DK2970422T3 - Il-22-polypeptider og il-22 fc-fusionsproteiner og fremgangsmåder til anvendelse - Google Patents
Il-22-polypeptider og il-22 fc-fusionsproteiner og fremgangsmåder til anvendelse Download PDFInfo
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- DK2970422T3 DK2970422T3 DK14729996.0T DK14729996T DK2970422T3 DK 2970422 T3 DK2970422 T3 DK 2970422T3 DK 14729996 T DK14729996 T DK 14729996T DK 2970422 T3 DK2970422 T3 DK 2970422T3
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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
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
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- 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
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- 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
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- 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
- A61P3/04—Anorexiants; Antiobesity agents
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- 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
- A61P3/06—Antihyperlipidemics
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- 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
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Claims (46)
1. IL-22 Fc-fusionsprotein, som binder til IL-22-receptor, hvilket IL-22 Fc-fusi-onsprotein omfatter et IL-22-polypeptid, som er linket til en Fc-region ved en linker, hvor Fc-regionen omfatter en hinge-region, et IgG CFI2-domæne og et IgG CFI3-domæne, hvor IL-22 Fc-fusionsproteinet omfatter en aminosyrese-kvens, som har mindst 95 % sekvensidentitet med aminosyresekvensen udvalgt fra gruppen bestående af SEQ ID NO:8 og SEQ ID NO: 10, hvor N297-resten er ændret til Gly eller Ala, og hvor Fc-regionen ikke er glykosyleret.
2. IL-22-Fc-fusionsprotein ifølge krav 1, hvor aminosyresekvensen har mindst 96 %, mindst 97 %, mindst 98 % eller mindst 99 % sekvensidentitet med aminosyresekvensen udvalgt fra gruppen bestående af SEQ ID NO:8 og SEQ ID NO:10.
3. IL-22-Fc-fusionsprotein ifølge krav 1 eller 2, hvor linkeren omfatter aminosyresekvensen SKYGPP (SEQ ID NO:43) eller RVESKYGPP (SEQ ID NO:44).
4. IL-22-Fc-fusionsprotein ifølge etaf kravene 1-3, hvor IL-22-Fc-fusionsprote-inet omfatter aminosyresekvensen af SEQ ID NO:8.
5. IL-22-Fc-fusionsprotein ifølge et af kravene 1-3, hvor IL-22-Fc-fusionsprote-inet omfatter aminosyresekvensen af SEQ ID NO:10.
6. IL-22-Fc-fusionsprotein ifølge etaf kravene 1-3, hvor IL-22-Fc-fusionsprote-inet består af aminosyresekvensen af SEQ ID NO:8 eller SEQ ID NO:10.
7. IL-22-Fc-fusionsprotein ifølge etaf kravene 1-6, hvor IL-22-Fc-fusionsprote-inet er fremstillet ved en fremgangsmåde omfattende trinnet med at dyrke en værtscelle, som kan eksprimere IL-22-Fc-fusionsproteinet under betingelser, som er egnede til ekspression af IL-22-Fc-fusionsproteinet, hvor værtscellen omfatter en vektor omfattende en nukleinsyre, der koder IL-22-Fc-fusionspro-teinet, hvor fremgangsmåden eventuelt endvidere omfatter trinnet med at opnå IL-22-Fc-fusionsproteinet fra cellekulturen eller kulturmediet.
8. IL-22- Fc-fusionsprotein ifølge krav 7, hvor værtscellen er en CHO-celle.
9. IL-22-Fc-fusionsprotein ifølge et af kravene 1-8, hvor IL-22-fusionsproteinet er et dimer-IL-22-Fc-fusionsprotein eller er et monomer-IL-22- Fc-fusionspro-tein.
10. IL-22-Fc-fusionsprotein ifølge et af kravene 1-9, hvor IL-22-polypeptidet omfatter aminosyresekvensen af SEQ ID NO:4.
11. Isoleret nukleinsyre, som koder IL-22-Fc-fusionsproteinet ifølge et af kravene 1-10.
12. Isoleret nukleinsyre ifølge krav 11, hvor nukleinsyren koder IL-22-Fc-fusi-onsproteinet, som omfatter eller består af aminosyresekvensen af SEQ ID NO:8 eller SEQ ID NO:10.
