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WO1994028024A1 - Polymere modifie aux glucides presentant une activite erythropoïetique - Google Patents

Polymere modifie aux glucides presentant une activite erythropoïetique Download PDF

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Publication number
WO1994028024A1
WO1994028024A1 PCT/US1994/006098 US9406098W WO9428024A1 WO 1994028024 A1 WO1994028024 A1 WO 1994028024A1 US 9406098 W US9406098 W US 9406098W WO 9428024 A1 WO9428024 A1 WO 9428024A1
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Prior art keywords
conjugate
polymer
glycoprotein
polyalkylene oxide
polyethylene glycol
Prior art date
Application number
PCT/US1994/006098
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English (en)
Inventor
Lee Chyi
Myung Cho-Ok
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Enzon, Inc.
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Publication date
Application filed by Enzon, Inc. filed Critical Enzon, Inc.
Priority to AU70970/94A priority Critical patent/AU7097094A/en
Publication of WO1994028024A1 publication Critical patent/WO1994028024A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/505—Erythropoietin [EPO]
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to conjugates of glycoproteins having erythropoietic activity with non- antigenic polymers.
  • the conjugates exhibit erythropoietic activities comparable to that of the corresponding non-conjugated glycoproteins.
  • EPO is a glycoprotein and a colony-stimulating factor regulating the formation of erythrocytes. Exogeneous EPO is indicated in the treatment of anemic disorders, hematopoietic dysfunction disorders and related diseases.
  • the hydroxyl end-groups of the polymer must first be converted into reactive functional groups. This process is frequently referred to as "activation” and the product is called an "activated polyalkylene oxide.”
  • activation the process is frequently referred to as "activation" and the product is called an "activated polyalkylene oxide.”
  • covalent attachment of the polymer is effected by reacting the activated polyalkylene oxides with e-amino moieties of lysine residues.
  • polypeptide activity is reduced or lost when the £-amino moieties of the lysine residues are modified.
  • Other proteins may have only a small number of available amino groups, and consequently very few polymer anchoring sites. As a result, many proteins of interest cannot be conjugated in this manner.
  • EPO EPO
  • human EPO only has eight free lysine residues having e-amino moieties available for polyalkylene oxide conjugation.
  • the degree of conjugation of these free lysine residues increases, the specific activity of the EPO decreases.
  • U.S. Patent No. 4,904,584 discloses polyalkylene oxide conjugation of lysine-depleted polypeptide variants, including EPO.
  • the variants have lysine attachment sites and allegedly provide a more homogeneous and less random attachment of polyalkylene oxide chains.
  • the disclosure of this patent is limited to covalent attachment of amino-reactive polyalkylene oxides to lysines.
  • Such variants are rare and impractical.
  • PAO conjugation with lysines can alter the charge or isoelectric point of the protein.
  • a biologically active conjugate is provided of a glycoprotein having the ability to effect erythropoiesis and having at least one oxidized carbohydrate moiety covalently linked to a non-antigenic polymer.
  • the conjugate is preferably EPO or a glycoprotein having erythropoietic activity covalently attached to an activated form of a polyalkylene oxide such as polyethylene glycol.
  • a polyalkylene oxide such as polyethylene glycol.
  • Polyethylene glycols having a molecular weight of about 5,000 are preferred.
  • the present invention also provides methods of preparing the conjugates. The methods include the step of reacting a glycoprotein having erythropoietic activity and having at least one oxidized carbohydrate moiety with an activated substantially non-antigenic polymer having a linking group for attaching the polymer to an oxidized carbohydrate. Thus, the non-antigenic polymer covalently attaches to the oxidized carbohydrate moiety of the glycoprotein.
  • Preferred methods include reacting EPO with an activated form of a polyalkylene oxide such as a hydrazide, hydrazine, semicarbazide, thiosemicarbazide, amine or hydroxylamine activated polyalkylene oxide.
  • a polyalkylene oxide such as a hydrazide, hydrazine, semicarbazide, thiosemicarbazide, amine or hydroxylamine activated polyalkylene oxide.
  • the invention also provides methods of treating anemia or other conditions associated with reduced endogenous erythropoietin or erythropoiesis.
  • treatment includes administering an effective amount of the conjugates described herein to mammals requiring such therapy.
  • conjugates having substantially prolonged erythropoietic activity .in vivo are provided. These high activity conjugates are substantially resistant to in vivo hydrolysis, and thus require less frequent administration and often lower dosages when compared to unmodified EPO and lysine-conjugates thereof.
  • the conjugates of the present invention include glycoproteins having the ability to effect erythropoiesis, the formation of erythrocytes.
  • glycoproteins can be prepared or obtained from a variety of sources, including recombinant or mammalian extracted EPO.
  • the EPO is prepared using recombinant techniques.
  • the recombinant forms may be human or animal based, natural or mutant strains.
  • the recombinantly prepared EPO such as that disclosed in U.S. Patent Nos. 4,703,008 or 4,835,260 may be used herein.
  • the disclosure of these patents are hereby incorporated by reference.
  • EPO may be obtained from mammalian sources such as human, bovine, ovine or porcine materials. See, for example, U.S. Patent Nos. 4,465,624 or 4,397,840, the disclosures of which are also hereby incorporated by reference.
  • the glycoprotein EPO has been characterized as a monomer weighing about 30,000 daltons having three possible gycosylation sites.
  • the protein: carbohydrate ratio has been estimated to be about 3:1 suggesting that there are a number of sites that can be made available for polymer attachment upon oxidation of the carbohydrate moieties of the glycoprotein.
  • the expression "the ability to effect erythropoiesis” means any glycoprotein, glycopolypeptide or portion thereof which demonstrates in vivo erythropoietic activity.
  • glycoproteins are prepared 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 glycoproteins are also contemplated. Such materials are obtained from transgenic animals, i.e., mice, pigs, cows, etc., wherein the glycoprotein is expressed in milk, blood or tissues.
  • Insect sources of recombinant EPO are also contemplated. See, for example, Krantz, Blood. 77(3) . 419-34 (February 1, 1991) .
  • the non-antigenic water-soluble polymers included in the conjugates are preferably polyalkylene oxides.
  • alpha- substituted polyalkylene oxide derivatives such as methoxypolyethylene glycols or other suitable alkyl- substituted derivatives such as C 1 -C 4 groups. It is preferred, however, that the non-antigenic polymer be a monomethyl-substituted PEG homopolymer.
  • Alternative polyalkylene oxides such as other polyethylene glycol homopolymers, polypropylene glycol homopolymers, other alkyl-polyethylene oxides, bis-polyethylene oxides and co-polymers or blocked co-polymers of polyalkylene oxides are also useful.
  • the bis-activated polymers can be homo or heterobifunctional.
  • the artisan can prpare cross ⁇ linked EPO conjugates or three-part conjugates containing EPO, a polymer and an additional substance which enhances bioactivity.
  • Such substances include interleukins such as IL-3 or IL-6, growth factors, stimulating factors such as CSF, GM-CSF, and the like, or peptides or other moieties known in the art to enhance the activity of glycopolypeptides in vivo.
  • PEG-based polymers In those aspects of the invention in which PEG-based polymers are used, it is preferred that they have number average molecular weights between about 200 and about 100,000 daltons, and preferably between about 2,000 and about 20,000 daltons. A molecular weight of 5,000 daltons is most preferred.
  • Alternative non-antigenic polymeric substances include materials such as dextrans, polyvinyl pyrrolidones, polysaccharides, starches, polyvinyl alcohols, polyacrylamides or other similar non- immunogenic polymers. Those of ordinary skill in the art realize that the foregoing is merely illustrative and unintended to restrict the type of non-antigenic polymers suitable for use herein.
  • One or more polymer chains are covalently attached to oxidized carbohydrate moieties of the glycoprotein by reacting suitably activated non- antigenic polymers with reactive carbonyl groups on oxidized carbohydrate moieties of the glycoprotein.
  • Reactive carbonyl groups can be generated on saccharide units of carbohydrate moieties of glycoproteins, for example, by oxidizing vicinal diols of the carbohydrate moieties with excess periodate utilizing a reaction well understood by those of ordinary skill in the art, or enzymatically, e.g., by use of galactose oxidase.
  • the reactive carbonyl group is defined as being either a ketone or aldehyde group, excluding other carboxyl-containing groups. Aldehyde groups are preferred, because they are more reactive than ketones.
  • Reactive carbonyl groups can be added to the glycoprotein, preferably to a targeted portion thereof, by reacting it with a polysaccharide functionalized to include a hydrazine, hydrazide, hydroxyamine, ⁇ emicarbazide or thiose icarbazide group.
  • the glycoprotein is then oxidized with periodate to generate reactive carbonyl groups for conjugation with an activated polymer of the present invention.
  • “Suitably activated non-antigenic polymers” is understood by those of ordinary skill in the art to mean that the polymer is functionalized to include a group reactive with oxidized carbohydrate moieties, such as hydrazide.
  • Preferred hydrazide activated polymers of the present invention are acyl hydrazides having a structure corresponding to Formula I:
  • R-Z-C-NH-NH (I) wherein R is one of the above-disclosed water-soluble non-antigenic polymers and Z is O, NH, S or a lower alkyl group containing up to ten carbon atoms. z is preferably 0, which forms a type of hydrazide linkage known as a semicarbazide linkage.
  • the semicarbazide derivative in which Z is 0 is prepared by reacting, for example, the ethoxypolyethylene glycol-N-succinimide carbonate (SC-m-PEG) described in U.S. Patent No. 5,122,614 with an excess of hydrazine in an organic solvent in which the reactants are soluble, such as methanol, methylene chloride, toluene and the like.
  • an organic solvent in which the reactants are soluble, such as methanol, methylene chloride, toluene and the like.
  • the disclosure of U.S. Patent No. 5,122,614 with respect to the preparation of methoxypolyethylene glycol-N-succinimide carbonate is hereby incorporated by reference. After the reaction is completed, the solvents and excess hydrazine are then removed utilizing conventional techniques.
  • the hydrazone can be reduced to the more stable alkyl hydrazide by reacting the hydrazone with, for example, NaBH or NaCNBH 3 .
  • the process of the present invention includes preparing or providing the activated polymer and thereafter reacting it with a glycoprotein having erythropoietic activity and having at least one oxidized carbohydrate moiety.
  • the carbohydrate moieties can be oxidized, for example, by reacting the glycoprotein in aqueous solution with sodium periodate or enzymatically using galactose oxidase or combination of neuraminidase and galactose oxidase as disclosed by Solomon et al. , J. Chromatography. 510. 321-9 (1990) .
  • the reaction runs rapidly to completion at room temperature.
