OA13063A - Chemically-modified human growth hormone conjugates. - Google Patents

Chemically-modified human growth hormone conjugates. Download PDF

Info

Publication number: OA13063A
Authority: OA; OAPI
Prior art keywords: conjugate; mpeg; hgh; group; leu
Prior art date: 2001-11-20

Application number

OA1200400143A

Other languages

English (en)

Inventor

Rory F Finn

Wei Liao

Ned R Siegel

Original Assignee

Pharmacia Corp

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.)

2001-11-20

Filing date

2002-11-20

Publication date

2006-11-10

2002-11-20 Application filed by Pharmacia Corp filed Critical Pharmacia Corp

2006-11-10 Publication of OA13063A publication Critical patent/OA13063A/en

Links

108010000521 Human Growth Hormone Proteins 0.000 title claims abstract description 219
102000002265 Human Growth Hormone Human genes 0.000 title claims abstract description 219
239000000854 Human Growth Hormone Substances 0.000 title claims abstract description 201
-1 poly(ethylene oxide) Polymers 0.000 claims description 112
229920001223 polyethylene glycol Polymers 0.000 claims description 70
229920000642 polymer Polymers 0.000 claims description 50
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 31
230000012010 growth Effects 0.000 claims description 25
150000001413 amino acids Chemical group 0.000 claims description 14
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
229910052799 carbon Inorganic materials 0.000 claims description 10
206010056438 Growth hormone deficiency Diseases 0.000 claims description 9
125000003277 amino group Chemical group 0.000 claims description 9
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
208000035475 disorder Diseases 0.000 claims description 9
239000000203 mixture Substances 0.000 claims description 9
229940093476 ethylene glycol Drugs 0.000 claims description 8
125000003396 thiol group Chemical group [H]S* 0.000 claims description 8
241000282414 Homo sapiens Species 0.000 claims description 7
239000002202 Polyethylene glycol Substances 0.000 claims description 7
125000000539 amino acid group Chemical group 0.000 claims description 7
125000000524 functional group Chemical group 0.000 claims description 7
102000018997 Growth Hormone Human genes 0.000 claims description 5
108010051696 Growth Hormone Proteins 0.000 claims description 5
230000001684 chronic effect Effects 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 5
150000002148 esters Chemical class 0.000 claims description 5
239000000122 growth hormone Substances 0.000 claims description 5
229920001427 mPEG Polymers 0.000 claims description 5
150000003141 primary amines Chemical class 0.000 claims description 5
108090000765 processed proteins & peptides Proteins 0.000 claims description 5
150000003573 thiols Chemical class 0.000 claims description 5
241001061127 Thione Species 0.000 claims description 4
208000026928 Turner syndrome Diseases 0.000 claims description 4
239000002253 acid Substances 0.000 claims description 4
208000037824 growth disorder Diseases 0.000 claims description 4
LFKYBJLFJOOKAE-UHFFFAOYSA-N imidazol-2-ylidenemethanone Chemical compound O=C=C1N=CC=N1 LFKYBJLFJOOKAE-UHFFFAOYSA-N 0.000 claims description 4
239000012948 isocyanate Substances 0.000 claims description 4
150000002513 isocyanates Chemical class 0.000 claims description 4
102000004196 processed proteins & peptides Human genes 0.000 claims description 4
MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 3
206010012559 Developmental delay Diseases 0.000 claims description 3
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 3
150000002540 isothiocyanates Chemical class 0.000 claims description 3
229920001184 polypeptide Polymers 0.000 claims description 3
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
230000001588 bifunctional effect Effects 0.000 claims description 2
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CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 claims description 2
150000002463 imidates Chemical class 0.000 claims description 2
229940002612 prodrug Drugs 0.000 claims description 2
239000000651 prodrug Substances 0.000 claims description 2
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 7
COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims 7
SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 3
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125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
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CHRCKSPMGYDLIA-SRVKXCTJSA-N Cys-Phe-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O CHRCKSPMGYDLIA-SRVKXCTJSA-N 0.000 claims 1
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UHPAZODVFFYEEL-QWRGUYRKSA-N Gly-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)CN UHPAZODVFFYEEL-QWRGUYRKSA-N 0.000 claims 1
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JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 claims 1
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LRAUKBMYHHNADU-DKIMLUQUSA-N Ile-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@@H](C)CC)CC1=CC=CC=C1 LRAUKBMYHHNADU-DKIMLUQUSA-N 0.000 claims 1