13. Isoleret nukleinsyre ifølge krav 11 eller 12, som omfatter eller består af polynukleotidsekvensen af SEQ ID NO:7 eller SEQ ID NO:9.
14. Vektor, som omfatter nukleinsyren ifølge et af kravene 11-13.
15. Værtscelle omfattende vektoren ifølge krav 14.
16. Værtscelle ifølge krav 15, hvor værtscellen er en prokaryotisk celle eller eukaryotisk celle eller en E. coli-celle eller en CHO-celle.
17. Fremgangsmåde til fremstilling af et IL-22-fusionsprotein, omfattende trinnet med at dyrke værtscellen ifølge krav 15 eller 16 under betingelser, som er egnede til ekspression af IL-22-Fc-fusionsproteinet.
18. Fremgangsmåde ifølge krav 17, endvidere omfattende trinnet med at opnå IL-22-Fc-fusionsproteinet fra cellekulturen eller kulturmediet.
19. Fremgangsmåde ifølge krav 17 eller 18, hvor værtscellen er en E. coli-celle.
20. Fremgangsmåde ifølge krav 17 eller 18, hvor værtscellen er en CFIO-celle.
21. Farmaceutisk sammensætning omfattende en terapeutisk virksom mængde af et IL-22 Fc-fusionsprotein ifølge et af kravene 1-10 og mindst en farmaceutisk acceptabel bærer.
22. Farmaceutisk sammensætning ifølge krav 21, hvor IL-22 Fc-fusionsprote-inet omfatter eller består af aminosyresekvensen af SEQ ID NO:8 eller SEQ ID NO:10.
23. Farmaceutisk sammensætning ifølge et af kravene 21-22, hvor IL-22 Fc-fusionsproteinet er fremstillet i en CHO-celle.
24. Farmaceutisk sammensætning ifølge et af kravene 21-23, endvidere omfattende et yderligere terapeutisk middel.
25. Farmaceutisk sammensætning ifølge krav 21, hvor den farmaceutiske acceptable bærer er et geleringsmiddel.
26. Farmaceutisk sammensætning ifølge krav 25, hvor geleringsmidlet er (i) et polysaccharid, (ii) et cellulosemiddel, (iii) methylcellulose, hydroxyethylcellu-lose, carboxymethylcellulose, hydroxypropylcellulose, POE-POP-blokpolyme-rer, alginat, hyaluronsyre, polyacrylsyre, hydroxyethylmethylcellulose eller hy-droxypropylmethylcellulose eller (iv) hydroxypropylmethylcellulose.
27. Farmaceutisk sammensætning ifølge et af kravene 25-26, hvor den farmaceutiske sammensætning er til topisk indgivelse.
28. Farmaceutisk sammensætning omfattende IL-22 Fc-fusionsproteinet ifølge et af kravene 1-10 eller farmaceutisk sammensætning ifølge et af kravene 21-24, til anvendelse i en fremgangsmåde til: (a) behandling af en inflammatorisk tarmsygdom (IBD) i et individ med behov herfor; (b) inhibering af mikrobiel infektion i tarmen, bevaring af bægerceller i tarmen under den mikrobielle infektion, forbedring af epitelcelleintegritet, epitelcelle-proliferation, epitelcelledifferentiering, epitelcellemigration eller epitel sårbehandling i tarmen, i et individ med behov herfor; (c) behandling af akut nyreskade eller akut pancreatitis i et individ med behov herfor; (d) forebyggelse eller behandling af en kardiovaskulær tilstand, hvilken tilstand omfatter en patologi af aterosklerotisk plakdannelse, i et individ med behov herfor; (e) behandling af metabolisk syndrom i et individ med behov herfor; eller (f) behandling af akut endotoksæmi, sepsis eller begge, i et individ med behov herfor.