  • the reaction medium is preferably buffered, depending upon the requirements of the glycoprotein.
  • the oxidized glycoprotein is then recovered and separated from the excess periodate by column chromatography.
  • the coupling reaction can be achieved by adding the activated polymer in situ before removing excess periodate.
  • the reaction is carried out in a buffer such as 0.1 M phosphate buffer at a pH of from about 5.0 to about 8.0 in the dark.
  • the glycoprotein having at least one oxidized carbohydrate moiety is reacted with an appropriate amount of the activated polymer, which is typically present in a several-fold molar excess over the glycoprotein.
  • the polymeric excess will range from about 5 to about 500 molar ratio excess and preferably from about 50 to about 300 molar ratio excess of the polymer of the glycoprotein.
  • the reaction is carried out at temperatures from about O'C to about 28"C over time periods ranging from a few minutes to as long as 24 hours. Temperatures from about 2 ⁇ C to about 22 ⁇ C are preferred and time periods of around about one hour are sufficient to carry out the conjugation reaction.
  • the desired product is recovered using known techniques and purified using column chromatography or similar apparatus, if necessary.
  • the conjugates have from about 1 to about 30 polymeric chains attached to the glycoprotein.
  • the temperature, reaction time, pH and molar excess of the polymer reacted with the glycoprotein for example, the artisan can tailor the number of polymeric chains attached.
  • different activated polymers will also contribute to the degree of conjugation. Conjugates containing from about 2 to about 12 polymeric chains are preferred, while conjugates containing from about 4 to about 7 polymeric chains are most preferred.
  • the conjugates of the present invention may further include one or more non- antigenic polymer chains covalently attached to the €-amino moieties of the lysine residues of the glycoprotein and/or the carbonyl groups of the glycoprotein.
  • Such conjugates thus include polymers attached at both oxidized carbohydrate moieties and lysines of the protein to further prolong circulating life.
  • the lysine conjugates may be formed by contacting the glycoprotein with an amine-reactive activated non-antigenic polymer.
  • a preferred amine- reactive polymer is the polyethylene glycol-N-succinimide carbonate (SC-PEG) disclosed by U.S. Patent No. 5,122,614.
  • SC-PEG polyethylene glycol-N-succinimide carbonate
  • the activated polyalkylene oxides described in U.S. Patent No. 4,179,337 may be used.
  • Molar excesses of SC-PEG ranging from 5 to 200 fold are contacted with the glycoprotein under the conditions similar to those described above for conjugation with hydrazide activated polymers. Temperatures during the conjugation, however, are preferably less than room temperature, and about O'C to 5*C. The appropriate molar excess to attain the desired degree of lysine conjugation can be readily determined by one of ordinary skill in the art without undue experimentation.
  • the glycoprotein is first reacted with the SC-PEG after oxidation of the carbohydrate moieties, followed by the removal of the unreacted SC-PEG using conventional techniques.
  • the oxidized carbohydrate moieties of the lysine-conjugated glycoprotein are then reacted with suitably activated polymers employing the process steps described above.
  • a one-pot technique may also be employed in which the amine-reactive polymer and oxidized carbohydrate reactive polymer are simultaneously reacted with the oxidized glycoprotein.
  • Alternative or further modifications such as cysteine residue modification' or carboxy1 modification are also contemplated.
  • PEG amine can also be used to react with oxidized carbohydrates to form a Schiff Base which also may be reduced in situ to a secondary amine.
  • Another aspect of the present invention provides methods of treatment for anemia or other hematopoietic disorders associated with low levels of or dysfunctional EPO.
  • the method includes administering an effective amount of the compositions described herein to alleviate the condition.
  • the amount of a conjugate used in the method of the present invention will vary somewhat from patient to patient; however, conjugates capable of delivering from about 0.1 to about 500 micrograms of EPO per administration and preferably about 5 to about 100 micrograms of EPO are contemplated.
  • the optimal dosing of the conjugate can be determined from clinical experience. Moreover, the dosage will also be dependant on the potency and pharmacokinetic profile of the EPO included in the conjugate.
  • the amount of a conjugate administered in an amount that is sufficient to significantly increase hematopoiesis is the highest dosage that does not cause clinically important side effects.
  • conjugates by covalently linking the non-antigenic polymer and the glycoprotein as described herein by attaching the polymer chain to an oxidized carbohydrate moiety of the glycoprotein, not only are the conjugates substantially resistant to hydrolysis in vivo, the conjugates also possess erythropoietic activity comparable to that of the corresponding non-conjugated glycoprotein.
  • the conjugates thus alleviate anemic conditions, for example, in vivo to a greater extent than prior art compositions.
  • Methoxypolyethylene glycol was obtained from Union Carbide. The solvents used, as well as NaCNBH 3 and NaI0 4 were obtained from Aldrich Chemicals of Milwaukee, Wisconsin.
  • EXAMPLE 1 Synthesis of mPEG-Beta Alanine-Hydrazide m-PEG (MW n 5000, 100 g, 20 mmol) was dissolved in toluene (250 mL) and azeotropically dried for two hours under reflux.
  • the solution was brought to 25"C, diluted with methylene chloride (50 mL) and then treated with phosgene (30 mL of 20% toluene solution, 56 mmol) overnight. The solvents and excess phosgene were removed by rotary evaporation under vacuum.
  • the solid residue of polymeric chloroformate was dissolved in methylene chloride (90 mL) and treated with beta-alanine ethyl ester hydrochloride (6.1 g, 40 mmol) predissolved in methylene chloride (total volume 30 mL) followed by triethylamine (8.4 mL, 60 mmol) .
  • the ester (62 g, 12 mmol) was then dissolved in pyridine (120 mL) and treated with hydrazine (12 mL, 0.375 mole) under reflux for six hours. The solution was rotary evaporated to dryness and the residue crystallized twice from isopropanol and dried in vacuo over P 2 0 5 - The yield was 60 g (97%) .
  • TNBS TNBS
  • EPO human recombinant Chinese
  • the degree of conjugation was 6 to 7 PEG' ⁇ per EPO molecule.
  • the EPO activity was measured by colorimetric assay with DAI-K cells, a murine lymphoblastic cell line dependent on IL-3, GM-CSF and EPO for growth. The cells are grown in IMDM containing 5% FCS and incubated at 37 ⁇ C in 5% C0 2 in air. The assay time is 72 hours. The cell growth is monitored by MTT dye uptake.
  • EXAMPLE 4 In this example, the PEG-EPO conjugates were prepared in the same manner as in Example 3, except that the activated PEG carbazate of Example 2 was used in place of the beta-alanine derivative of Example 1. The conjugates showed a similar activity.
  • the PEG-EPO conjugates of Examples 3 and 4 were further modified.
  • the hydrazone bonds linking the polymer to the glycoprotein were reduced by using NaBH 4 .
  • the solutions containing each of the respective conjugates were mixed with 0.1 molar NaBH 4 overnight at 4*C. Thereafter, each of the mixtures was dialyzed into 0.1 M phosphate buffer, pH 7, to remove the excess reagents.
  • the reduction step can be done immediately after conjugation. This way, NaI0 4 , the unreacted PEG and NaBH 4 can then be removed at the same time.
  • Example 3 the same recombinant EPO of Example 3 was conjugated with SC-m-PEG.
  • 7.5 mg of the EPO in citrate buffer was dialyzed against 0.1 M sodium phosphate buffer solution, pH 7.0 using the Centricon-10.
  • the final concentration of the EPO was about 3 mg/mL.
  • a two-fold molar excess of the SC-m-PEG was added to the solution and the reaction mixture was stirred for one hour at room temperature. The reaction was quenched by adding 0.1 M glycine. The excess SC-m-PEG was removed by centrifugation.
  • the m-PEG-EPO was purified on an anion exchange chromatography column. EPO activity was measured as in Example 3. The degree of conjugation was two PEG's per EPO molecule and the activity was 11.6 pg/mL.
  • EXAMPLE 7 EXAMPLE 7
  • Example 3 was conjugated with SC-m-PEG as in Example 6; however, 5.1 mg of the EPO was reacted with a four-fold molar excess of SC-m-PEG.
  • the m-PEG-EPO was purified, the modification was checked and the EPO activity was measured as in Example 3. The degree of conjugation was four PEG'S per EPO molecule and the activity was 26 pg/mL.
  • the circulating half-lives of three PEG-EPO conjugates prepared above were compared to the recombinant EPO from which they were prepared in rats. Twelve rats about 300 + 25 g were used for this experiment. Three rats were injected i.p. with the native human recombinant EPO and three each were similarly injected with the m-PEG-EPO of Examples 3, 6 and 7 at a dose of 16 to 20 IU/kg. At various time points, the rats were bled and plasma prepared. The plasma was stored at 4*C until assayed. EPO activity was determined using the colorimetric assay described in Example 3.
  • Tj The half-lives (Tj,) and specific activities are reported in the following table, as well as the molecular weights, numbers of free lysines and numbers of m-PEG conjugates. As noted above, the molecular weight, and consequently the number of free lysines and number of m-PEG conjugates, were determined by SDS-gel and size exclusion chromatography.
  • m-PEG-EPO conjugates prepared in accordance with the present invention have a substantial increase in circulating life when compared to native EPO.
  • the conjugates of the present invention also have a substantially increased specific activity when compared to the lysine-conjugated EPO , s, as expressed in terms of the concentration required to produce Maxj. cell growth.

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Abstract

L'invention concerne des conjugués biologiquement actifs de glycoproteines à activité érythropoïétique et présentant au moins une fraction glucide oxydé liée de manière covalente à un polymère non-antigénique. L'invention porte également sur des procédés de préparation desdits conjugués et des procédés de traitement dans lesquels ces derniers sont utilisés.