BCXBIONYYJCSDF-CIUDSAMLSA-N Ile-Val Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(O)=O BCXBIONYYJCSDF-CIUDSAMLSA-N 0.000 claims 1
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XIRYQRLFHWWWTC-QEJZJMRPSA-N Leu-Ala-Phe Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 XIRYQRLFHWWWTC-QEJZJMRPSA-N 0.000 claims 1
HFBCHNRFRYLZNV-GUBZILKMSA-N Leu-Glu-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HFBCHNRFRYLZNV-GUBZILKMSA-N 0.000 claims 1
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LXKNSJLSGPNHSK-KKUMJFAQSA-N Leu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N LXKNSJLSGPNHSK-KKUMJFAQSA-N 0.000 claims 1
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POFWRMVFWIJXHP-UHFFFAOYSA-N n-benzyl-9-(oxan-2-yl)purin-6-amine Chemical compound C=1C=CC=CC=1CNC(C=1N=C2)=NC=NC=1N2C1CCCCO1 POFWRMVFWIJXHP-UHFFFAOYSA-N 0.000 description 1
ZHCAAFJSYLFLPX-UHFFFAOYSA-N nitrocyclohexatriene Chemical group [O-][N+](=O)C1=CC=C=C[CH]1 ZHCAAFJSYLFLPX-UHFFFAOYSA-N 0.000 description 1
229910052757 nitrogen Inorganic materials 0.000 description 1
239000002736 nonionic surfactant Substances 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
239000012038 nucleophile Substances 0.000 description 1
229960002446 octanoic acid Drugs 0.000 description 1
229940099216 oncaspar Drugs 0.000 description 1
210000000056 organ Anatomy 0.000 description 1
150000002894 organic compounds Chemical class 0.000 description 1
229920000620 organic polymer Polymers 0.000 description 1
150000002923 oximes Chemical class 0.000 description 1
125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
239000002245 particle Substances 0.000 description 1
230000037361 pathway Effects 0.000 description 1
OJUGVDODNPJEEC-UHFFFAOYSA-N phenylglyoxal Chemical class O=CC(=O)C1=CC=CC=C1 OJUGVDODNPJEEC-UHFFFAOYSA-N 0.000 description 1
229910052698 phosphorus Inorganic materials 0.000 description 1
239000011574 phosphorus Substances 0.000 description 1
230000006461 physiological response Effects 0.000 description 1
208000003068 pituitary dwarfism Diseases 0.000 description 1
230000001817 pituitary effect Effects 0.000 description 1
210000003635 pituitary gland Anatomy 0.000 description 1
230000003169 placental effect Effects 0.000 description 1
108010019492 placental lactogen receptor Proteins 0.000 description 1
230000036470 plasma concentration Effects 0.000 description 1
229920003196 poly(1,3-dioxolane) Polymers 0.000 description 1
229920002401 polyacrylamide Polymers 0.000 description 1
229920001281 polyalkylene Polymers 0.000 description 1
239000002861 polymer material Substances 0.000 description 1
229920005862 polyol Polymers 0.000 description 1
150000003077 polyols Chemical class 0.000 description 1
229920000136 polysorbate Polymers 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
230000002035 prolonged effect Effects 0.000 description 1
230000029983 protein stabilization Effects 0.000 description 1
230000017854 proteolysis Effects 0.000 description 1
150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
229920005604 random copolymer Polymers 0.000 description 1
239000011535 reaction buffer Substances 0.000 description 1
238000001525 receptor binding assay Methods 0.000 description 1
238000006268 reductive amination reaction Methods 0.000 description 1
230000000717 retained effect Effects 0.000 description 1
238000005185 salting out Methods 0.000 description 1
150000003839 salts Chemical class 0.000 description 1
125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
208000002491 severe combined immunodeficiency Diseases 0.000 description 1
238000002741 site-directed mutagenesis Methods 0.000 description 1
210000002356 skeleton Anatomy 0.000 description 1
239000011734 sodium Substances 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
230000003093 somatogenic effect Effects 0.000 description 1
108010042603 somatotropin 20K Proteins 0.000 description 1
125000006850 spacer group Chemical group 0.000 description 1
238000013223 sprague-dawley female rat Methods 0.000 description 1
238000013222 sprague-dawley male rat Methods 0.000 description 1
238000010186 staining Methods 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
239000000758 substrate Substances 0.000 description 1
150000003900 succinic acid esters Chemical class 0.000 description 1
150000003457 sulfones Chemical class 0.000 description 1
229910052717 sulfur Inorganic materials 0.000 description 1
239000012730 sustained-release form Substances 0.000 description 1
230000008685 targeting Effects 0.000 description 1
WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
238000012360 testing method Methods 0.000 description 1
210000002303 tibia Anatomy 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
238000012546 transfer Methods 0.000 description 1
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
238000000108 ultra-filtration Methods 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
210000001835 viscera Anatomy 0.000 description 1
230000003442 weekly effect Effects 0.000 description 1
238000005303 weighing Methods 0.000 description 1

