polypeptides and uses thereof |
US9382305B2 (en) | 2011-07-01 | 2016-07-05 | Bayer Intellectual Property Gmbh | Relaxin fusion polypeptides and uses thereof |
EP3088005A1 (en) | 2011-07-05 | 2016-11-02 | biOasis Technologies Inc | P97-antibody conjugates |
WO2013006706A1 (en) | 2011-07-05 | 2013-01-10 | Bioasis Technologies Inc. | P97-antibody conjugates and methods of use |
WO2013185115A1 (en) | 2012-06-08 | 2013-12-12 | Sutro Biopharma, Inc. | Antibodies comprising site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
EP3505534A1 (en) | 2012-06-08 | 2019-07-03 | Sutro Biopharma, Inc. | Antibodies comprising sitespecific nonnatural amino acid residues, methods of their preparation and methods of their use |
EP3135690A1 (en) | 2012-06-26 | 2017-03-01 | Sutro Biopharma, Inc. | Modified fc proteins comprising site-specific non-natural amino acid residues, conjugates of the same, methods of their preparation and methods of their use |
WO2014022515A1 (en) | 2012-07-31 | 2014-02-06 | Bioasis Technologies, Inc. | Dephosphorylated lysosomal storage disease proteins and methods of use thereof |
EP4074728A1 (en) | 2012-08-31 | 2022-10-19 | Sutro Biopharma, Inc. | Modified peptides comprising an azido group |
WO2014036492A1 (en) | 2012-08-31 | 2014-03-06 | Sutro Biopharma, Inc. | Modified amino acids comprising an azido group |
EP3584255A1 (en) | 2012-08-31 | 2019-12-25 | Sutro Biopharma, Inc. | Modified amino acids comprising an azido group |
US9579390B2 (en) | 2012-11-12 | 2017-02-28 | Redwood Bioscience, Inc. | Compounds and methods for producing a conjugate |
US9833515B2 (en) | 2012-11-16 | 2017-12-05 | Redwood Bioscience, Inc. | Hydrazinyl-indole compounds and methods for producing a conjugate |
US9310374B2 (en) | 2012-11-16 | 2016-04-12 | Redwood Bioscience, Inc. | Hydrazinyl-indole compounds and methods for producing a conjugate |
US9605078B2 (en) | 2012-11-16 | 2017-03-28 | The Regents Of The University Of California | Pictet-Spengler ligation for protein chemical modification |
US10888623B2 (en) | 2012-11-16 | 2021-01-12 | Redwood Bioscience, Inc. | Hydrazinyl-indole compounds and methods for producing a conjugate |
US11426465B2 (en) | 2012-11-16 | 2022-08-30 | Redwiid Bioscience, Inc. | Hydrazinyl-indole compounds and methods for producing a conjugate |
US10314919B2 (en) | 2012-11-16 | 2019-06-11 | Redwood Bioscience, Inc. | Hydrazinyl-indole compounds and methods for producing a conjugate |
WO2014160438A1 (en) | 2013-03-13 | 2014-10-02 | Bioasis Technologies Inc. | Fragments of p97 and uses thereof |
EP3336103A1 (en) | 2013-07-10 | 2018-06-20 | Sutro Biopharma, Inc. | Antibodies comprising multiple site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
WO2015006555A2 (en) | 2013-07-10 | 2015-01-15 | Sutro Biopharma, Inc. | Antibodies comprising multiple site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
WO2015031673A2 (en) | 2013-08-28 | 2015-03-05 | Bioasis Technologies Inc. | Cns-targeted conjugates having modified fc regions and methods of use thereof |
WO2015054658A1 (en) | 2013-10-11 | 2015-04-16 | Sutro Biopharma, Inc. | Modified amino acids comprising tetrazine functional groups, methods of preparation, and methods of their use |
WO2015081282A1 (en) | 2013-11-27 | 2015-06-04 | Redwood Bioscience, Inc. | Hydrazinyl-pyrrolo compounds and methods for producing a conjugate |
US11248031B2 (en) | 2014-10-24 | 2022-02-15 | Bristol-Myers Squibb Company | Methods of treating diseases associated with fibrosis using modified FGF-21 polypeptides |
US10377806B2 (en) | 2014-10-24 | 2019-08-13 | Bristol-Myers Squibb Company | Methods of treating diseases associated with fibrosis using modified FGF-21 polypeptides and uses thereof |
US9434778B2 (en) | 2014-10-24 | 2016-09-06 | Bristol-Myers Squibb Company | Modified FGF-21 polypeptides comprising an internal deletion and uses thereof |
US9631004B2 (en) | 2014-10-24 | 2017-04-25 | Bristol-Myers Squibb Company | Modified FGF-21 polypeptides comprising an internal deletion and uses thereof |
US10189883B2 (en) | 2014-10-24 | 2019-01-29 | Bristol-Myers Squibb Company | Therapeutic uses of modified FGF-21 polypeptides |
US11613607B2 (en) | 2016-10-07 | 2023-03-28 | Tokyo Institute Of Technology | Branched type hetero monodispersed polyethylene glycol, production method thereof, and conjugate thereof |
US11185570B2 (en) | 2017-02-08 | 2021-11-30 | Bristol-Myers Squibb Company | Method of treating cardiovascular disease and heart failure with modified relaxin polypeptides |