PCT/US1994/006098 1993-06-01 1994-05-31 Polymere modifie aux glucides presentant une activite erythropoïetique WO1994028024A1 (fr)

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AU70970/94A AU7097094A (en) 1993-06-01 1994-05-31 Carbohydrate-modified polymer conjugates with erythropoietic activity

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US6959193A 1993-06-01 1993-06-01
US08/069,591 1993-06-01

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Cited By (135)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998005363A2 (fr) * 1996-08-02 1998-02-12 Ortho-Mcneil Pharmaceutical, Inc. Polypeptides possedant un polymere soluble dans l'eau a n-terminal lie par covalence simple
US6066673A (en) * 1998-03-12 2000-05-23 The Procter & Gamble Company Enzyme inhibitors
WO2001002017A2 (fr) * 1999-07-02 2001-01-11 F. Hoffmann-La Roche Ag Derives de l'erythropoietine
WO2002019963A2 (fr) * 2000-09-08 2002-03-14 Gryphon Therapeutics, Inc. Protéines de synthèse stimulant l'érythropoïèse
JP2003530361A (ja) * 2000-04-07 2003-10-14 アムジェン インコーポレーテッド 化学的に修飾した新規なエリスロポエチン刺激タンパク質組成物および方法
WO2004000366A1 (fr) 2002-06-21 2003-12-31 Novo Nordisk Health Care Ag Glycoformes du facteur vii pegylees
EP1374908A2 (fr) * 1998-10-09 2004-01-02 The Regents Of The University Of Michigan Conjugués de polymère - médicament comprenant des groupes de liaison hydrazide
EP1398322A1 (fr) * 2002-09-11 2004-03-17 Fresenius Kabi Deutschland GmbH Polypeptides HASylés, en particulier érythropoiétine HASylée
EP1400533A1 (fr) * 2002-09-11 2004-03-24 Fresenius Kabi Deutschland GmbH Polypeptides hasylés, érythropoiétine hasylée en particulier
WO2005014035A2 (fr) * 2003-08-08 2005-02-17 Novo Nordisk Health Care Ag Utilisation de galactose oxydase pour la conjugaison chimique selective de molecules d'extraction a des proteines d'interet therapeutique
WO2006009901A2 (fr) 2004-06-18 2006-01-26 Ambrx, Inc. Nouveaux polypeptides de liaison a l'antigene et leurs utilisations
US6995245B2 (en) 2003-05-30 2006-02-07 Centocor, Inc. Formation of novel erythropoietin conjugates using transglutaminase
US7074755B2 (en) 2003-05-17 2006-07-11 Centocor, Inc. Erythropoietin conjugate compounds with extended half-lives
EP1681303A1 (fr) 2002-09-11 2006-07-19 Fresenius Kabi Deutschland GmbH Polypeptides HASylés, en particulier érythropoiétine HASylée
WO2006091871A1 (fr) 2005-02-23 2006-08-31 Halozyme Therapeutics, Inc. Glycosaminoglycanases solubles et procedes de preparation et d'utilisation de glycosaminoglycanases solubles
WO2006134173A2 (fr) 2005-06-17 2006-12-21 Novo Nordisk Health Care Ag Reduction et derivation selectives de proteines conçues par le genie genetique comprenant au moins une cysteine non native
US7169754B2 (en) 2000-05-15 2007-01-30 Hoffmann-La Roche Inc. Erythropoietin composition
WO2008019214A1 (fr) 2006-08-04 2008-02-14 Prolong Pharmaceuticals, Inc. Erythropoïétine modifiée
WO2008030558A2 (fr) 2006-09-08 2008-03-13 Ambrx, Inc. Polypeptide plasmatique humain modifié ou squelettes de fc et leurs utilisations
EP1982732A2 (fr) 2000-02-11 2008-10-22 Maxygen Holdings Ltd. Molécules de type facteur VII ou VIIA
US7459436B2 (en) 2002-11-22 2008-12-02 Hoffmann-La Roche Inc. Treatment of disturbances of iron distribution
US7459429B2 (en) 2003-12-19 2008-12-02 Hoffmann-La Roche Inc. Method of treating disturbances of iron distribution in inflammatory intestinal diseases
US7459435B2 (en) 2002-08-29 2008-12-02 Hoffmann-La Roche Inc. Treatment of disturbances of iron distribution
US7538092B2 (en) 2002-10-08 2009-05-26 Fresenius Kabi Deutschland Gmbh Pharmaceutically active oligosaccharide conjugates
WO2009067636A2 (fr) 2007-11-20 2009-05-28 Ambrx, Inc. Polypeptides d'insuline modifiés et leurs utilisations
US7541328B2 (en) 2002-03-06 2009-06-02 Fresenius Kabi Deutschland Gmbh Coupling proteins to a modified polysaccharide
EP2070950A1 (fr) 2007-12-14 2009-06-17 Fresenius Kabi Deutschland GmbH Dérivés hydroxyalkylés de l'amidon et leur procédé de préparation
EP2070951A1 (fr) 2007-12-14 2009-06-17 Fresenius Kabi Deutschland GmbH Procédé de production d'un dérivé hydroxyalkyle de l'amidon avec deux liens
EP2080771A2 (fr) 2001-02-27 2009-07-22 Maxygen Aps Nouvelles molécules de type interféron beta
EP2080525A1 (fr) * 2001-10-10 2009-07-22 BioGeneriX AG Remodelage et Glycoconjugaison de Peptides
DE202008017456U1 (de) 2007-08-27 2009-08-27 Biogenerix Ag Flüssig-Formulierung von G-CSF-Konjugaten
US7587286B2 (en) 2003-03-31 2009-09-08 Xencor, Inc. Methods for rational pegylation of proteins
US7610156B2 (en) 2003-03-31 2009-10-27 Xencor, Inc. Methods for rational pegylation of proteins
US7632823B2 (en) 2005-08-18 2009-12-15 Ambrx, Inc. Compositions of tRNA and uses thereof
EP2133098A1 (fr) 2000-01-10 2009-12-16 Maxygen Holdings Ltd Conjugués G-CSF
US7638299B2 (en) 2004-07-21 2009-12-29 Ambrx, Inc. Biosynthetic polypeptides utilizing non-naturally encoded amino acids
US7642340B2 (en) 2003-03-31 2010-01-05 Xencor, Inc. PEGylated TNF-α variant proteins
WO2010011735A2 (fr) 2008-07-23 2010-01-28 Ambrx, Inc. Polypeptides g-csf bovins modifiés et leurs utilisations
US20100062973A1 (en) * 2005-03-11 2010-03-11 Fresenius Kabi Deutschland Gmbh Production of bioactive glycoproteins from inactive starting material
DE20321793U1 (de) 2002-09-11 2010-06-02 Fresenius Kabi Deutschland Gmbh Hydroxyalkylstärke-Derivate
US7736872B2 (en) 2004-12-22 2010-06-15 Ambrx, Inc. Compositions of aminoacyl-TRNA synthetase and uses thereof
WO2010077297A1 (fr) 2008-12-09 2010-07-08 Halozyme, Inc. Polypeptides ph20 solubles étendus et leurs applications
EP2213733A2 (fr) 2006-05-24 2010-08-04 Novo Nordisk Health Care AG Analogues de facteur IX ayant une demi-vie prolongée in vivo
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 (fr) 2003-10-10 2010-12-22 Novo Nordisk A/S Dérives de IL-21
EP2270037A2 (fr) 2004-03-11 2011-01-05 Fresenius Kabi Deutschland GmbH Facteur IX hasylés
EP2284191A2 (fr) 2004-12-22 2011-02-16 Ambrx, Inc. Procédé de préparation de hGH
DE202005021885U1 (de) 2004-03-11 2011-03-03 Fresenius Kabi Deutschland Gmbh Hydroxyalkylstärke-Protein-Konjugate, durch reduktive Aminierung hergestellt
WO2011034604A2 (fr) 2009-09-17 2011-03-24 Baxter Healthcare, S.A. Co-formulation stable de hyalyronidase et d'immunoglobuline et ses procédés d'utilisation
WO2011012850A3 (fr) * 2009-07-27 2011-04-14 Lipoxen Technologies Limited Glyco-polysialylation de protéines de coagulation non sanguine
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 (fr) 2004-02-02 2011-06-01 Ambrx, Inc. Polypeptides d'hormone de croissance humaine et leur utilisations
EP2327723A2 (fr) 2003-10-10 2011-06-01 Xencor, Inc. Variantes tnf-alpha à base de protéine pour le traitement des troubles associés au tnf-alpha
US8012931B2 (en) 2007-03-30 2011-09-06 Ambrx, Inc. Modified FGF-21 polypeptides and their uses
WO2011107591A1 (fr) 2010-03-05 2011-09-09 Rigshospitalet Molécules chimériques inhibitrices d'activation du complément
WO2011143274A1 (fr) 2010-05-10 2011-11-17 Perseid Therapeutics Polypeptides inhibiteurs de vla4
US8063015B2 (en) 2003-04-09 2011-11-22 Novo Nordisk A/S Glycopegylation methods and proteins/peptides produced by the methods
US8093356B2 (en) 2005-06-03 2012-01-10 Ambrx, Inc. Pegylated human interferon polypeptides
WO2012012300A2 (fr) 2010-07-20 2012-01-26 Halozyme, Inc. Effets secondaires indésirables associés à l'administration d'un agent anti-hyaluronane et procédés pour améliorer ou prévenir ces effets secondaires
WO2012016131A1 (fr) * 2010-07-30 2012-02-02 Baxter International Inc. Catalyseurs nucléophiles pour une liaison oxime
US8114630B2 (en) 2007-05-02 2012-02-14 Ambrx, Inc. Modified interferon beta polypeptides and their uses
WO2012024452A2 (fr) 2010-08-17 2012-02-23 Ambrx, Inc. Polypeptides de relaxine modifiés et leurs utilisations
US8207112B2 (en) 2007-08-29 2012-06-26 Biogenerix Ag Liquid formulation of G-CSF conjugate
WO2012109387A1 (fr) 2011-02-08 2012-08-16 Halozyme, Inc. Composition et formulation lipidique d'une enzyme dégradant le hyaluronane et son utilisation pour le traitement de l'hyperplasie bénigne de la prostate
US8247381B2 (en) 2003-03-14 2012-08-21 Biogenerix Ag Branched water-soluble polymers and their conjugates
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
WO2012174480A2 (fr) 2011-06-17 2012-12-20 Halozyme, Inc. Procédés de perfusion d'insuline sous-cutanée continue utilisant une enzyme de dégradation de l'hyaluronane
WO2013004607A1 (fr) 2011-07-01 2013-01-10 Bayer Intellectual Property Gmbh Polypeptides de fusion de relaxine et leurs utilisations
US8361961B2 (en) 2004-01-08 2013-01-29 Biogenerix Ag O-linked glycosylation of peptides
WO2013040501A1 (fr) 2011-09-16 2013-03-21 Pharmathene, Inc. Compositions et combinaisons d'accepteurs biologiques organophosphorés et d'enzymes dégradant le hyaluronane, et leurs utilisations
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