29. Farmaceutisk sammensætning til anvendelse ifølge krav 28(a), hvor IBD'et er ulcerøs kolitis eller Crohns sygdom.
30. Farmaceutisk sammensætning til anvendelse ifølge krav 28(b), hvor epitelcellen er en intestinal epitelcelle.
31. Farmaceutisk sammensætning til anvendelse ifølge krav 28(d), (i) hvor den kardiovaskulære tilstand er udvalgt fra gruppen bestående af koronar aterie-sygdom, koronar mikrovaskulær sygdom, slagtilfælde, carotis- arteriesygdom, perifer arteriesygdom og kronisk nyresygdom; (ii) endvidere omfattende forsinkelsen af progressionen af aterosklerotisk plakdannelse eller forebyggelse af tegn på aterosklerose, hvor eventuelt tegnene på aterosklerose omfatter plakakkumulation eller vaskulær inflammation; eller (iii) hvor det er blevet konstateret, at individet er i risiko for at udvikle en kardiovaskulær tilstand.
32. Farmaceutisk sammensætning til anvendelse ifølge krav 28(e), endvidere omfattende reduktion af en eller flere risikofaktorer associeret med metabolisk syndrom, herunder en eller flere af abdominal obesitet, hyperglykæmi, dysli-pidæmi og forhøjet blodtryk.
33. Farmaceutisk sammensætning til anvendelse ifølge krav 28(e) eller 32, endvidere omfattende reduktion af niveauet af bakterielt lipopolysaccharid (LPS) i individet.
34. Farmaceutisk sammensætning til anvendelse ifølge et af kravene 28(e) eller (f), 32 eller 33, hvor individet har behov for en ændring i HDL/LDL-lipidpro-filen.
35. Farmaceutisk sammensætning til anvendelse ifølge et af kravene 28-34, hvor den farmaceutiske sammensætning omfatter et IL-22 Fc- fusionsprotein omfattende eller bestående af aminosyresekvensen af SEQ ID NO:8 eller SEQ ID NO:10.
36. Farmaceutisk sammensætning til anvendelse ifølge et af kravene 28-35, hvor individet får co-indgivet mindst et yderligere terapeutisk middel.
37. Farmaceutisk sammensætning til anvendelse ifølge et af kravene 28-36, hvor den farmaceutiske sammensætning indgives intravenøst, subkutant eller intraperitonealt.
38. Farmaceutisk sammensætning omfattende IL-22 Fc-fusionsproteinet ifølge et af kravene 1-10 eller farmaceutisk sammensætning ifølge et af kravene 21-27, til anvendelse i en fremgangsmåde til fremskyndelse eller forbedring af sårheling i et individ.
39. Farmaceutisk sammensætning til anvendelse ifølge krav 38, hvor såret er et kronisk sår eller et inficeret sår.
40. Farmaceutisk sammensætning til anvendelse ifølge et af kravene 38-39, hvor individet er diabetisk, hvor eventuelt det diabetiske individ har type II diabetes.
41. Farmaceutisk sammensætning til anvendelse ifølge et af kravene 38-40, hvor såret er et diabetisk fodsår.
42. Farmaceutisk sammensætning til anvendelse ifølge et af kravene 38-41, hvor den farmaceutiske sammensætning indgives, indtil der er en komplet sårlukning.
43. Farmaceutisk sammensætning til anvendelse ifølge et af kravene 38-42, hvor IL-22 Fc fusionsproteinet omfatter eller består af aminosyresekvensen udvalgt fra gruppen bestående af SEQ ID NO:8 og SEQ ID NO:10.
44. Farmaceutisk sammensætning til anvendelse ifølge et af kravene 38-43, hvor individet får co-indgivet mindst et yderligere terapeutisk middel til fremskyndelse eller forbedring af sårheling.
45. Farmaceutisk sammensætning til anvendelse ifølge et af kravene 38-44, hvor den farmaceutiske sammensætning indgives intravenøst, subkutant, intraperitonealt eller topisk.
