WO1996001275A1 - Facteur de croissance de type proche de l'insuline i authentique, o-glycosyle, variantes tronquees de celui-ci, procede de preparation et compositions pharmaceutiques - Google Patents
Facteur de croissance de type proche de l'insuline i authentique, o-glycosyle, variantes tronquees de celui-ci, procede de preparation et compositions pharmaceutiques Download PDFInfo
- Publication number
- WO1996001275A1 WO1996001275A1 PCT/SE1995/000774 SE9500774W WO9601275A1 WO 1996001275 A1 WO1996001275 A1 WO 1996001275A1 SE 9500774 W SE9500774 W SE 9500774W WO 9601275 A1 WO9601275 A1 WO 9601275A1
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- WIPO (PCT)
- Prior art keywords
- igf
- glycosylated
- amino acid
- polypeptide chain
- mannose residues
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 8
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims abstract description 111
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims abstract description 109
- 150000001413 amino acids Chemical class 0.000 claims abstract description 33
- 229920001184 polypeptide Polymers 0.000 claims abstract description 26
- 125000000311 mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims abstract description 24
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims abstract description 22
- 102000003746 Insulin Receptor Human genes 0.000 claims abstract description 15
- 108010001127 Insulin Receptor Proteins 0.000 claims abstract description 15
- 230000012010 growth Effects 0.000 claims abstract description 14
- 102000004877 Insulin Human genes 0.000 claims abstract description 11
- 108090001061 Insulin Proteins 0.000 claims abstract description 11
- 229940125396 insulin Drugs 0.000 claims abstract description 11
- 239000003085 diluting agent Substances 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- 239000003937 drug carrier Substances 0.000 claims abstract description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 6
- 230000007812 deficiency Effects 0.000 claims abstract description 5
- 210000005253 yeast cell Anatomy 0.000 claims abstract description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 38
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 32
- 102000028416 insulin-like growth factor binding Human genes 0.000 claims description 10
- 108091022911 insulin-like growth factor binding Proteins 0.000 claims description 10
- 208000001362 Fetal Growth Retardation Diseases 0.000 claims description 5
- 206010070531 Foetal growth restriction Diseases 0.000 claims description 5
- 208000030941 fetal growth restriction Diseases 0.000 claims description 5
- 230000016784 immunoglobulin production Effects 0.000 claims description 3
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- 102100036202 Serum amyloid P-component Human genes 0.000 description 47
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- 235000001014 amino acid Nutrition 0.000 description 24
- 230000027455 binding Effects 0.000 description 24
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 23
- 101001055320 Myxine glutinosa Insulin-like growth factor Proteins 0.000 description 22
- 239000012634 fragment Substances 0.000 description 15
- 102000005962 receptors Human genes 0.000 description 15
- 108020003175 receptors Proteins 0.000 description 15
- 102000004375 Insulin-like growth factor-binding protein 1 Human genes 0.000 description 13
- 108090000957 Insulin-like growth factor-binding protein 1 Proteins 0.000 description 13
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 10
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 230000002608 insulinlike Effects 0.000 description 10
- 108010031794 IGF Type 1 Receptor Proteins 0.000 description 9
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 9
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 8
- 230000013595 glycosylation Effects 0.000 description 8
- 230000004989 O-glycosylation Effects 0.000 description 7
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- 102000014914 Carrier Proteins Human genes 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 210000001789 adipocyte Anatomy 0.000 description 3
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 3
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- 238000010828 elution Methods 0.000 description 3
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- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 102100022708 Insulin-like growth factor-binding protein 3 Human genes 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
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- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 208000037824 growth disorder Diseases 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 102000044162 human IGF1 Human genes 0.000 description 2
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- 238000004987 plasma desorption mass spectroscopy Methods 0.000 description 2
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- AOFUBOWZWQFQJU-SNOJBQEQSA-N (2r,3s,4s,5r)-2,5-bis(hydroxymethyl)oxolane-2,3,4-triol;(2s,3r,4s,5s,6r)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O.OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O AOFUBOWZWQFQJU-SNOJBQEQSA-N 0.000 description 1
- HBOMLICNUCNMMY-KJFJCRTCSA-N 1-[(4s,5s)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1C1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-KJFJCRTCSA-N 0.000 description 1
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- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
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- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
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- 238000013507 mapping Methods 0.000 description 1
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- SKEFKEOTNIPLCQ-LWIQTABASA-N mating hormone Chemical compound C([C@@H](C(=O)NC(CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCS(C)=O)C(=O)NC(CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CN=CN1 SKEFKEOTNIPLCQ-LWIQTABASA-N 0.000 description 1
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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
- C07K14/65—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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
-
- 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 invention relates to O-glycosylated authentic IGF-I, having three or more
- the invention have substantially no insulin receptor affinity, which makes them
- the invention also relates to a method of obtaining IGF-I as defined above by
- IGF-I together with a pharmaceutically acceptable carrier, diluent or excipient. It also relates to the use of the O-glycosylated IGF-I in the preparation of a
- Insulin-like growth factor- 1 is a growth factor comprising 70 amino acid
- the endogenous human form is non-glycosylated.