WO2013063155A2 (fr) 2011-10-24 2013-05-02 Halozyme, Inc. Diagnostic compagnon pour le traitement avec un agent anti-hyaluronane et procédés d'utilisation dudit diagnostic
EP2633866A2 (fr) 2003-10-17 2013-09-04 Novo Nordisk A/S Thérapie combinée
WO2013151774A1 (fr) 2012-04-04 2013-10-10 Halozyme, Inc. Polythérapie par un agent anti-hyaluronane et un taxane ciblant une tumeur
EP2662090A1 (fr) 2008-04-14 2013-11-13 Halozyme, Inc. Hyaluronidases modifiées et utilisations pour traiter des maladies et des pathologies associées à l'acide hyaluronique
WO2013173557A1 (fr) * 2012-05-16 2013-11-21 Baxter International Inc. Catalyseur nucléophile pour liaison oxime et utilisation de ses analyses rmn
WO2013185115A1 (fr) 2012-06-08 2013-12-12 Sutro Biopharma, Inc. Anticorps comprenant des résidus d'acides aminés non endogènes spécifiques d'un site, leurs procédés de préparation et leurs procédés d'utilisation
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
US8637640B2 (en) 2009-07-27 2014-01-28 Baxter International Inc. Blood coagulation protein conjugates
US8637007B2 (en) 2006-12-15 2014-01-28 Baxter International Inc. Factor VIIa-polysialic acid conjugate having prolonged in vivo half-life
US8642737B2 (en) 2010-07-26 2014-02-04 Baxter International Inc. Nucleophilic catalysts for oxime linkage
WO2014036492A1 (fr) 2012-08-31 2014-03-06 Sutro Biopharma, Inc. Acides aminés modifiés comprenant un groupe azido
EP2705850A2 (fr) 2008-04-28 2014-03-12 Halozyme, Inc. Super fast-acting insulin compositions
WO2014062856A1 (fr) 2012-10-16 2014-04-24 Halozyme, Inc. Hypoxie et hyaluronane et leurs marqueurs pour le diagnostic et la surveillance de maladies et de pathologies, et méthodes associées
US8716239B2 (en) 2001-10-10 2014-05-06 Novo Nordisk A/S Granulocyte colony stimulating factor: remodeling and glycoconjugation G-CSF
US8716240B2 (en) 2001-10-10 2014-05-06 Novo Nordisk A/S Erythropoietin: remodeling and glycoconjugation of erythropoietin
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]
US8809501B2 (en) 2009-07-27 2014-08-19 Baxter International Inc. Nucleophilic catalysts for oxime linkage
US8841439B2 (en) 2005-11-03 2014-09-23 Novo Nordisk A/S Nucleotide sugar purification using membranes
EP2805964A1 (fr) 2009-12-21 2014-11-26 Ambrx, Inc. Polypeptides modifiés de somatotrophine bovine et leurs utilisations
EP2805965A1 (fr) 2009-12-21 2014-11-26 Ambrx, Inc. Polypeptides modifiés de somatotrophine bovine et leurs utilisations
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
WO2015003167A1 (fr) 2013-07-03 2015-01-08 Halozyme, Inc. Variants de hyaluronidase ph20 thermiquement stables et leurs utilisations
WO2015006555A2 (fr) 2013-07-10 2015-01-15 Sutro Biopharma, Inc. Anticorps comprenant plusieurs résidus d'acides aminés non naturels site-spécifiques, des procédés permettant leur préparation et leurs méthodes d'utilisation
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
US9005625B2 (en) 2003-07-25 2015-04-14 Novo Nordisk A/S Antibody toxin conjugates
WO2015054658A1 (fr) 2013-10-11 2015-04-16 Sutro Biopharma, Inc. Acides aminés modifiés comprenant des groupes fonctionnels de tétrazine, procédés de préparation et procédés d'utilisation associés
US9029331B2 (en) 2005-01-10 2015-05-12 Novo Nordisk A/S Glycopegylated granulocyte colony stimulating factor
US9050304B2 (en) 2007-04-03 2015-06-09 Ratiopharm Gmbh Methods of treatment using glycopegylated G-CSF
US9121025B2 (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
US9187532B2 (en) 2006-07-21 2015-11-17 Novo Nordisk A/S Glycosylation of peptides via O-linked glycosylation sequences
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
US9200049B2 (en) 2004-10-29 2015-12-01 Novo Nordisk A/S Remodeling and glycopegylation of fibroblast growth factor (FGF)
WO2016033555A1 (fr) 2014-08-28 2016-03-03 Halozyme, Inc. Thérapie combinée associant une enzyme dégradant le hyaluronane et un inhibiteur des postes de contrôle immunitaire
WO2016061286A2 (fr) 2014-10-14 2016-04-21 Halozyme, Inc. Compositions d'adénosine désaminase-2 (ada2), variants de cette dernière et leurs procédés d'utilisation
JP2016113626A (ja) * 2009-07-27 2016-06-23 リポクセン テクノロジーズ リミテッド 非血液凝固タンパク質の糖ポリシアル酸化
US9434778B2 (en) 2014-10-24 2016-09-06 Bristol-Myers Squibb Company Modified FGF-21 polypeptides comprising an internal deletion and uses thereof
US9447401B2 (en) 2011-12-30 2016-09-20 Halozyme, Inc. PH20 polypeptide variants, formulations 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 (fr) 2008-02-08 2016-12-14 Ambrx, Inc. Polypeptides d'insuline modifiés et utilisations de ceux-ci
US9567386B2 (en) 2010-08-17 2017-02-14 Ambrx, Inc. Therapeutic uses of modified relaxin polypeptides
EP3135690A1 (fr) 2012-06-26 2017-03-01 Sutro Biopharma, Inc. Proteines fc modifiees contenant des residus specifiques d'acides amines non naturels, leurs conjugues, leurs procedes de preparation et leurs procedes d'utilisation
US9775889B2 (en) 2008-03-06 2017-10-03 Halozyme, Inc. Methods of treatment of cellulite
US9993529B2 (en) 2011-06-17 2018-06-12 Halozyme, Inc. Stable formulations of a hyaluronan-degrading enzyme
WO2018230903A1 (fr) 2017-06-12 2018-12-20 한국코러스 주식회사 Composition d'érythropoïétine à stabilité améliorée et procédé de préparation de cette dernière
WO2018237201A1 (fr) 2017-06-22 2018-12-27 Catalyst Biosciences, Inc. Polypeptides de sérine protéase 1 de type à membrane modifiée (mtsp-1) et leurs procédés d'utilisation
US10266578B2 (en) 2017-02-08 2019-04-23 Bristol-Myers Squibb Company Modified relaxin polypeptides comprising a pharmacokinetic enhancer and uses thereof
WO2019222435A1 (fr) 2018-05-16 2019-11-21 Halozyme, Inc. Procédés de sélection de sujets pour une polythérapie anticancéreuse avec un ph20 soluble conjugué à un polymère
WO2020056066A1 (fr) 2018-09-11 2020-03-19 Ambrx, Inc. Conjugués polypeptidiques d'interleukine-2 et leurs utilisations
WO2020082057A1 (fr) 2018-10-19 2020-04-23 Ambrx, Inc. Conjugués polypeptidiques d'interleukine-10, dimères de ceux-ci et leurs utilisations
WO2020140101A1 (fr) 2018-12-28 2020-07-02 Catalyst Biosciences, Inc. Polypeptides activateurs de plasminogène de type urokinase modifiés et leurs procédés d'utilisation
WO2020168017A1 (fr) 2019-02-12 2020-08-20 Ambrx, Inc. Contenant de compositions, procédés et utilisations de conjugués anticorps-agonistes tlr
WO2021183832A1 (fr) 2020-03-11 2021-09-16 Ambrx, Inc. Conjugués polypeptidiques d'interleukine-2 et leurs procédés d'utilisation
WO2022040596A1 (fr) 2020-08-20 2022-02-24 Ambrx, Inc. Conjugués anticorps-agonistes de tlr, procédés et utilisations de ceux-ci
US11273202B2 (en) 2010-09-23 2022-03-15 Elanco Us Inc. Formulations for bovine granulocyte colony stimulating factor and variants thereof
WO2022212899A1 (fr) 2021-04-03 2022-10-06 Ambrx, Inc. Conjugués anticorps-médicament anti-her2 et leurs utilisations
US11613744B2 (en) 2018-12-28 2023-03-28 Vertex Pharmaceuticals Incorporated Modified urokinase-type plasminogen activator polypeptides and methods of use

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4179337A (en) * 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4847325A (en) * 1988-01-20 1989-07-11 Cetus Corporation Conjugation of polymer to colony stimulating factor-1
CA2003743A1 (fr) * 1988-11-23 1990-05-23 Daniel J. Capon Derives polypeptidiques
US5089261A (en) * 1989-01-23 1992-02-18 Cetus Corporation Preparation of a polymer/interleukin-2 conjugate
US5103039A (en) * 1990-08-24 1992-04-07 Xoma Corporation Activated polymers and conjugates thereof
US5122164A (en) * 1990-03-29 1992-06-16 The Boc Group, Inc. Process for producing oxygen enriched product stream
WO1992016555A1 (fr) * 1991-03-18 1992-10-01 Enzon, Inc. Conjuges de polypeptides et de glycopolypeptides associes a des polymeres, contenant de l'hydrazine

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4179337A (en) * 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4847325A (en) * 1988-01-20 1989-07-11 Cetus Corporation Conjugation of polymer to colony stimulating factor-1
CA2003743A1 (fr) * 1988-11-23 1990-05-23 Daniel J. Capon Derives polypeptidiques
US5089261A (en) * 1989-01-23 1992-02-18 Cetus Corporation Preparation of a polymer/interleukin-2 conjugate
US5122164A (en) * 1990-03-29 1992-06-16 The Boc Group, Inc. Process for producing oxygen enriched product stream
US5103039A (en) * 1990-08-24 1992-04-07 Xoma Corporation Activated polymers and conjugates thereof
WO1992016555A1 (fr) * 1991-03-18 1992-10-01 Enzon, Inc. Conjuges de polypeptides et de glycopolypeptides associes a des polymeres, contenant de l'hydrazine

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ADVANCED DRUG DELIVERY REVIEWS, Volume 6, issued 1991, M.L. NUCCI et al., "The Therapeutic Value of Poly(Ethylene Glycol)-Modified Proteins", pages 133-151. *