Classifications

- 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
- C07K14/61—Growth hormone [GH], i.e. somatotropin
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH

Landscapes

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

OA1200400143A 2001-11-20 2002-11-20 Chemically-modified human growth hormone conjugates. OA13063A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US33190701P	2001-11-20	2001-11-20

Publications (1)

Publication Number	Publication Date
OA13063A true OA13063A (en)	2006-11-10

Family

ID=23295870

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
OA1200400143A OA13063A (en)	2001-11-20	2002-11-20	Chemically-modified human growth hormone conjugates.

Country Status (25)

Country	Link
EP (1)	EP1453859A2 (sr)
JP (2)	JP2005525302A (sr)
KR (2)	KR20050044858A (sr)
CN (1)	CN1608079A (sr)
AP (1)	AP2004003050A0 (sr)
AU (1)	AU2002356990A1 (sr)
BR (1)	BR0214451A (sr)
CA (1)	CA2467731A1 (sr)
CO (1)	CO5580794A2 (sr)
EA (2)	EA008505B1 (sr)
EC (1)	ECSP045114A (sr)
GE (1)	GEP20063860B (sr)
HR (1)	HRP20040448A2 (sr)
HU (1)	HUP0500997A2 (sr)
IL (1)	IL162031A0 (sr)
IS (1)	IS7268A (sr)
MA (1)	MA27544A1 (sr)
MX (1)	MXPA04004809A (sr)
NO (1)	NO20042182L (sr)
OA (1)	OA13063A (sr)
PL (1)	PL374354A1 (sr)
RS (1)	RS53104A (sr)
TN (1)	TNSN04090A1 (sr)
WO (1)	WO2003044056A2 (sr)
ZA (1)	ZA200403907B (sr)

Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US20030171285A1 (en) *	2001-11-20	2003-09-11	Finn Rory F.	Chemically-modified human growth hormone conjugates
US7041855B2 (en)	2001-12-11	2006-05-09	Sun Bio, Inc.	Monofunctional polyethylene glycol aldehydes
WO2003049699A2 (en) *	2001-12-11	2003-06-19	Sun Bio, Inc.	Novel monofunctional polyethylene glycol aldehydes
US6956135B2 (en)	2001-12-11	2005-10-18	Sun Bio, Inc.	Monofunctional polyethylene glycol aldehydes
US6916962B2 (en)	2001-12-11	2005-07-12	Sun Bio, Inc.	Monofunctional polyethylene glycol aldehydes
DK1476181T3 (en) *	2002-01-18	2016-05-23	Biogen Ma Inc	POLYALKYLENE POLYMER COMPOUNDS AND USE THEREOF
MXPA05002620A (es)	2002-09-09	2005-05-05	Nektar Therapeutics Al Corp	Alcanales polimericos solubles en agua.
EP1591467A1 (en) *	2002-09-09	2005-11-02	Nektar Therapeutics Al, Corporation	Conjugate between a polyethylene glycol having a terminal alkanal group and a human growth hormone
US20040142870A1 (en) *	2002-11-20	2004-07-22	Finn Rory F.	N-terminally monopegylated human growth hormone conjugates, process for their preparation, and methods of use thereof
US20050281778A1 (en) *	2003-03-28	2005-12-22	Myung-Ok Park	Human growth hormone conjugated with biocompatible polymer
EP1673464A2 (en) *	2003-10-10	2006-06-28	Novo Nordisk A/S	Conjugation of peptides
US7524813B2 (en)	2003-10-10	2009-04-28	Novo Nordisk Health Care Ag	Selectively conjugated peptides and methods of making the same
EP2368579A1 (en) *	2004-01-21	2011-09-28	Novo Nordisk Health Care AG	Transglutaminase mediated conjugation of peptides
JP2008511610A (ja) *	2004-08-31	2008-04-17	ファルマシア・アンド・アップジョン・カンパニー・エルエルシー	グリセロール分岐のポリエチレングリコール−ヒト成長ホルモン結合体、それらの製造方法及び使用方法
MX2007007590A (es)	2004-12-22	2007-12-10	Ambrx Inc	Composiciones que contienen, metodos que involucran y usos de aminoacidos no naturales y polipeptidos.
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
EP2284191A3 (en) *	2004-12-22	2011-07-20	Ambrx, Inc.	Process for the preparation of hGH
JP2008531482A (ja)	2005-02-10	2008-08-14	ノボノルディスクアクティーゼルスカブ	Ｃ末端がｐｅｇ化された成長ホルモン
BRPI0609079A2 (pt)	2005-04-18	2010-11-16	Novo Nordisk As	peptìdeo, composição farmacêutica, método para o tratamento de cáncer, uso de um peptìdeo construto de ácido nucleico, vetor, hospedeiro, e, anticorpo
WO2007025988A2 (en)	2005-08-30	2007-03-08	Novo Nordisk Health Care Ag	Liquid formulations of pegylated growth hormone
HRP20110404T1 (hr) *	2005-11-08	2011-08-31	Ambrx	Ubrzivači za modifikaciju ne-prirodnih aminokiselina i polipeptida ne-prirodnih aminokiselina
ES2529065T3 (es) *	2005-12-14	2015-02-16	Ambrx, Inc.	Composiciones que contienen, procedimientos que implican y usos de aminoácidos no naturales y polipéptidos
US9175061B2 (en) *	2006-07-07	2015-11-03	Novo Nordisk Health Care Ag	Protein conjugates and methods for their preparation
CN101108895B (zh) *	2006-07-19	2011-10-26	北京键凯科技有限公司	聚乙二醇乙醛衍生物及其与药物的结合物
CN101553501A (zh)	2006-10-26	2009-10-07	诺沃-诺迪斯克有限公司	Il-21变种
CL2008002399A1 (es) *	2007-08-16	2009-01-02	Pharmaessentia Corp	Conjugado sustancialmente puro que posee una porcion polimerica, una porcion proteica (interferon alfa 2b) y un ligante alifatico de 1 a 10 atomos de carbono, util en el tratamiento de las hepatitis b o c.
BRPI0822530B1 (pt) *	2008-04-03	2022-03-22	Biosteed Gene Expression Tech. Co., Ltd	Método de preparação de um hormônio de crescimento humano glicolado por polietileno (modificado por peg), hormônio do crescimento humano modificado por peg de menor peso molecular aparente e seu uso, preparação de hormônio do crescimento humano modificado por peg de menor peso molecular aparente e seu método de preparação e composição
DK2279007T3 (en)	2008-04-29	2016-08-22	Ascendis Pharma Growth Disorders Div As	Pegylated recombinant relations of human growth hormone
KR101104574B1 (ko) *	2008-05-14	2012-01-11	성균관대학교산학협력단	폴리에틸렌글리콜로 화학적으로 수식된 인간 성장 호르몬, 이의 제조방법 및 용도
CN102131844B (zh) *	2008-07-31	2016-03-02	药华医药股份有限公司	肽-聚合物缀合物
MX2011000847A (es)	2008-08-06	2011-02-25	Novo Nordisk Healthcare Ag	Proteinas conjugadas con eficacia prolongada in vivo.
RU2409669C9 (ru) *	2008-08-18	2012-05-27	ООО "Саентифик Фьючер Менеджмент" ("Scientific Future Management", "SFM")	Способ иммобилизации биологически активного вещества (бав) на носитель (варианты) и конъюгат бав-носитель, полученный данными способами
EP2331139B1 (en) *	2008-09-11	2019-04-17	Nektar Therapeutics	Polymeric alpha-hydroxy aldehyde and ketone reagents and conjugation method
MX2011007736A (es)	2009-01-22	2011-09-06	Novo Nordisk Healthcare Ag	Compuestos de hormona del crecimiento estables.
WO2011015649A1 (en)	2009-08-06	2011-02-10	Novo Nordisk Health Care Ag	Growth hormones with prolonged in-vivo efficacy
DK2512450T3 (en)	2009-12-15	2018-04-23	Ascendis Pharma Endocrinology Div A/S	Dry growth hormone composition transiently bound to a polymer carrier
CN118767117A (zh)	2010-01-22	2024-10-15	诺沃—诺迪斯克保健股份有限公司	体内功效延长的生长激素
BR112012018162A2 (pt)	2010-01-22	2017-10-03	Novo Nordisk Healthcare Ag	Compostos de hormônio do crescimento estáveis
CA2798518A1 (en) *	2010-05-17	2011-11-24	Cebix, Inc.	Pegylated c-peptide
EP2446898A1 (en)	2010-09-30	2012-05-02	Laboratorios Del. Dr. Esteve, S.A.	Use of growth hormone to enhance the immune response in immunosuppressed patients
EA019967B1 (ru) *	2011-12-21	2014-07-30	Общество С Ограниченной Ответственностью "Форт" (Ооо "Форт")	Ковалентный конъюгат полиэтиленгликоля с гормоном роста человека
CN105120887A (zh)	2013-04-05	2015-12-02	诺和诺德保健股份有限公司	生长激素化合物制剂
US11559567B2 (en)	2014-11-06	2023-01-24	Pharmaessentia Corporation	Dosage regimen for pegylated interferon
US10799563B2 (en)	2014-11-18	2020-10-13	Ascendis Pharma Endocrinology Division	Polymeric hGH prodrugs
PL3220892T3 (pl)	2014-11-21	2022-01-31	Ascendis Pharma Endocrinology Division A/S	Postacie dawkowane długo działającego hormonu wzrostu
KR20170125839A (ko) *	2015-03-11	2017-11-15	넥타르 테라퓨틱스	Ｉｌ-7 부분 및 중합체의 접합체
KR102152437B1 (ko) *	2015-09-18	2020-09-07	고쿠리츠 다이가쿠 호징 미야자키 다이가쿠	장시간 작용형 아드레노메둘린 유도체
SG11202108735QA (en)	2019-03-04	2021-09-29	Ascendis Pharma Endocrinology Div A/S	Long-acting growth hormone dosage forms with superior efficacy to daily somatropin
CN114539384B (zh) *	2020-11-19	2024-09-06	江苏众红生物工程创药研究院有限公司	聚乙二醇化长效生长激素及其制备方法和医药应用