- Recombinant human insulin-like growth factor I (rhIGF-I) can be produced by
- glycosylation One such modification that has been observed in proteins produced in yeast is glycosylation.
- Protein glycosylation in yeast can occur both as N- and O-linked, but since IGF-
- O-glycosylation is to be expected in IGF-I.
- One site for O-glycosylation at Thr29 is to be expected in IGF-I.
- Yeast is known to contain carboxypeptidases (JONES, E. W., (1990), "Tackling
- IGF-I polypeptide chain It is suggested that this glycosylated variant of IGF-I
- WO 93/08826 discloses (4-70) IGF -I and (54-67)IGF-I, the truncated variants
- WO 87/01038 discloses peptide analogues of IGF-I in which 1-5 amino acid
- glycosylated authentic IGF-I gIGF-I
- C-IGF-I glycosylated authentic IGF-I
- Lys68Ser69Ala70 and furthermore glycosylated at Thr29.
- therapeutical agents especially in the view of the less adverse effects such as decreased insulin-like effects although having a normal, expected IGF-I effect .
- hypoglycaemia due to decreased binding to IGF binding protein
- IGFBP-1 insulin receptor 1
- IUGR intrauterine growth retardation
- FIGS 1-6 illustrate the invention.
- Figure 1 shows the IGF-I peptides after digestion with S. aureus V8 protease
- Figure 2 shows the purification step based on hydrophobic interaction of
- Figure 3 shows the elution profile of affinity-chromatography of the "fraction 8"
- Figure 4 shows the elution profile of reversed phase chromatography (RP-
- Figure 5 shows the peptide map of SAP V8 digests of the two main variants, z and x2, compared to authentic rhIGF-I (DSQ 93).
- Figure 6 shows the peptide map of SAP V8 digests of the x3, x4 and x5
- the invention relates to O-glycosylated authentic IGF-I, having three or more
- the invention have substantially no insulin receptor affinity, which makes them
- IGF- polypeptide chain amino acid of the IGF- polypeptide chain or O-glycosylated (1-69)IGF-I,
- the invention also relates to a method of obtaining IGF-I as defined above by
- IGF-I insulin growth factor-I
- IGFBP-1 IGF binding protein 1
- IGFBP1 elevated IGFBP levels, particularly IGFBP1.
- the new glycosylated IGF variants may be administrated in doses ranging
- the IGF-I gene was expressed in Saccharomyces cerevisiae using an alpha-
- the yeast fermentation medium contained authentic human IGF-I and
- IGF-I was achieved by hydrophobic interaction chromatography (HI-HPLC). The fraction before the peak of authentic rIGF-I (fraction 8) was collected for the
- the x-fraction was further purified on RPV-HPLC and the main peak was
- Figure 5 shows the peptide map of SAP V8 digests of the two
- x2 O-glycosylated authentic IGF-I, having four or five mannose
- z O-glycosylated authentic IGF-I, having three mannose residues
- x4 O-glycosylated (1-69)IGF-I, having two mannose residues to the
- x5 O-glycosylated (1-67)IGF-I, having two mannose residues to the
- SAP 5 SAP 9:1, SAP 9:2, SAP 5 and SAP 9 are shown in Figures 5 and 6.