BIOCATALYSIS, Volume 2, issued 1989, URRUTIGOITY et al., "Biocatalysis in Organic Solvents with a Polymer-Bound Horseradish Peroxidase", pages 145-149. *
J. MILTON HARRIS, Editor, "Poly(Ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications", Published 1992, by PLENUM PRESS (N.Y.), pages 347-370. *
PROC. NATL. ACAD. SCI., USA, Volume 83, issued April 1986, J.D. RODWELL et al., "Site-Specific Covalent Modifications of Monoclonal Antibodies: In Vitro and In Vivo Evaluations", pages 2632-2636. *
THE JOURNAL OF BIOLOGICAL CHEMISTRY, Volume 267, No. 11, issued 15 April 1992, M. HIGUCHI et al., "Role of Sugar Chains in the Expression of the Biological Activity of Human Erythropoietin", pages 7703-7709. *

Cited By (307)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998005363A3 (fr) * 1996-08-02 1998-05-07 Ortho Pharma Corp Polypeptides possedant un polymere soluble dans l'eau a n-terminal lie par covalence simple
US6077939A (en) * 1996-08-02 2000-06-20 Ortho-Mcneil Pharmaceutical, Inc. Methods and kits for making polypeptides having a single covalently bound N-terminal water-soluble polymer
WO1998005363A2 (fr) * 1996-08-02 1998-02-12 Ortho-Mcneil Pharmaceutical, Inc. Polypeptides possedant un polymere soluble dans l'eau a n-terminal lie par covalence simple
EP1731174A3 (fr) * 1996-08-02 2007-01-17 Ortho-McNeil Pharmaceutical, Inc. Polypeptides possédant un polyéthylène glycol à N-terminal par liaison via hydrazone ou oxime
US6066673A (en) * 1998-03-12 2000-05-23 The Procter & Gamble Company Enzyme inhibitors
US7186413B2 (en) 1998-10-09 2007-03-06 The Regents Of The University Of Michigan Hydrogels and water soluble polymeric carriers for drug delivery
EP1374908A3 (fr) * 1998-10-09 2004-03-24 The Regents Of The University Of Michigan Conjugués de polymère - médicament comprenant des groupes de liaison hydrazide
EP1374908A2 (fr) * 1998-10-09 2004-01-02 The Regents Of The University Of Michigan Conjugués de polymère - médicament comprenant des groupes de liaison hydrazide
WO2001002017A3 (fr) * 1999-07-02 2001-08-09 Hoffmann La Roche Derives de l'erythropoietine
US6340742B1 (en) 1999-07-02 2002-01-22 Roche Diagnostics Gmbh Erythropoietin conjugates
CZ301833B6 (cs) * 1999-07-02 2010-07-07 F. Hoffmann-La Roche Ag Konjugát erytropoetinu s polyethylenglykolem, zpusob jeho prípravy a lécivo pro lécení anemie s jeho obsahem
WO2001002017A2 (fr) * 1999-07-02 2001-01-11 F. Hoffmann-La Roche Ag Derives de l'erythropoietine
EP2133098A1 (fr) 2000-01-10 2009-12-16 Maxygen Holdings Ltd Conjugués G-CSF
EP2319541A1 (fr) 2000-02-11 2011-05-11 Bayer HealthCare LLC Conjugués de type facteur VII ou VIIA
EP1982732A2 (fr) 2000-02-11 2008-10-22 Maxygen Holdings Ltd. Molécules de type facteur VII ou VIIA
JP2003530361A (ja) * 2000-04-07 2003-10-14 アムジェン インコーポレーテッド 化学的に修飾した新規なエリスロポエチン刺激タンパク質組成物および方法
US7169754B2 (en) 2000-05-15 2007-01-30 Hoffmann-La Roche Inc. Erythropoietin composition
US7202208B2 (en) 2000-05-15 2007-04-10 Hoffman-La Roche Inc. Erythropoietin composition
WO2002019963A3 (fr) * 2000-09-08 2003-02-06 Gryphon Therapeutics Inc Protéines de synthèse stimulant l'érythropoïèse
WO2002019963A2 (fr) * 2000-09-08 2002-03-14 Gryphon Therapeutics, Inc. Protéines de synthèse stimulant l'érythropoïèse
EP2080771A2 (fr) 2001-02-27 2009-07-22 Maxygen Aps Nouvelles molécules de type interféron beta
EP2080525A1 (fr) * 2001-10-10 2009-07-22 BioGeneriX AG Remodelage et Glycoconjugaison de Peptides
EP2279753A3 (fr) * 2001-10-10 2011-10-12 Novo Nordisk A/S Remodelage et gluco-conjugaison de peptides
US8716239B2 (en) 2001-10-10 2014-05-06 Novo Nordisk A/S Granulocyte colony stimulating factor: remodeling and glycoconjugation G-CSF
US8716240B2 (en) 2001-10-10 2014-05-06 Novo Nordisk A/S Erythropoietin: remodeling and glycoconjugation of erythropoietin
US8916518B2 (en) 2002-03-06 2014-12-23 Fresenius Kabi Deutschland Gmbh Coupling proteins to a modified polysaccharide
US7541328B2 (en) 2002-03-06 2009-06-02 Fresenius Kabi Deutschland Gmbh Coupling proteins to a modified polysaccharide
WO2004000366A1 (fr) 2002-06-21 2003-12-31 Novo Nordisk Health Care Ag Glycoformes du facteur vii pegylees
US7459435B2 (en) 2002-08-29 2008-12-02 Hoffmann-La Roche Inc. Treatment of disturbances of iron distribution
EP2154160A1 (fr) 2002-09-11 2010-02-17 Fresenius Kabi Deutschland GmbH Dérivés hydroxyalkyle de l'amidon
EP1400533A1 (fr) * 2002-09-11 2004-03-24 Fresenius Kabi Deutschland GmbH Polypeptides hasylés, érythropoiétine hasylée en particulier
DE20321836U1 (de) 2002-09-11 2011-04-07 Fresenius Kabi Deutschland Gmbh Hydroxyalkylstärkederivate
EP2316850A2 (fr) 2002-09-11 2011-05-04 Fresenius Kabi Deutschland GmbH Polypeptides hasylés, érythropoiétine hasylée en particulier
EP1398322A1 (fr) * 2002-09-11 2004-03-17 Fresenius Kabi Deutschland GmbH Polypeptides HASylés, en particulier érythropoiétine HASylée
EP2272865A2 (fr) 2002-09-11 2011-01-12 Fresenius Kabi Deutschland GmbH Procédé de production de dérivés hydroxyalkyle de l'amidon
WO2004024761A1 (fr) * 2002-09-11 2004-03-25 Fresenius Kabi Deutschland Gmbh Polypeptides-has, notamment, erythropoietine-has ayant subi une acylation
EP2017287A2 (fr) 2002-09-11 2009-01-21 Fresenius Kabi Deutschland GmbH Procédé de production de dérivés hydroxyalkyle de l'amidon
EP2316850A3 (fr) * 2002-09-11 2011-11-09 Fresenius Kabi Deutschland GmbH Polypeptides hasylés, érythropoiétine hasylée en particulier
DE20321793U1 (de) 2002-09-11 2010-06-02 Fresenius Kabi Deutschland Gmbh Hydroxyalkylstärke-Derivate
EP2143736A1 (fr) 2002-09-11 2010-01-13 Fresenius Kabi Deutschland GmbH Derives d'amidon hydroxyalyle
KR101174510B1 (ko) * 2002-09-11 2012-08-16 프레제니우스 카비 도이치란트 게엠베하 하이드록시알킬전분화 폴리펩티드, 특히 하이드록시알킬전분화 에리트로포이에틴
EP1681303A1 (fr) 2002-09-11 2006-07-19 Fresenius Kabi Deutschland GmbH Polypeptides HASylés, en particulier érythropoiétine HASylée
US7538092B2 (en) 2002-10-08 2009-05-26 Fresenius Kabi Deutschland Gmbh Pharmaceutically active oligosaccharide conjugates
US7459436B2 (en) 2002-11-22 2008-12-02 Hoffmann-La Roche Inc. Treatment of disturbances of iron distribution
US8247381B2 (en) 2003-03-14 2012-08-21 Biogenerix Ag Branched water-soluble polymers and their conjugates
US7587286B2 (en) 2003-03-31 2009-09-08 Xencor, Inc. Methods for rational pegylation of proteins
US7610156B2 (en) 2003-03-31 2009-10-27 Xencor, Inc. Methods for rational pegylation of proteins
US7642340B2 (en) 2003-03-31 2010-01-05 Xencor, Inc. PEGylated TNF-α variant proteins
US8063015B2 (en) 2003-04-09 2011-11-22 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
US8853161B2 (en) 2003-04-09 2014-10-07 Novo Nordisk A/S Glycopegylation methods and proteins/peptides produced by the methods
US7074755B2 (en) 2003-05-17 2006-07-11 Centocor, Inc. Erythropoietin conjugate compounds with extended half-lives
US6995245B2 (en) 2003-05-30 2006-02-07 Centocor, Inc. Formation of novel erythropoietin conjugates using transglutaminase
US9005625B2 (en) 2003-07-25 2015-04-14 Novo Nordisk A/S Antibody toxin conjugates
JP2011157365A (ja) * 2003-08-08 2011-08-18 Novo Nordisk Health Care Ag 治療的な関心対象のタンパク質に対する遅延分子の選択的な化学物質接合のためのガラクトースオキシダーゼの使用
WO2005014035A3 (fr) * 2003-08-08 2005-07-28 Novo Nordisk Healthcare Ag Utilisation de galactose oxydase pour la conjugaison chimique selective de molecules d'extraction a des proteines d'interet therapeutique
JP2007501812A (ja) * 2003-08-08 2007-02-01 ノボ　ノルディスク　アクティーゼルスカブ ペプチドのための結合剤として新しい構造上十分に定義された枝分れしたポリマーの合成および適用
WO2005014035A2 (fr) * 2003-08-08 2005-02-17 Novo Nordisk Health Care Ag Utilisation de galactose oxydase pour la conjugaison chimique selective de molecules d'extraction a des proteines d'interet therapeutique
JP2007501811A (ja) * 2003-08-08 2007-02-01 ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト 治療的な関心対象のタンパク質に対する遅延分子の選択的な化学物質接合のためのガラクトースオキシダーゼの使用。
EP2327723A2 (fr) 2003-10-10 2011-06-01 Xencor, Inc. Variantes tnf-alpha à base de protéine pour le traitement des troubles associés au tnf-alpha
EP2263684A1 (fr) 2003-10-10 2010-12-22 Novo Nordisk A/S Dérives de IL-21
EP2633866A2 (fr) 2003-10-17 2013-09-04 Novo Nordisk A/S Thérapie combinée
EP2641611A2 (fr) 2003-10-17 2013-09-25 Novo Nordisk A/S Thérapie combinée
US8916360B2 (en) 2003-11-24 2014-12-23 Novo Nordisk A/S Glycopegylated erythropoietin
US8633157B2 (en) 2003-11-24 2014-01-21 Novo Nordisk A/S Glycopegylated erythropoietin
US8632770B2 (en) 2003-12-03 2014-01-21 Novo Nordisk A/S Glycopegylated factor IX
US7459429B2 (en) 2003-12-19 2008-12-02 Hoffmann-La Roche Inc. Method of treating disturbances of iron distribution in inflammatory intestinal diseases
US8361961B2 (en) 2004-01-08 2013-01-29 Biogenerix Ag O-linked glycosylation of peptides
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
US8906676B2 (en) 2004-02-02 2014-12-09 Ambrx, Inc. Modified human four helical bundle polypeptides and their uses
EP2327724A2 (fr) 2004-02-02 2011-06-01 Ambrx, Inc. Polypeptides d'hormone de croissance humaine et leur utilisations