Family Cites Families (13)

* 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
US4904584A (en) *	1987-12-23	1990-02-27	Genetics Institute, Inc.	Site-specific homogeneous modification of polypeptides
ES2113354T3 (es) *	1990-05-04	1998-05-01	American Cyanamid Co	Estabilizacion de somatotropinas y otras proteinas por modificacion de residuos de cisteina.
JPH06506217A (ja) *	1991-03-18	1994-07-14	エンゾン，インコーポレーテッド	ポリペプチドまたはグリコポリペプチドとポリマーとのヒドラジン含有結合体
AU2147192A (en) *	1991-06-28	1993-01-25	Genentech Inc.	Method of stimulating immune response using growth hormone
NZ250375A (en) *	1992-12-09	1995-07-26	Ortho Pharma Corp	Peg hydrazone and peg oxime linkage forming reagents and protein derivatives
US5824784A (en) *	1994-10-12	1998-10-20	Amgen Inc.	N-terminally chemically modified protein compositions and methods
JP3628333B2 (ja) *	1995-09-21	2005-03-09	ジェネンテックインコーポレーテッド	ヒト成長ホルモン変異体
IL133974A0 (en) *	1997-07-14	2001-04-30	Bolder Biotechnology Inc	Derivatives of growth hormone and related proteins
ATE526401T1 (de) *	1999-01-14	2011-10-15	Bolder Biotechnology Inc	Verfahren zur herstellung von proteinen mit freien cysteinresten
IL144361A0 (en) *	1999-01-29	2002-05-23	Hoffmann La Roche	Gcsf conjugates
WO2001076639A2 (en) *	2000-04-06	2001-10-18	Pharmacia Corporation	Chemically-modified myelopoietin conjugates
WO2002055532A2 (en) *	2001-01-11	2002-07-18	Maxygen Aps	Variant growth hormone molecules conjugated with macromolecular compounds