- IGF-I receptor The structure-function relationship of the IGF-I receptor is also similar to the
- the insulin receptor and the IGF-I receptor seem to be identical at least
- IGF-I or IGF-I variants is therefore their affinity to, and the bioeffects
- IGF BP3 is the major circulating IGF BP form in adults, and normally binds
- IGF which IGF can be shuttled from the circulation to the target cells for receptor
- IGF BPl is believed to be important both for the transport of IGF-I to the target
- IGFBP-1 has been shown to inhibit the insulin-like activities of IGF-I, both in vitro and in vivo. IGFBP-1 displays a pattern of regulation
- insulin is known to regulate the production of hepatic IGFBP-1.
- IGFBP-1 not only acutely regulates IGF action with respect to blood sugar
- controlled diabetes is accompanied by a decrease in IGFBP-3 and IGF-I while
- IGFBP-1 serum levels are high. IGFBP-1 is further believed to control fetal
- IGF variants with altered affinities for binding to the IGFBPs concomitant with changes in receptor binding, may demonstrate
- the 1-69 dimannosyl Thr29 variant (x4) demonstrated a potency of 50% and
- the growth promoting effect of the glycosylated variants was thus more or less
- weight BPl was tested by a Biacore method. This method measures binding
- binding can be compensated for by other intrinsic properties of the variants e.g.
- the variants have an
- the lipogenisis assay indicates that the variants can be selective for
- IGFBPs IGF Binding proteins
- the IGF BPl binding is lower than for authentic IGF-I but not as low as for the
- the IGF BP3 binding is the same as for IGF-I indicating similarities in half-life.
- the earlier identified glycosylated variant with mannose on Thr29 has a
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Immunology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
La présente invention concerne des facteurs de croissance de type proche de l'insuline I (IGF-I) authentique O-glycosylés, portant au moins 3 restes de mannose sur l'acide aminé Ser69 de la chaîne polypeptidique du facteur IGF, ou tronqués et portant 2 restes de mannose sur l'acide aminé Thr29 de la chaîne polypeptidique tronquée du facteur IGF. Les facteurs IGF-I O-glycosylés selon la présente invention ne présentent sensiblement aucune affinité pour le récepteur de l'insuline, ce qui les rend précieux dans un traitement thérapeutique. L'invention concerne également un procédé d'obtention desdits facteurs IGF-I qui consiste à exprimer les facteurs IGF-I dans des cellules de levure, et à isoler de leur milieu les facteurs IGF-I O-glycosylés de la présente invention. L'invention concerne en outre une composition pharmaceutique contenant ces facteurs IGF-I ainsi qu'un vecteur, un diluant ou un excipient pharmaceutiquement acceptables. L'invention concerne enfin l'utilisation des facteurs IGF-I O-glycosylés pour la préparation d'un médicament destiné notamment au traitement des états liés au déficit de croissance et des états insulino-résistants.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP95925201A EP0769022A1 (fr) | 1994-07-01 | 1995-06-22 | Facteur de croissance de type proche de l'insuline i authentique, o-glycosyle, variantes tronquees de celui-ci, procede de preparation et compositions pharmaceutiques |
| AU29406/95A AU2940695A (en) | 1994-07-01 | 1995-06-22 | O-glycosylated authentic igf-i and truncated variants thereof, a method of preparation thereof and pharmaceutical compositions |
| JP8503823A JPH10502623A (ja) | 1994-07-01 | 1995-06-22 | Ｏ−グリコシル化真正ｉｇｆ−ｉおよびその切断変種、その製造方法、並びに医薬組成物 |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9402332A SE9402332D0 (sv) | 1994-07-01 | 1994-07-01 | Igf-1 |