US8907064B2 (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
US9260472B2 (en) 2004-02-02 2016-02-16 Ambrx, Inc. Modified human four helical bundle polypeptides and their uses
EP2336192A1 (fr) 2004-03-11 2011-06-22 Fresenius Kabi Deutschland GmbH Conjugues d'amidon hydroxyalkyle et d'une protein, preparer par amination réductive
DE202005021885U1 (de) 2004-03-11 2011-03-03 Fresenius Kabi Deutschland Gmbh Hydroxyalkylstärke-Protein-Konjugate, durch reduktive Aminierung hergestellt
EP2270036A2 (fr) 2004-03-11 2011-01-05 Fresenius Kabi Deutschland GmbH Polypeptides hasylés
US8840879B2 (en) 2004-03-11 2014-09-23 Fresenius Kabi Deutschland Gmbh Conjugates of hydroxyalkyl starch and a protein
EP2270037A2 (fr) 2004-03-11 2011-01-05 Fresenius Kabi Deutschland GmbH Facteur IX hasylés
WO2006009901A2 (fr) 2004-06-18 2006-01-26 Ambrx, Inc. Nouveaux polypeptides de liaison a l'antigene et leurs utilisations
US9175083B2 (en) 2004-06-18 2015-11-03 Ambrx, Inc. Antigen-binding polypeptides and their uses
US7632924B2 (en) 2004-06-18 2009-12-15 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]
US7638299B2 (en) 2004-07-21 2009-12-29 Ambrx, Inc. Biosynthetic polypeptides utilizing non-naturally encoded amino acids
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)
US8178494B2 (en) 2004-12-22 2012-05-15 Ambrx, Inc. Modified human growth hormone formulations with an increased serum half-life
EP2284191A2 (fr) 2004-12-22 2011-02-16 Ambrx, Inc. Procédé de préparation de hGH
US7829310B2 (en) 2004-12-22 2010-11-09 Ambrx, Inc. Compositions of aminoacyl-tRNA synthetase and uses thereof
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
US7939496B2 (en) * 2004-12-22 2011-05-10 Ambrx, Inc. Modified human growth horomone polypeptides and their uses
US7846689B2 (en) 2004-12-22 2010-12-07 Ambrx, Inc. Compositions of aminoacyl-tRNA synthetase and uses thereof
US7959926B2 (en) 2004-12-22 2011-06-14 Ambrx, Inc. Methods for expression and purification of recombinant human growth hormone mutants
US7736872B2 (en) 2004-12-22 2010-06-15 Ambrx, Inc. Compositions of aminoacyl-TRNA synthetase and uses thereof
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
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
US8178108B2 (en) 2004-12-22 2012-05-15 Ambrx, Inc. Methods for expression and purification of recombinant human growth hormone
US7858344B2 (en) 2004-12-22 2010-12-28 Ambrx, Inc. Compositions of aminoacyl-tRNA synthetase and uses thereof
US7838265B2 (en) 2004-12-22 2010-11-23 Ambrx, Inc. Compositions of aminoacyl-tRNA synthetase and uses thereof
US8163695B2 (en) 2004-12-22 2012-04-24 Ambrx Formulations of human growth hormone comprising a non-naturally encoded amino acid
US7883866B2 (en) 2004-12-22 2011-02-08 Ambrx, Inc. Compositions of aminoacyl-tRNA synthetase and uses thereof
US8143216B2 (en) 2004-12-22 2012-03-27 Ambrx, Inc. Modified human growth hormone
US9029331B2 (en) 2005-01-10 2015-05-12 Novo Nordisk A/S Glycopegylated granulocyte colony stimulating factor
WO2006091871A1 (fr) 2005-02-23 2006-08-31 Halozyme Therapeutics, Inc. Glycosaminoglycanases solubles et procedes de preparation et d'utilisation de glycosaminoglycanases solubles
US10588983B2 (en) 2005-02-23 2020-03-17 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases
EP3045472A1 (fr) 2005-02-23 2016-07-20 Halozyme, Inc. Glycosaminoglycanases solubles et procédés de préparation et d'utilisation de glycosaminoglycanases solubles
EP3943501A1 (fr) 2005-02-23 2022-01-26 Halozyme, Inc. Glycosaminoglycanases solubles et procédés de préparation et d'utilisation de glycosaminoglycanases solubles
US20100062973A1 (en) * 2005-03-11 2010-03-11 Fresenius Kabi Deutschland Gmbh Production of bioactive glycoproteins from inactive starting material
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
EP2360170A2 (fr) 2005-06-17 2011-08-24 Novo Nordisk Health Care AG Réduction et dérivatisation de protéines obtenues par génie génétique comprenant au moins une cystéine non native
WO2006134173A2 (fr) 2005-06-17 2006-12-21 Novo Nordisk Health Care Ag Reduction et derivation selectives de proteines conçues par le genie genetique comprenant au moins une cysteine non native
US7632823B2 (en) 2005-08-18 2009-12-15 Ambrx, Inc. Compositions of tRNA and uses thereof
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
EP2213733A2 (fr) 2006-05-24 2010-08-04 Novo Nordisk Health Care AG Analogues de facteur IX ayant une demi-vie prolongée in vivo
US9187532B2 (en) 2006-07-21 2015-11-17 Novo Nordisk A/S Glycosylation of peptides via O-linked glycosylation sequences
WO2008019214A1 (fr) 2006-08-04 2008-02-14 Prolong Pharmaceuticals, Inc. Erythropoïétine modifiée
US8765924B2 (en) 2006-08-04 2014-07-01 Prolong Pharmaceuticals, Inc. Modified erythropoietin
US8420792B2 (en) 2006-09-08 2013-04-16 Ambrx, Inc. Suppressor tRNA transcription in vertebrate cells
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
WO2008030558A2 (fr) 2006-09-08 2008-03-13 Ambrx, Inc. Polypeptide plasmatique humain modifié ou squelettes de fc et leurs utilisations
US8022186B2 (en) 2006-09-08 2011-09-20 Ambrx, Inc. Modified human plasma polypeptide or Fc scaffolds and their uses
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
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
US8637007B2 (en) 2006-12-15 2014-01-28 Baxter International Inc. Factor VIIa-polysialic acid conjugate having prolonged in vivo half-life
US8383365B2 (en) 2007-03-30 2013-02-26 Ambrx, Inc. Methods of making FGF-21 mutants comprising non-naturally encoded phenylalanine derivatives
US10961291B2 (en) 2007-03-30 2021-03-30 Ambrx, Inc. Modified FGF-21 polypeptides and their uses
US11993637B2 (en) 2007-03-30 2024-05-28 Ambrx, Inc. Modified FGF-21 polypeptides with non-naturally encoded amino acids
US9517273B2 (en) 2007-03-30 2016-12-13 Ambrx, Inc. Methods of treatment using modified FGF-21 polypeptides comprising non-naturally occurring amino acids
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
US9079971B2 (en) 2007-03-30 2015-07-14 Ambrx, Inc. Modified FGF-21 polypeptides comprising non-naturally occurring amino acids
US10377805B2 (en) 2007-03-30 2019-08-13 Ambrx, Inc. Modified FGF-21 polypeptides comprising non-naturally encoding amino acids 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
EP2578235A2 (fr) 2007-08-27 2013-04-10 BioGeneriX AG Formulation liquide de conjugué de G-CSF
DE202008017456U1 (de) 2007-08-27 2009-08-27 Biogenerix Ag Flüssig-Formulierung von G-CSF-Konjugaten
US8207112B2 (en) 2007-08-29 2012-06-26 Biogenerix Ag Liquid formulation of G-CSF conjugate
WO2009067636A2 (fr) 2007-11-20 2009-05-28 Ambrx, Inc. Polypeptides d'insuline modifiés et leurs utilisations
US8946148B2 (en) 2007-11-20 2015-02-03 Ambrx, Inc. Modified insulin polypeptides and their uses
EP2930182A1 (fr) 2007-11-20 2015-10-14 Ambrx, Inc. Polypeptides d'insuline modifiés et utilisations de ceux-ci
EP2070951A1 (fr) 2007-12-14 2009-06-17 Fresenius Kabi Deutschland GmbH Procédé de production d'un dérivé hydroxyalkyle de l'amidon avec deux liens
EP2070950A1 (fr) 2007-12-14 2009-06-17 Fresenius Kabi Deutschland GmbH Dérivés hydroxyalkylés de l'amidon et leur procédé de préparation
US9938333B2 (en) 2008-02-08 2018-04-10 Ambrx, Inc. Modified leptin polypeptides and their uses
EP3103880A1 (fr) 2008-02-08 2016-12-14 Ambrx, Inc. Polypeptides d'insuline modifiés et utilisations de ceux-ci
US9150848B2 (en) 2008-02-27 2015-10-06 Novo Nordisk A/S Conjugated factor VIII molecules
US9775889B2 (en) 2008-03-06 2017-10-03 Halozyme, Inc. Methods of treatment of cellulite
US9833498B2 (en) 2008-03-06 2017-12-05 Halozyme, Inc. Methods of treatment of collagen-mediated diseases and conditions
EP2662090A1 (fr) 2008-04-14 2013-11-13 Halozyme, Inc. Hyaluronidases modifiées et utilisations pour traiter des maladies et des pathologies associées à l'acide hyaluronique
US10328130B2 (en) 2008-04-14 2019-06-25 Halozyme, Inc. Modified hyaluronidases and uses in treating hyaluronan-associated diseases and conditions
EP3192525A1 (fr) 2008-04-14 2017-07-19 Halozyme, Inc. Hyaluronidases modifiées pour son utilisation dans le traitement de maladies et d'états associés à l'acide hyaluronique
EP2705850A2 (fr) 2008-04-28 2014-03-12 Halozyme, Inc. Super fast-acting insulin compositions
EP3225248A1 (fr) 2008-07-23 2017-10-04 Ambrx, Inc. Polypeptides g-csf bovins modifiés et leurs utilisations
WO2010011735A2 (fr) 2008-07-23 2010-01-28 Ambrx, Inc. Polypeptides g-csf bovins modifiés et leurs utilisations
US10138283B2 (en) 2008-07-23 2018-11-27 Ambrx, Inc. Modified bovine G-CSF polypeptides and their uses
US9156899B2 (en) 2008-09-26 2015-10-13 Eli Lilly And Company 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
EP3216800A1 (fr) 2008-09-26 2017-09-13 Ambrx, Inc. Polypeptides d'érythropoïétine animale modifiés et leurs utilisations
US8569233B2 (en) 2008-09-26 2013-10-29 Eli Lilly And Company Modified animal erythropoietin polypeptides and their uses