2002
- 2002-11-20 HR HR20040448A patent/HRP20040448A2/hr not_active Application Discontinuation
- 2002-11-20 CA CA002467731A patent/CA2467731A1/en not_active Abandoned
- 2002-11-20 OA OA1200400143A patent/OA13063A/en unknown
- 2002-11-20 KR KR1020047007708A patent/KR20050044858A/ko not_active Abandoned
- 2002-11-20 EA EA200400565A patent/EA008505B1/ru unknown
- 2002-11-20 IL IL16203102A patent/IL162031A0/xx unknown
- 2002-11-20 EA EA200700431A patent/EA200700431A1/ru unknown
- 2002-11-20 CN CNA028259289A patent/CN1608079A/zh active Pending
- 2002-11-20 AU AU2002356990A patent/AU2002356990A1/en not_active Abandoned
- 2002-11-20 WO PCT/US2002/037270 patent/WO2003044056A2/en not_active Ceased
- 2002-11-20 RS YU53104A patent/RS53104A/sr unknown
- 2002-11-20 EP EP02803695A patent/EP1453859A2/en not_active Withdrawn
- 2002-11-20 HU HU0500997A patent/HUP0500997A2/hu unknown
- 2002-11-20 BR BRPI0214451-4A patent/BR0214451A/pt not_active IP Right Cessation
- 2002-11-20 KR KR1020077011730A patent/KR20070072924A/ko not_active Withdrawn
- 2002-11-20 AP APAP/P/2004/003050A patent/AP2004003050A0/en unknown
- 2002-11-20 PL PL02374354A patent/PL374354A1/xx unknown
- 2002-11-20 GE GE5599A patent/GEP20063860B/en unknown
- 2002-11-20 MX MXPA04004809A patent/MXPA04004809A/es not_active Application Discontinuation
- 2002-11-20 JP JP2003545691A patent/JP2005525302A/ja active Pending
2004
- 2004-05-17 IS IS7268A patent/IS7268A/is unknown
- 2004-05-19 MA MA27686A patent/MA27544A1/fr unknown
- 2004-05-20 EC EC2004005114A patent/ECSP045114A/es unknown
- 2004-05-20 ZA ZA200403907A patent/ZA200403907B/en unknown
- 2004-05-20 CO CO04046633A patent/CO5580794A2/es not_active Application Discontinuation
- 2004-05-20 TN TNP2004000090A patent/TNSN04090A1/fr unknown
- 2004-05-26 NO NO20042182A patent/NO20042182L/no not_active Application Discontinuation
2006
- 2006-07-14 JP JP2006193577A patent/JP2006321808A/ja active Pending

Also Published As

Publication number	Publication date
MA27544A1 (fr)	2005-10-03
HRP20040448A2 (en)	2006-02-28
JP2005525302A (ja)	2005-08-25
NO20042182L (no)	2004-08-11
KR20070072924A (ko)	2007-07-06
GEP20063860B (en)	2006-06-26
EP1453859A2 (en)	2004-09-08
WO2003044056A2 (en)	2003-05-30
RS53104A (sr)	2006-10-27
TNSN04090A1 (fr)	2006-06-01
ECSP045114A (es)	2004-07-23
PL374354A1 (en)	2005-10-17
KR20050044858A (ko)	2005-05-13
EA200700431A1 (ru)	2008-02-28
ZA200403907B (en)	2007-12-27
CA2467731A1 (en)	2003-05-30
IL162031A0 (en)	2005-11-20
MXPA04004809A (es)	2004-08-11
EA200400565A1 (ru)	2005-06-30
CN1608079A (zh)	2005-04-20
WO2003044056A3 (en)	2003-08-21
JP2006321808A (ja)	2006-11-30
HUP0500997A2 (en)	2007-11-28
CO5580794A2 (es)	2005-11-30
AP2004003050A0 (en)	2004-06-30
BR0214451A (pt)	2006-05-30
EA008505B1 (ru)	2007-06-29
IS7268A (is)	2004-05-17
AU2002356990A1 (en)	2003-06-10

Publication	Publication Date	Title
OA13063A (en)	2006-11-10	Chemically-modified human growth hormone conjugates.
US20030171285A1 (en)	2003-09-11	Chemically-modified human growth hormone conjugates
KR100776862B1 (ko)	2007-11-28	엔 말단 모노피이지화된 인간 성장 호르몬 접합체, 그의제조 방법, 및 그의 사용 방법
NL1029828C2 (nl)	2006-10-20	Conjugaten van glycerol-vertakt polyethyleenglycol en menselijk groeihormoon, werkwijzen voor de bereiding daarvan en werkwijzen voor gebruik daarvan.
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US20040038892A1 (en)	2004-02-26	Chemically-modified human growth hormone conjugates
EP1861125A2 (en)	2007-12-05	Conjugates of an hgh moiety and peg derivatives
US20090203589A1 (en)	2009-08-13	Chemically modified human growth hormone receptor antagonist conjugates
HK1072058A (en)	2005-08-12	Chemically-modified human growth hormone conjugates
HK1104913A (en)	2008-01-25	Glycerol branched polyethylene glycol human growth hormone conjugates, process for their preparation, and methods of use thereof