| SE9402332-2 | 1994-07-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996001275A1 true WO1996001275A1 (fr) | 1996-01-18 |
Family
ID=20394599
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE1995/000774 WO1996001275A1 (fr) | 1994-07-01 | 1995-06-22 | Facteur de croissance de type proche de l'insuline i authentique, o-glycosyle, variantes tronquees de celui-ci, procede de preparation et compositions pharmaceutiques |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0769022A1 (fr) |
| JP (1) | JPH10502623A (fr) |
| AU (1) | AU2940695A (fr) |
| CA (1) | CA2193399A1 (fr) |
| IL (1) | IL114270A0 (fr) |
| SE (1) | SE9402332D0 (fr) |
| WO (1) | WO1996001275A1 (fr) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996033216A1 (fr) * | 1995-04-21 | 1996-10-24 | Pharmacia & Upjohn Ab | Igf-i tronque |
| US6660279B2 (en) * | 1998-09-01 | 2003-12-09 | Astrazeneca Ab | Stability for injection solutions |
| EP2241575A1 (fr) * | 2005-01-07 | 2010-10-20 | Regeneron Pharmaceuticals, Inc. | Polypeptides de fusion IGF-1 et utilisations thérapeutiques |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990002198A1 (fr) * | 1988-08-20 | 1990-03-08 | Kabi Pharmacia Ab | Igf-1 o-glycosyle |
| WO1993002695A1 (fr) * | 1991-08-01 | 1993-02-18 | Genentech, Inc. | Igf-1 utilise pour ameliorer l'etat pathologique du systeme nerveux |
-
1994
- 1994-07-01 SE SE9402332A patent/SE9402332D0/xx unknown
-
1995
- 1995-06-22 CA CA002193399A patent/CA2193399A1/fr not_active Abandoned
- 1995-06-22 WO PCT/SE1995/000774 patent/WO1996001275A1/fr not_active Application Discontinuation
- 1995-06-22 AU AU29406/95A patent/AU2940695A/en not_active Abandoned
- 1995-06-22 EP EP95925201A patent/EP0769022A1/fr not_active Withdrawn
- 1995-06-22 IL IL11427095A patent/IL114270A0/xx unknown
- 1995-06-22 JP JP8503823A patent/JPH10502623A/ja active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990002198A1 (fr) * | 1988-08-20 | 1990-03-08 | Kabi Pharmacia Ab | Igf-1 o-glycosyle |
| WO1993002695A1 (fr) * | 1991-08-01 | 1993-02-18 | Genentech, Inc. | Igf-1 utilise pour ameliorer l'etat pathologique du systeme nerveux |
Non-Patent Citations (2)
| Title |
|---|
| CHEMICAL ABSTRACTS, Volume 111, No. 11, 11 Sept. 1989, (Columbus, Ohio, USA), GELLERFORS PAER et al., "Isolation and Characterization of A Glycosylated Form of Human Insulin-Like Growth Factor I Produced in Saccharomyces Cerevisiae", page 90588, The Abstract No. 90592g; & J. BIOL. CHEM., 1989, 264(19), 1144. * |
| FEBS LETTERS, Volume 248, No. 1,2, May 1989, KARL HARD et al., "O-Mannosylation of Recombinant Human Insulin-Like Growth Factor I (IGF-I) Produced in Saccharomyces Cerevisiae", pages 111-114. * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996033216A1 (fr) * | 1995-04-21 | 1996-10-24 | Pharmacia & Upjohn Ab | Igf-i tronque |
| US6660279B2 (en) * | 1998-09-01 | 2003-12-09 | Astrazeneca Ab | Stability for injection solutions |
| US6998136B2 (en) | 1998-09-01 | 2006-02-14 | Astrazeneca Ab | Stability for injection solutions |
| EP2241575A1 (fr) * | 2005-01-07 | 2010-10-20 | Regeneron Pharmaceuticals, Inc. | Polypeptides de fusion IGF-1 et utilisations thérapeutiques |
| US8158581B2 (en) | 2005-01-07 | 2012-04-17 | Regeneron Pharmaceuticals, Inc. | IGF-1 fusion polypeptides and therapeutic uses thereof |
| US8445434B2 (en) | 2005-01-07 | 2013-05-21 | Regeneron Pharmaceuticals, Inc. | IGF-1 fusion polypeptides and therapeutic uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0769022A1 (fr) | 1997-04-23 |
| CA2193399A1 (fr) | 1996-01-18 |
| SE9402332D0 (sv) | 1994-07-01 |
| JPH10502623A (ja) | 1998-03-10 |
| IL114270A0 (en) | 1995-10-31 |
| AU2940695A (en) | 1996-01-25 |
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