US8278418B2 (en) 2008-09-26 2012-10-02 Ambrx, Inc. Modified animal erythropoietin polypeptides and their uses
US9644014B2 (en) 2008-09-26 2017-05-09 Ambrx, Inc. Modified animal erythropoietin polypeptides and their uses
US9121025B2 (en) 2008-09-26 2015-09-01 Ambrx, Inc. Non-natural amino acid replication-dependent microorganisms and vaccines
WO2010077297A1 (fr) 2008-12-09 2010-07-08 Halozyme, Inc. Polypeptides ph20 solubles étendus et leurs applications
US8927249B2 (en) 2008-12-09 2015-01-06 Halozyme, Inc. Extended soluble PH20 polypeptides and uses thereof
EP3037529A1 (fr) 2008-12-09 2016-06-29 Halozyme, Inc. Polypeptides ph20 solubles étendus et leurs utilisations
RU2533619C2 (ru) * 2009-07-27 2014-11-20 Лайпоксен Текнолоджиз Лимитед Гликополисиалирование белков, не являющихся белками свертывания крови
US11564992B2 (en) 2009-07-27 2023-01-31 Takeda Pharmaceutical Company Limited Nucleophilic catalysts for oxime linkage
JP2013500375A (ja) * 2009-07-27 2013-01-07 リポクセン テクノロジーズ リミテッド 非血液凝固タンパク質の糖ポリシアル酸化
US9795683B2 (en) 2009-07-27 2017-10-24 Lipoxen Technologies Limited Glycopolysialylation of non-blood coagulation proteins
US8637640B2 (en) 2009-07-27 2014-01-28 Baxter International Inc. Blood coagulation protein conjugates
US11040109B2 (en) 2009-07-27 2021-06-22 Takeda Pharmaceutical Company Limited Blood coagulation protein conjugates
US10772968B2 (en) 2009-07-27 2020-09-15 Lipoxen Technologies Limited Glycopolysialylation of non-blood coagulation proteins
US9492555B2 (en) 2009-07-27 2016-11-15 Baxalta Incorporated Nucleophilic catalysts for oxime linkage
EP3081233A1 (fr) * 2009-07-27 2016-10-19 Baxalta GmbH Glycopolysialylation de protéines autres que des protéines de coagulation sanguine
US9731024B2 (en) 2009-07-27 2017-08-15 Baxalta Incorporated Nucleophilic catalysts for oxime linkage
US8809501B2 (en) 2009-07-27 2014-08-19 Baxter International Inc. Nucleophilic catalysts for oxime linkage
WO2011012850A3 (fr) * 2009-07-27 2011-04-14 Lipoxen Technologies Limited Glyco-polysialylation de protéines de coagulation non sanguine
JP2018024882A (ja) * 2009-07-27 2018-02-15 リポクセン テクノロジーズ リミテッド 非血液凝固タンパク質の糖ポリシアル酸化
JP2020037701A (ja) * 2009-07-27 2020-03-12 バクサルタ インコーポレイテッド 非血液凝固タンパク質の糖ポリシアル酸化
US10576160B2 (en) 2009-07-27 2020-03-03 Baxalta Incorporated Nucleophilic catalysts for oxime linkage
JP2016113626A (ja) * 2009-07-27 2016-06-23 リポクセン テクノロジーズ リミテッド 非血液凝固タンパク質の糖ポリシアル酸化
JP2022058911A (ja) * 2009-07-27 2022-04-12 バクサルタ インコーポレイテッド 非血液凝固タンパク質の糖ポリシアル酸化
AU2015242970B2 (en) * 2009-07-27 2017-10-12 Baxalta GmbH Glycopolysialylation of non-blood coagulation proteins
US10414793B2 (en) 2009-07-27 2019-09-17 Baxalta Incorporated Nucleophilic catalysts for oxime linkage
US10350301B2 (en) 2009-07-27 2019-07-16 Baxalta Incorporated Blood coagulation protein conjugates
WO2011034604A2 (fr) 2009-09-17 2011-03-24 Baxter Healthcare, S.A. Co-formulation stable de hyalyronidase et d'immunoglobuline et ses procédés d'utilisation
US9084743B2 (en) 2009-09-17 2015-07-21 Baxter International Inc. Stable co-formulation of hyaluronidase and immunoglobulin, and methods of use thereof
EP2805964A1 (fr) 2009-12-21 2014-11-26 Ambrx, Inc. Polypeptides modifiés de somatotrophine bovine et leurs utilisations
EP2805965A1 (fr) 2009-12-21 2014-11-26 Ambrx, Inc. Polypeptides modifiés de somatotrophine bovine et leurs utilisations
WO2011107591A1 (fr) 2010-03-05 2011-09-09 Rigshospitalet Molécules chimériques inhibitrices d'activation du complément
EP3815708A1 (fr) 2010-03-05 2021-05-05 Omeros Corporation Molécules chimères inhibitrices de l'activation du complément
WO2011143274A1 (fr) 2010-05-10 2011-11-17 Perseid Therapeutics Polypeptides inhibiteurs de vla4
US10265410B2 (en) 2010-07-20 2019-04-23 Halozyme, Inc. Adverse side-effects associated with administration of an anti-hyaluronan agent and methods for ameliorating or preventing the side-effects
WO2012012300A2 (fr) 2010-07-20 2012-01-26 Halozyme, Inc. Effets secondaires indésirables associés à l'administration d'un agent anti-hyaluronane et procédés pour améliorer ou prévenir ces effets secondaires
US9878046B2 (en) 2010-07-20 2018-01-30 Halozyme, Inc. Adverse side-effects associated with administration of an anti-hyaluronan agent and methods for ameliorating or preventing the side-effects
US8642737B2 (en) 2010-07-26 2014-02-04 Baxter International Inc. Nucleophilic catalysts for oxime linkage
EP3505186B1 (fr) * 2010-07-30 2022-01-12 Takeda Pharmaceutical Company Limited Catalyseurs nucléophiles pour liaison oxime
EA025738B1 (ru) * 2010-07-30 2017-01-30 Баксалта Инкорпорейтид Способ конъюгирования водорастворимого полимера с терапевтическим белком (варианты) и полученный модифицированный белок (варианты)
CN108079312A (zh) * 2010-07-30 2018-05-29 百深有限责任公司 用于肟键联的亲核性催化剂
WO2012016131A1 (fr) * 2010-07-30 2012-02-02 Baxter International Inc. Catalyseurs nucléophiles pour une liaison oxime
CN103370082A (zh) * 2010-07-30 2013-10-23 巴克斯特国际公司 用于肟键联的亲核性催化剂
US11439710B2 (en) 2010-08-17 2022-09-13 Ambrx, Inc. Nucleic acids encoding modified relaxin polypeptides
US11786578B2 (en) 2010-08-17 2023-10-17 Ambrx, Inc. Modified relaxin polypeptides and their uses
EP4302783A2 (fr) 2010-08-17 2024-01-10 Ambrx, Inc. Polypeptides de relaxine modifiés et leurs utilisations
US9452222B2 (en) 2010-08-17 2016-09-27 Ambrx, Inc. Nucleic acids encoding modified relaxin polypeptides
US10751391B2 (en) 2010-08-17 2020-08-25 Ambrx, Inc. Methods of treatment using modified relaxin polypeptides comprising a non-naturally encoded amino acid
US10702588B2 (en) 2010-08-17 2020-07-07 Ambrx, Inc. Modified relaxin polypeptides comprising a non-naturally encoded amino acid in the A chain
US10253083B2 (en) 2010-08-17 2019-04-09 Ambrx, Inc. Therapeutic uses of modified relaxin polypeptides
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
WO2012024452A2 (fr) 2010-08-17 2012-02-23 Ambrx, Inc. Polypeptides de relaxine modifiés et leurs utilisations
US9962450B2 (en) 2010-08-17 2018-05-08 Ambrx, Inc. Method of treating heart failure with modified relaxin polypeptides
US11311605B2 (en) 2010-08-17 2022-04-26 Ambrx, Inc. Methods of treating heart failure and fibrotic disorders using modified relaxin polypeptides
US11273202B2 (en) 2010-09-23 2022-03-15 Elanco Us Inc. Formulations for bovine granulocyte colony stimulating factor and variants thereof
US12138296B2 (en) 2010-09-23 2024-11-12 Elanco Us Inc. Formulations for bovine granulocyte colony stimulating factor and variants thereof
US9333244B2 (en) 2011-02-08 2016-05-10 Halozyme, Inc. Composition and lipid formulation of a hyaluronan-degrading enzyme and the use thereof for treatment of benign prostatic hyperplasia
WO2012109387A1 (fr) 2011-02-08 2012-08-16 Halozyme, Inc. Composition et formulation lipidique d'une enzyme dégradant le hyaluronane et son utilisation pour le traitement de l'hyperplasie bénigne de la prostate
EP2907504A1 (fr) 2011-02-08 2015-08-19 Halozyme, Inc. Composition et formulation de lipides d'une enzyme de dégradation d'hyaluronan et leur utilisation pour le traitement de l'hyperplasie bénigne de la prostate
US9993529B2 (en) 2011-06-17 2018-06-12 Halozyme, Inc. Stable formulations of a hyaluronan-degrading enzyme
WO2012174480A2 (fr) 2011-06-17 2012-12-20 Halozyme, Inc. Procédés de perfusion d'insuline sous-cutanée continue utilisant une enzyme de dégradation de l'hyaluronane
US9382305B2 (en) 2011-07-01 2016-07-05 Bayer Intellectual Property Gmbh Relaxin fusion polypeptides and uses thereof
WO2013004607A1 (fr) 2011-07-01 2013-01-10 Bayer Intellectual Property Gmbh Polypeptides de fusion de relaxine et leurs utilisations
WO2013040501A1 (fr) 2011-09-16 2013-03-21 Pharmathene, Inc. Compositions et combinaisons d'accepteurs biologiques organophosphorés et d'enzymes dégradant le hyaluronane, et leurs utilisations
EP2915542A1 (fr) 2011-10-24 2015-09-09 Halozyme, Inc. Diagnostic accompagnant une thérapie d'agent anti-hyaluronan et procédés d'utilisation associés
US8846034B2 (en) 2011-10-24 2014-09-30 Halozyme, Inc. Companion diagnostic for anti-hyaluronan agent therapy and methods of use thereof
US9458442B2 (en) 2011-10-24 2016-10-04 Halozyme, Inc. Companion diagnostic for anti-hyaluronan agent therapy and methods of use thereof
WO2013063155A2 (fr) 2011-10-24 2013-05-02 Halozyme, Inc. Diagnostic compagnon pour le traitement avec un agent anti-hyaluronane et procédés d'utilisation dudit diagnostic
US12018298B2 (en) 2011-12-30 2024-06-25 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US12123035B2 (en) 2011-12-30 2024-10-22 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US12104185B2 (en) 2011-12-30 2024-10-01 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US11952600B2 (en) 2011-12-30 2024-04-09 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US12264345B1 (en) 2011-12-30 2025-04-01 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US12104184B2 (en) 2011-12-30 2024-10-01 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US12091692B2 (en) 2011-12-30 2024-09-17 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US12077791B2 (en) 2011-12-30 2024-09-03 Halozyme, Inc. PH20 polypeptide variants with a modification at position 309 of the PH20 polypeptide and a method of making thereof
