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WO2007010552B1 - N- terminal peg conjugate of erythropoietin - Google Patents

N- terminal peg conjugate of erythropoietin

Info

Publication number
WO2007010552B1
WO2007010552B1 PCT/IN2006/000103 IN2006000103W WO2007010552B1 WO 2007010552 B1 WO2007010552 B1 WO 2007010552B1 IN 2006000103 W IN2006000103 W IN 2006000103W WO 2007010552 B1 WO2007010552 B1 WO 2007010552B1
Authority
WO
WIPO (PCT)
Prior art keywords
conjugate
mpeg
epo
erythropoietin
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2006/000103
Other languages
French (fr)
Other versions
WO2007010552A3 (en
WO2007010552A2 (en
Inventor
Subhash V Kapre
Umesh S Shaligram
Kwang Nho
Gunwon Bae
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Serum Institute of India Pvt Ltd
Sunbio Inc
Original Assignee
Serum Institute of India Pvt Ltd
Sunbio Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Serum Institute of India Pvt Ltd, Sunbio Inc filed Critical Serum Institute of India Pvt Ltd
Publication of WO2007010552A2 publication Critical patent/WO2007010552A2/en
Publication of WO2007010552A3 publication Critical patent/WO2007010552A3/en
Publication of WO2007010552B1 publication Critical patent/WO2007010552B1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

The present invention refers to conjugate of erythropoietin having higher bioactivity comprises an Erythropoietin glycoprotein having N-terminal α - amino group and aldehyde derivatives of polyethylene glycol, said erythropoietin glycoprotein being selected from the group consisting of human erythropoietin and analogs thereof, said aldehyde derivative of methoxy polyethylene glycol of the formula: PEG-R-CHO wherein R= alkyl group of formula -(CH2)n wherein n=2 to 4. The formula of the conjugate of the present invention is: PEG-R-CONH-EPO wherein R=alkyl group of formula -(CH2)n wherein n=2 to 4. Said erythropoietin according to the present invention is a recombinant erythropoietin (rhEPO) produced in animal cells; said erythropoietin conjugate is prepared by expressing, fermenting, and purifying rhEPO protein in recombinant animal cells and reacting EPO with PEG- Aldehyde to obtain N-terminally pegylated EPO by reductive amination reaction and then further purified to obtain pure N-terminally pegylated EPO.

Claims

AMENDED CLAIMS received by the International Bureau on 10 July 2007 (10.07.2007)
1. A conjugate comprising a human recombinant Erythropoietin glycoprotein having N- terminal [alpha] - amino group and a propionaldehyde derivative of methoxy polyethylene glycol (mPEG) of the formula mPEG-(CH2)2-CHO, the said conjugate having enhanced in vivo activity over that of the Non-glycosylated PEGylated EPO.
2. (New) A conjugate comprising a human recombinant Erythropoietin glycoprotein having N- terminal [alpha] - amino group and a propionaldehyde derivative of methoxy polyethylene glycol
(mPEG) of the formula mPEG-(CH2)2-CHO, the said conjugate having enhanced in vivo activity over that of the EPO pegylated with mPEG(30 kDa)-butyraldehyde.
3. The conjugate as claimed in claim 1 or 2 having the formula mPEG-(CH2)2-CONH-EPO.
4. The conjugate as claimed in claim 1 or 2 wherein the methoxy polyethylene glycol (mPEG) is a mono or branched polyethylene glycol preferably monoPEG.
5. The conjugate as claimed in claim 1 to 4 wherein the molecular weight of propionaldehyde mPEG is about 20 - kDa.
6. The conjugate as claimed in claim 1 or 2 wherein the said human recombinant erythropoietin (rhEPO) is produced in Chinese Hamster Ovary (CHO) cells.
7. A process of making the conjugate of claim 1 or 2 comprising:
(a) expressing, fermenting, and purifying rhEPO protein in recombinant Chinese Hamster Ovary (CHO) cells.
(b) reacting EPO with mPEG-propionaldehyde to obtain N-terminally pegylated EPO.
8. The process of claim 7 further comprises a step of purification of PEG-N-EPO.
9. The process of claim 7 wherein step b is a reductive amination reaction using mPEG-pripionaldehyde.
10. The process as claimed in claim 7 wherein the fermentation step is serum free.
11. The process of claim 7 wherein in step b mPEG - propionaldehyde is added at an about molar ratio of 7.5:1 of PEG: EPO.
12. The process of claim 7 wherein the mPEG is mono or branched PEG.
19
13. A pharmaceutical composition comprising the conjugate of claim 1 or 2 and a pharmaceutically acceptable excipient.
14. A method of treating anemia in a patient afflicted with chronic renal failure (CRF) resulting from chemotherapy, comprising administering to said patient an effective amount of conjugate of claim 1 or 2.
20
PCT/IN2006/000103 2005-03-17 2006-03-16 N- terminal peg conjugate of erythropoietin Ceased WO2007010552A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN291/MUM/2005 2005-03-17
IN291MU2005 2005-03-17