46. Farmaceutisk sammensætning til anvendelse ifølge et af kravene 28-45, hvor individet er et menneske.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361800148P | 2013-03-15 | 2013-03-15 | |
US201361800795P | 2013-03-15 | 2013-03-15 | |
US201361801144P | 2013-03-15 | 2013-03-15 | |
US201361821062P | 2013-05-08 | 2013-05-08 | |
US201361860176P | 2013-07-30 | 2013-07-30 | |
PCT/US2014/029652 WO2014145016A2 (en) | 2013-03-15 | 2014-03-14 | Il-22 polypeptides and il-22 fc fusion proteins and methods of use |
Publications (1)
Publication Number | Publication Date |
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DK2970422T3 true DK2970422T3 (da) | 2018-07-16 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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DK14729996.0T DK2970422T3 (da) | 2013-03-15 | 2014-03-14 | Il-22-polypeptider og il-22 fc-fusionsproteiner og fremgangsmåder til anvendelse |
Country Status (29)
Country | Link |
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US (12) | US10160793B2 (da) |
EP (2) | EP3385277A1 (da) |
JP (3) | JP6456356B2 (da) |
KR (1) | KR102426481B1 (da) |
CN (1) | CN105143252A (da) |
AU (3) | AU2014233494B2 (da) |
BR (1) | BR112015023140A8 (da) |
CA (1) | CA2903587C (da) |
CL (1) | CL2015002654A1 (da) |
DK (1) | DK2970422T3 (da) |
EA (1) | EA035645B1 (da) |
ES (1) | ES2676023T3 (da) |
HK (1) | HK1218424A1 (da) |
HR (1) | HRP20181090T1 (da) |
HU (1) | HUE039291T2 (da) |
LT (1) | LT2970422T (da) |
MX (2) | MX368005B (da) |
PE (2) | PE20151673A1 (da) |
PH (2) | PH12015502125A1 (da) |
PL (1) | PL2970422T3 (da) |
PT (1) | PT2970422T (da) |
RS (1) | RS57393B1 (da) |
SG (2) | SG11201507429TA (da) |
SI (1) | SI2970422T1 (da) |
TR (1) | TR201809571T4 (da) |
TW (2) | TWI772250B (da) |
UA (1) | UA118843C2 (da) |
WO (1) | WO2014145016A2 (da) |
ZA (1) | ZA201506297B (da) |
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AU2014346554B2 (en) * | 2013-11-07 | 2020-06-04 | Evive Biotechnology (Shanghai) Ltd | Methods of use for IL-22 in the treatment of gastrointestinal graft vs. host disease |
CN104623637A (zh) | 2013-11-07 | 2015-05-20 | 健能隆医药技术(上海)有限公司 | Il-22二聚体在制备静脉注射药物中的应用 |
UA123432C2 (uk) | 2014-07-30 | 2021-04-07 | Нджм Біофармасьютікалз, Інк. | Димер та спосіб його застосування для лікування метаболічних розладів |
AU2015339130C1 (en) | 2014-10-31 | 2021-03-18 | Ngm Biopharmaceuticals, Inc. | Compositions and methods of use for treating metabolic disorders |
US11566082B2 (en) | 2014-11-17 | 2023-01-31 | Cytiva Bioprocess R&D Ab | Mutated immunoglobulin-binding polypeptides |
WO2016108130A1 (en) * | 2014-12-30 | 2016-07-07 | Sun Pharmaceutical Industries Limited | Topical pharmaceutical compositions comprising nebivolol for the treatment of diabetic wounds |
MY188430A (en) | 2015-04-10 | 2021-12-08 | Amgen Inc | Interleukin-2 muteins for the expansion of t-regulatory cells |
CN106317225A (zh) * | 2015-06-28 | 2017-01-11 | 复旦大学 | 具有靶向性长效白细胞介素22融合蛋白及其制备方法和用途 |
ES2778430T3 (es) * | 2015-07-16 | 2020-08-10 | Philogen Spa | Inmunoconjugados de IL22 |
AU2016304764C1 (en) | 2015-08-07 | 2023-06-01 | Imaginab, Inc. | Antigen binding constructs to target molecules |
EP3167892A1 (en) | 2015-11-10 | 2017-05-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for preventing or treating imflammatory bowel diseases |
MY194669A (en) | 2016-03-31 | 2022-12-12 | Ngm Biopharmaceuticals Inc | Binding Proteins and Methods of use Thereof |
WO2017181143A1 (en) | 2016-04-15 | 2017-10-19 | Generon (Shanghai) Corporation, Ltd. | Use of il-22 in treating necrotizing enterocolitis |
WO2017191817A1 (ja) * | 2016-05-02 | 2017-11-09 | 味の素株式会社 | アジド基含有Fcタンパク質 |
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