US10865400B2 (en) 2011-12-30 2020-12-15 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
EP3130347A1 (fr) 2011-12-30 2017-02-15 Halozyme, Inc. Variants polypeptidiques ph20, formulations et utilisations de ceux-ci
US12110520B2 (en) 2011-12-30 2024-10-08 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US9447401B2 (en) 2011-12-30 2016-09-20 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US12060590B2 (en) 2011-12-30 2024-08-13 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US12037618B2 (en) 2011-12-30 2024-07-16 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US11066656B2 (en) 2011-12-30 2021-07-20 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US12054758B2 (en) 2011-12-30 2024-08-06 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US11041149B2 (en) 2011-12-30 2021-06-22 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US12049652B2 (en) 2011-12-30 2024-07-30 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US12152262B2 (en) 2011-12-30 2024-11-26 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US12195773B2 (en) 2011-12-30 2025-01-14 Halozyme, Inc. PH20 polypeptide variants, formulations and uses thereof
US9913822B2 (en) 2012-04-04 2018-03-13 Halozyme, Inc. Combination therapy with an anti-hyaluronan agent and therapeutic agent
US10137104B2 (en) 2012-04-04 2018-11-27 Halozyme, Inc. Combination therapy with an anti-hyaluronan agent and therapeutic agent
WO2013151774A1 (fr) 2012-04-04 2013-10-10 Halozyme, Inc. Polythérapie par un agent anti-hyaluronane et un taxane ciblant une tumeur
WO2013173557A1 (fr) * 2012-05-16 2013-11-21 Baxter International Inc. Catalyseur nucléophile pour liaison oxime et utilisation de ses analyses rmn
EA028186B1 (ru) * 2012-05-16 2017-10-31 Баксалта Инкорпорейтид Способ конъюгации водорастворимого полимера с терапевтическим белком (варианты) и полученный модифицированный белок
WO2013173543A1 (fr) * 2012-05-16 2013-11-21 Baxter International Inc. Catalyseurs nucléophiles pour liaison oxime
EP3505534A1 (fr) 2012-06-08 2019-07-03 Sutro Biopharma, Inc. Anticorps comprenant des résidus d'acides aminés non endogènes spécifiques d'un site, leurs procédés de préparation et leurs procédés d'utilisation
WO2013185115A1 (fr) 2012-06-08 2013-12-12 Sutro Biopharma, Inc. Anticorps comprenant des résidus d'acides aminés non endogènes spécifiques d'un site, leurs procédés de préparation et leurs procédés d'utilisation
EP3135690A1 (fr) 2012-06-26 2017-03-01 Sutro Biopharma, Inc. Proteines fc modifiees contenant des residus specifiques d'acides amines non naturels, leurs conjugues, leurs procedes de preparation et leurs procedes d'utilisation
EP3584255A1 (fr) 2012-08-31 2019-12-25 Sutro Biopharma, Inc. Acides aminés modifiés comprenant un groupe azido
EP4074728A1 (fr) 2012-08-31 2022-10-19 Sutro Biopharma, Inc. Peptides modifiés comprenant un groupe azido
WO2014036492A1 (fr) 2012-08-31 2014-03-06 Sutro Biopharma, Inc. Acides aminés modifiés comprenant un groupe azido
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
WO2014062856A1 (fr) 2012-10-16 2014-04-24 Halozyme, Inc. Hypoxie et hyaluronane et leurs marqueurs pour le diagnostic et la surveillance de maladies et de pathologies, et méthodes associées
WO2015003167A1 (fr) 2013-07-03 2015-01-08 Halozyme, Inc. Variants de hyaluronidase ph20 thermiquement stables et leurs utilisations
WO2015006555A2 (fr) 2013-07-10 2015-01-15 Sutro Biopharma, Inc. Anticorps comprenant plusieurs résidus d'acides aminés non naturels site-spécifiques, des procédés permettant leur préparation et leurs méthodes d'utilisation
EP3336103A1 (fr) 2013-07-10 2018-06-20 Sutro Biopharma, Inc. Anticorps comprenant plusieurs résidus d'acides aminés non naturels sitespécifiques, des procédés permettant leur préparation et leurs méthodes d'utilisation
WO2015054658A1 (fr) 2013-10-11 2015-04-16 Sutro Biopharma, Inc. Acides aminés modifiés comprenant des groupes fonctionnels de tétrazine, procédés de préparation et procédés d'utilisation associés
WO2016033555A1 (fr) 2014-08-28 2016-03-03 Halozyme, Inc. Thérapie combinée associant une enzyme dégradant le hyaluronane et un inhibiteur des postes de contrôle immunitaire
US11414489B2 (en) 2014-08-28 2022-08-16 Halozyme, Inc. Combination therapy with a hyaluronan-degrading enzyme and an immune checkpoint inhibitor
WO2016061286A2 (fr) 2014-10-14 2016-04-21 Halozyme, Inc. Compositions d'adénosine désaminase-2 (ada2), variants de cette dernière et leurs procédés d'utilisation
US11584923B2 (en) 2014-10-14 2023-02-21 Halozyme, Inc. Compositions of adenosine deaminase-2 (ADA2), variants thereof and methods of using same
US9969998B2 (en) 2014-10-14 2018-05-15 Halozyme, Inc. Compositions of adenosine deaminase-2 (ADA2), variants thereof and methods of using same
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
US12247058B2 (en) 2014-10-24 2025-03-11 Bristol-Myers Squibb Company Nucleic acids encoding modified FGF-21 polypeptides, vectors and cells containing, and use thereof
US10189883B2 (en) 2014-10-24 2019-01-29 Bristol-Myers Squibb Company Therapeutic uses of modified FGF-21 polypeptides
US11248031B2 (en) 2014-10-24 2022-02-15 Bristol-Myers Squibb Company Methods of treating diseases associated with fibrosis using modified FGF-21 polypeptides
US12097241B2 (en) 2017-02-08 2024-09-24 Bristol-Myers Squibb Company Methods of treating kidney failure, and/or improving or stablizing renal function using modified relaxin polypeptides
US11364281B2 (en) 2017-02-08 2022-06-21 Bristol-Myers Squibb Company Modified relaxin polypeptides comprising a pharmacokinetic enhancer and pharmaceutical compositions 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
US12097242B2 (en) 2017-02-08 2024-09-24 Bristol-Myers Squibb Company Treatment of fibrosis, 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
WO2018230903A1 (fr) 2017-06-12 2018-12-20 한국코러스 주식회사 Composition d'érythropoïétine à stabilité améliorée et procédé de préparation de cette dernière
US10781435B2 (en) 2017-06-22 2020-09-22 Catalyst Biosciences, Inc. Modified membrane type serine protease 1 (MTSP-1) polypeptides and methods of use
US11807882B2 (en) 2017-06-22 2023-11-07 Vertex Pharmaceuticals Incorporated Modified membrane type serine protease 1 (MTSP-1) polypeptides and methods of use
US12173337B2 (en) 2017-06-22 2024-12-24 Vertex Pharmaceuticals, Incorporated Nucleic acid encoding modified membrane type serine protease 1 (MTSP-1) polypeptides and methods of use
US11401513B2 (en) 2017-06-22 2022-08-02 Catalyst Biosciences, Inc. Modified membrane type serine protease 1 (MTSP-1) polypeptides and methods of use
US10954501B2 (en) 2017-06-22 2021-03-23 Catalyst Biosciences, Inc. Nucleic acid encoding modified membrane type serine protease 1 (MTSP-1) polypeptides and methods of use
WO2018237201A1 (fr) 2017-06-22 2018-12-27 Catalyst Biosciences, Inc. Polypeptides de sérine protéase 1 de type à membrane modifiée (mtsp-1) et leurs procédés d'utilisation
WO2019222435A1 (fr) 2018-05-16 2019-11-21 Halozyme, Inc. Procédés de sélection de sujets pour une polythérapie anticancéreuse avec un ph20 soluble conjugué à un polymère
US12049485B2 (en) 2018-09-11 2024-07-30 Ambrx, Inc. Interleukin-2 polypeptide conjugates and their uses
EP4389145A2 (fr) 2018-09-11 2024-06-26 Ambrx, Inc. Conjugués polypeptidiques d'interleukine-2 et leurs utilisations
WO2020056066A1 (fr) 2018-09-11 2020-03-19 Ambrx, Inc. Conjugués polypeptidiques d'interleukine-2 et leurs utilisations
WO2020082057A1 (fr) 2018-10-19 2020-04-23 Ambrx, Inc. Conjugués polypeptidiques d'interleukine-10, dimères de ceux-ci et leurs utilisations
WO2020140101A1 (fr) 2018-12-28 2020-07-02 Catalyst Biosciences, Inc. Polypeptides activateurs de plasminogène de type urokinase modifiés et leurs procédés d'utilisation
US11613744B2 (en) 2018-12-28 2023-03-28 Vertex Pharmaceuticals Incorporated Modified urokinase-type plasminogen activator polypeptides and methods of use
WO2020168017A1 (fr) 2019-02-12 2020-08-20 Ambrx, Inc. Contenant de compositions, procédés et utilisations de conjugués anticorps-agonistes tlr
WO2021183832A1 (fr) 2020-03-11 2021-09-16 Ambrx, Inc. Conjugués polypeptidiques d'interleukine-2 et leurs procédés d'utilisation
WO2022040596A1 (fr) 2020-08-20 2022-02-24 Ambrx, Inc. Conjugués anticorps-agonistes de tlr, procédés et utilisations de ceux-ci
WO2022212899A1 (fr) 2021-04-03 2022-10-06 Ambrx, Inc. Conjugués anticorps-médicament anti-her2 et leurs utilisations

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