Publications (3)

Publication Number Publication Date
WO2007010552A2 WO2007010552A2 (en) 2007-01-25
WO2007010552A3 WO2007010552A3 (en) 2007-07-12
WO2007010552B1 true WO2007010552B1 (en) 2007-08-23

Family

ID=37528505

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2006/000103 Ceased WO2007010552A2 (en) 2005-03-17 2006-03-16 N- terminal peg conjugate of erythropoietin

Country Status (1)

Country Link
WO (1) WO2007010552A2 (en)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT2540309T (en) 2005-08-05 2018-01-10 Araim Pharmaceuticals, Inc. Tissue protective peptides and uses thereof
KR101486449B1 (en) 2008-01-11 2015-01-26 세리나 쎄라퓨틱스, 인코포레이티드 Multifunctional forms of polyoxazoline copolymers and drug compositions comprising the same
US8101706B2 (en) 2008-01-11 2012-01-24 Serina Therapeutics, Inc. Multifunctional forms of polyoxazoline copolymers and drug compositions comprising the same
KR20180123731A (en) * 2008-01-22 2018-11-19 아라임 파마슈티칼즈, 인크. Tissue protective peptides and peptide analogs for preventing and treating diseases and disorders associated with tissue damage
EP2616101B1 (en) 2010-09-14 2014-07-09 F.Hoffmann-La Roche Ag Method for purifying pegylated erythropoietin
CN102453087B (en) * 2010-10-22 2013-12-25 广东赛保尔生物医药技术有限公司 Purification and preparation method of mono-substituted PEG-EPO
CN102816227A (en) * 2012-08-30 2012-12-12 深圳赛保尔生物药业有限公司 Erythropoietin recovery method
CN109096483B (en) * 2017-06-28 2020-09-04 北京键凯科技股份有限公司 Branched polyglyol epoxy derivative cross-linked sodium hyaluronate gel and preparation and application thereof
CN111801120A (en) 2017-12-29 2020-10-20 豪夫迈·罗氏有限公司 Methods for providing pegylated protein compositions
ES2909454T3 (en) * 2017-12-29 2022-05-06 Hoffmann La Roche Procedure for Providing a PEGylated Protein Composition
JP7137625B2 (en) * 2017-12-29 2022-09-14 エフ．ホフマン－ラ ロシュ アーゲー Methods for providing PEGylated protein compositions
CN113301922A (en) * 2018-11-05 2021-08-24 百时美施贵宝公司 Method for purifying pegylated proteins
CN119080909A (en) * 2024-08-29 2024-12-06 深圳赛保尔生物药业有限公司 Composition loaded with PEG-EPO and mesenchymal stem cells, medicine and preparation method thereof

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5824784A (en) * 1994-10-12 1998-10-20 Amgen Inc. N-terminally chemically modified protein compositions and methods
JP4410852B2 (en) * 1996-08-02 2010-02-03 オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド Polypeptide having a single covalent N-terminal water-soluble polymer
JP2002531089A (en) * 1998-11-30 2002-09-24 イーライ・リリー・アンド・カンパニー Erythropoietic compounds
DE60144439D1 (en) * 2000-12-20 2011-05-26 Hoffmann La Roche CONJUGATES OF ERYTHROPOIETIN (EPO) WITH POLYETHYLENE GLYCOL (PEG)
WO2004009627A1 (en) * 2002-07-19 2004-01-29 Cangene Corporation Pegylated erythropoietic compounds
BR0314172A (en) * 2002-09-09 2005-07-26 Nektar Therapeutics Al Corp Water-soluble polymer, composition, hydrate or acetal form, compound, composition, uses of compound and conjugate, and process for preparing conjugate

Also Published As

Publication number Publication date
WO2007010552A3 (en) 2007-07-12
WO2007010552A2 (en) 2007-01-25

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