KR950703999A - MODIFIED INSULIN-LIKE GROWTH FACTORS - Google Patents

MODIFIED INSULIN-LIKE GROWTH FACTORS

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Publication number
KR950703999A
KR950703999A KR1019950702108A KR19950702108A KR950703999A KR 950703999 A KR950703999 A KR 950703999A KR 1019950702108 A KR1019950702108 A KR 1019950702108A KR 19950702108 A KR19950702108 A KR 19950702108A KR 950703999 A KR950703999 A KR 950703999A
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South Korea
Prior art keywords
igf
peg
mutein
polyethylene glycol
conjugate
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KR1019950702108A
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Korean (ko)
Inventor
조지 엔. 콕스
마틴 제이. 맥더모트
Original Assignee
토마스 이. 워크맨 주니어
암겐 보울더 인코포레이티드
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Publication of KR950703999A publication Critical patent/KR950703999A/en

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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
    • C07K14/575—Hormones
    • C07K14/65—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • 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
    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Genetics & Genomics (AREA)
  • Toxicology (AREA)
  • Diabetes (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)

Abstract

본 발명은 약리학적 성질과 생물학적 성질이 개선된 인슐린 유사 성장인자(IGF)의 변성된 형태를 제공하는 것이다. 이러한 변성물로는 천연 IGF 아미노산 시퀀스에 시스테인을 첨가하거나 치환하여 제조된 IGF 뮤테인 뿐만 아니라 유이 시스테인 부위에 폴리에틸렌 글리콜(PEG)이 부착된 상기 뮤테인 등이 있다. 본 발명은 또한 상기한 변성된 형태의 IGF의 제조방법을 제공하는 것이다. IGF-PEG 컨쥬게이트물은 제약 조성물로 제조될 수 있고 IGF와 관련된 상태의 치료에 사용될 수 있다.The present invention provides a modified form of insulin like growth factor (IGF) with improved pharmacological and biological properties. Such modifications include IGF mutein prepared by adding or replacing cysteine to a natural IGF amino acid sequence, as well as the mutein to which polyethylene glycol (PEG) is attached to a yui cysteine site. The present invention also provides a method for preparing the modified form of IGF described above. IGF-PEG conjugates can be prepared in pharmaceutical compositions and used to treat conditions associated with IGF.

Description

변성된 인슐린-유사 성장인자(MODIFIED INSULIN-LIKE GROWTH FACTORS)MODIFIED INSULIN-LIKE GROWTH FACTORS

본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음Since this is an open matter, no full text was included.

Claims (25)