US10266578B2 (en) | 2017-02-08 | 2019-04-23 | Bristol-Myers Squibb Company | Modified relaxin polypeptides comprising a pharmacokinetic enhancer and uses thereof |
US11364281B2 (en) | 2017-02-08 | 2022-06-21 | Bristol-Myers Squibb Company | Modified relaxin polypeptides comprising a pharmacokinetic enhancer and pharmaceutical compositions thereof |
WO2019133399A1 (en) | 2017-12-26 | 2019-07-04 | Becton, Dickinson And Company | Deep ultraviolet-excitable water-solvated polymeric dyes |
WO2019191482A1 (en) | 2018-03-30 | 2019-10-03 | Becton, Dickinson And Company | Water-soluble polymeric dyes having pendant chromophores |
WO2020023300A1 (en) | 2018-07-22 | 2020-01-30 | Bioasis Technologies, Inc. | Treatment of lymmphatic metastases |
WO2020056066A1 (en) | 2018-09-11 | 2020-03-19 | Ambrx, Inc. | Interleukin-2 polypeptide conjugates and their uses |
WO2020082057A1 (en) | 2018-10-19 | 2020-04-23 | Ambrx, Inc. | Interleukin-10 polypeptide conjugates, dimers thereof, and their uses |
WO2020168017A1 (en) | 2019-02-12 | 2020-08-20 | Ambrx, Inc. | Compositions containing, methods and uses of antibody-tlr agonist conjugates |
WO2021183832A1 (en) | 2020-03-11 | 2021-09-16 | Ambrx, Inc. | Interleukin-2 polypeptide conjugates and methods of use thereof |
WO2021236526A1 (en) | 2020-05-18 | 2021-11-25 | Bioasis Technologies, Inc. | Compositions and methods for treating lewy body dementia |
WO2021255524A1 (en) | 2020-06-17 | 2021-12-23 | Bioasis Technologies, Inc. | Compositions and methods for treating frontotemporal dementia |
WO2022040596A1 (en) | 2020-08-20 | 2022-02-24 | Ambrx, Inc. | Antibody-tlr agonist conjugates, methods and uses thereof |
WO2022212899A1 (en) | 2021-04-03 | 2022-10-06 | Ambrx, Inc. | Anti-her2 antibody-drug conjugates and uses thereof |
EP4155349A1 (en) | 2021-09-24 | 2023-03-29 | Becton, Dickinson and Company | Water-soluble yellow green absorbing dyes |
WO2024007016A2 (en) | 2022-07-01 | 2024-01-04 | Beckman Coulter, Inc. | Novel fluorescent dyes and polymers from dihydrophenanthrene derivatives |
WO2024044327A1 (en) | 2022-08-26 | 2024-02-29 | Beckman Coulter, Inc. | Dhnt monomers and polymer dyes with modified photophysical properties |
Also Published As
Publication number | Publication date |
---|---|
JP4961025B2 (en) | 2012-06-27 |
NZ337845A (en) | 2001-03-30 |
JP4612919B2 (en) | 2011-01-12 |
JP2001519784A (en) | 2001-10-23 |
ES2249824T3 (en) | 2006-04-01 |
US6566506B2 (en) | 2003-05-20 |
JP2010174245A (en) | 2010-08-12 |
EP0973819B1 (en) | 2005-08-31 |
DK0973819T3 (en) | 2005-12-19 |
DE69831402D1 (en) | 2005-10-06 |
US6113906A (en) | 2000-09-05 |
CA2283939C (en) | 2003-10-28 |
AU743108B2 (en) | 2002-01-17 |
DE69831402T2 (en) | 2006-06-29 |
CA2283939A1 (en) | 1998-09-24 |
AU6463098A (en) | 1998-10-12 |
SI0973819T1 (en) | 2006-02-28 |
US20020052443A1 (en) | 2002-05-02 |
EP0973819A4 (en) | 2000-04-05 |
US5919455A (en) | 1999-07-06 |
ATE303412T1 (en) | 2005-09-15 |
EP0973819A1 (en) | 2000-01-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0973819B1 (en) | Non-antigenic branched polymer conjugates | |
CA2174325C (en) | Non-antigenic branched polymer conjugates | |
EP0769955B1 (en) | Non-antigenic amine derived polymers and polymer conjugates | |
EP0824126B1 (en) | Preparation of carboxylic acid-containing polyether and biologically active substances derived thereof | |
US5756593A (en) | Method of preparing polyalkyene oxide carboxylic acids | |
KR100653153B1 (en) | Sterically hindered derivatives of water soluble polymers | |
US7049285B2 (en) | Biocompatible polymers including peptide spacer | |
EP1579873A1 (en) | Polymeric prodrugs | |
EP1988912B1 (en) | Methods of preparing activated polymers having alpha nitrogen groups |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 337845 Country of ref document: NZ |
|
ENP | Entry into the national phase |
Ref document number: 2283939 Country of ref document: CA Ref country code: CA Ref document number: 2283939 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 64630/98 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 1998 540638 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1998910376 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 1998910376 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 64630/98 Country of ref document: AU |
|
WWG | Wipo information: grant in national office |
Ref document number: 1998910376 Country of ref document: EP |