폴리에틸렌 글리콜(PEG)과 IGF의 뮤테인으로 이루어지고, 상기 뮤테인의 N-터미널 영역의 유리 시스테인에서 상기 뮤테인에 상기 PEG가 부착되어 있는 폴리에틸렌 글리콜 컨쥬게이트물.A polyethylene glycol conjugate comprising a mutein of polyethylene glycol (PEG) and IGF, wherein the PEG is attached to the mutein in the free cysteine of the N-terminal region of the mutein. 제1항에 있어서, PEG가 말레이미드, 설프히드릴, 티올, 트리플레이트, 트레실레이트, 아지리딘, 엑시란 및 5-피리딜로 이루어진 군에서 선택된 활성기에 의하여 유리 시스테인에 부착되는 것인 폴리에틸렌 글리콜 컨쥬게이트물.The polyethylene of claim 1 wherein the PEG is attached to the free cysteine by an active group selected from the group consisting of maleimide, sulfhydryl, thiol, triflate, tresylate, aziridine, excyran and 5-pyridyl. Glycol conjugates. 제1항에 있어서, IGF가 IGF-1인 것인 폴리에틸렌 글리콜 컨쥬게이트물.The polyethylene glycol conjugate of claim 1 wherein the IGF is IGF-1. 제3항에 있어서, 유리 시스테인은 IGF-1의 N-말란의 제1아미노산 앞에 발생하는 것인 폴리에틸렌 글리콜 컨쥬게이트물.The polyethylene glycol conjugate of claim 3 wherein the free cysteine occurs before the first amino acid of N-malane of IGF-1. 제4항에 있어서, 유리 시스테인은 IGF-1의 N-말단의 제1아미노산에 이웃하는 것인 폴리에틸렌 글리콜 컨쥬게이트물.The polyethylene glycol conjugate of claim 4 wherein the free cysteine is neighboring the N-terminal first amino acid of IGF-1. 제3항에 있어서, 유리 시스테인은 IGF-1이 N-말단의 처음 약 20개의 아미노산 중 임의의 이웃한 2개의 아미노산 사이에 발생하는 것인 폴리에티렌 글리콜 컨쥬게이트물.4. The polystyrene glycol conjugate of claim 3, wherein the free cysteine occurs where IGF-1 occurs between any two adjacent amino acids of the first about 20 amino acids of the N-terminus. 제3항에 있어서, 유리 시스테인이 IGF-1의 N-말단의 처음 약 20개 아미노산 중 하나로 치환되는 것인 폴리에틸렌 글리콜 컨쥬게이트물.The polyethylene glycol conjugate of claim 3 wherein the free cysteine is substituted with one of the first about 20 amino acids at the N-terminus of IGF-1. 제7항에 있어서, 유리 시스테인이 IGF-1의 N-말단의 제1아미노산으로 치환되는 것인 폴리에틸렌 글리콜 컨쥬게이트물.8. The polyethylene glycol conjugate of claim 7, wherein the free cysteine is substituted with the N-terminal first amino acid of IGF-1. 제7항에 있어서, 유리 시스테인이 IGF-1의 N-말단의 제2아미노산으로 치환되는 것인 폴리에틸렌 글리콜 컨쥬게이트물.8. The polyethylene glycol conjugate of claim 7, wherein the free cysteine is substituted with the N-terminal second amino acid of IGF-1. 제7항에 있어서, 유리 시스테인이 IGF-1의 N-말단의 제3아미노산으로 치환되는 것인 폴리엔틸렌 글리콜 컨쥬게이트물.8. The polyentylene glycol conjugate of claim 7, wherein the free cysteine is substituted with the N-terminal third amino acid of IGF-1. 제1항에 있어서, PEG가 5 kDa, 8.5 kDa, 10 kDa, 및 20 kDa로 이루어진 군에서 선택된 분자량을 가지는 것인 폴리에틸렌 글리콜 컨쥬게이트물.The polyethylene glycol conjugate of claim 1 wherein the PEG has a molecular weight selected from the group consisting of 5 kDa, 8.5 kDa, 10 kDa, and 20 kDa. 제11항에 있어서, PEG가 분자량이 8.5 kDa인 것인 폴리에틸렌 글리콜 컨쥬게이트물.The polyethylene glycol conjugate of claim 11 wherein the PEG has a molecular weight of 8.5 kDa. 제1항에 있어서, 상기 PEG가 부착된 제2 폴리펩티드를 포함하는 폴리에틸렌 글리콜 컨쥬게이트물.The polyethylene glycol conjugate of claim 1 comprising a second polypeptide to which said PEG is attached. 제13항에 있어서, 제2 폴리펩티드가 IGF의 뮤테인인 것인 폴리에틸렌 글리콘 컨쥬게이트물.The polyethylene glycoconjugate of claim 13 wherein the second polypeptide is a mutein of IGF. N-터미널 영역에 유리 시스테인을 가지는 IGF 뮤테인. .IGF muteins with free cysteines in the N-terminal region. . 제l5항에 있어서, 상기 뮤테인이 재조합 생성물인 것인 IGF 뮤테인.The IGF mutein according to claim 15, wherein the mutein is a recombinant product. 제16항에 있어서, 상기 뮤테인이 E. coli에 의해 발현되는 것인 IGF 뮤테인.The IGF mutein of claim 16, wherein said mutein is expressed by E. coli. N-터미널 영역에 유리 시스테인을 가지는 IGF뮤테인의 유리 시스테인에 PEG를 부착하는 것으로 이루어진 제1항에 따른 컨쥬게이트물의 제조방법.A method for preparing the conjugate according to claim 1, comprising attaching PEG to the free cysteine of an IGF mutein having a free cysteine in the N-terminal region. 제18항에 있어서, PEG가 말레이미드, 설프히드릴, 티올, 트리플레이트, 트레실레이트, 아지리딘, 엑시란 및 5-퍼리딜로 이루어진 군에서 선택된 활성기에 의하여 유리 시스테인에 부착되는 것인 방법.The method of claim 18, wherein the PEG is attached to the free cysteine by an activator selected from the group consisting of maleimide, sulfhydryl, thiol, triflate, tresylate, aziridine, excyran and 5-perridyl. . 제19항에 있어서, 활성기가 말레이미드인 것인 방법.The method of claim 19, wherein the active group is maleimide. 제18항에 있어서, PEG는 IGF 뮤테인과 다른 폴리펩티드에 부착되는 것인 방법.The method of claim 18, wherein the PEG is attached to the IGF mutein and another polypeptide. 제21항에 있어서, 상기 다른 폴리펩티드가 ICF 뮤테인인 것인 방법.The method of claim 21, wherein said other polypeptide is an ICF mutein. 제약적으로 허용가능한 담체와 제1항에 따른 TGF와 PEG의 컨쥬게이트물로 이루어진 제약 조성물.A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a conjugate of TGF and PEG according to claim 1. 환자에게 제1항에 따른 IGF와 PEG의 컨쥬게이트물을 투여하는 것으로 이루어진 IGF와 결합된 상태를 치료하는 방법.A method of treating a condition associated with IGF, comprising administering a conjugate of IGF and PEG to a patient. 제24항에 있어서, 상기 PEG 컨쥬게이트물은 제약적으로 허용가능한 담체와 함께 환자에게 투여되는 것인 방법.The method of claim 24, wherein the PEG conjugate is administered to the patient with a pharmaceutically acceptable carrier. ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.※ Note: The disclosure is based on the initial application.
KR1019950702108A 1992-11-25 1993-11-24 MODIFIED INSULIN-LIKE GROWTH FACTORS KR950703999A (en)

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US98051992A 1992-11-25 1992-11-25
US07/980,519 1992-11-25
PCT/US1993/011458 WO1994012219A2 (en) 1992-11-25 1993-11-24 Modified insulin-like growth factors

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JP (1) JPH08506095A (en)
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AU (1) AU6048294A (en)
CA (1) CA2149048A1 (en)
WO (1) WO1994012219A2 (en)

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AU6048294A (en) 1994-06-22
WO1994012219A2 (en) 1994-06-09
WO1994012219A3 (en) 1994-07-21
JPH08506095A (en) 1996-07-02
CA2149048A1 (en) 1994-06-09

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