JP6696915B2 - Ｍｉｃ−１融合タンパク質及びその使用 - Google Patents
Ｍｉｃ−１融合タンパク質及びその使用 Download PDFInfo
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- 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
- C07K14/475—Growth factors; Growth regulators
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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
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- C07—ORGANIC CHEMISTRY
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Landscapes
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP14173664 | 2014-06-24 | ||
| EP14173664.5 | 2014-06-24 | ||
| PCT/EP2015/063596 WO2015197446A1 (en) | 2014-06-24 | 2015-06-17 | Mic-1 fusion proteins and uses thereof |
Publications (3)
| Publication Number | Publication Date |
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| JP2017528419A JP2017528419A (ja) | 2017-09-28 |
| JP2017528419A5 JP2017528419A5 (enExample) | 2018-07-12 |
| JP6696915B2 true JP6696915B2 (ja) | 2020-05-20 |
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| JP2016574944A Expired - Fee Related JP6696915B2 (ja) | 2014-06-24 | 2015-06-17 | Ｍｉｃ−１融合タンパク質及びその使用 |
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| JP (1) | JP6696915B2 (enExample) |
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| AU (1) | AU2015279525A1 (enExample) |
| BR (1) | BR112016029848A2 (enExample) |
| CA (1) | CA2952293A1 (enExample) |
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Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2694092B1 (en) | 2011-04-08 | 2017-01-04 | Amgen Inc. | Method of treating or ameliorating metabolic disorders using growth differentiation factor 15 (gdf-15) |
| US9862752B2 (en) | 2013-07-31 | 2018-01-09 | Amgen Inc. | Growth differentiation factor 15 (GDF-15) constructs |
| US10588980B2 (en) | 2014-06-23 | 2020-03-17 | Novartis Ag | Fatty acids and their use in conjugation to biomolecules |
| JP6946304B2 (ja) | 2015-12-22 | 2021-10-06 | ノバルティス アーゲー | 増殖分化因子１５（ｇｄｆ−１５）を使用して代謝障害を処置するまたは軽快させる方法 |
| US10336812B2 (en) * | 2016-05-10 | 2019-07-02 | Janssen Biotech, Inc. | GDF15 fusion proteins and uses thereof |
| KR102433503B1 (ko) * | 2016-05-24 | 2022-08-18 | 노보 노르디스크 에이/에스 | Mic-1 화합물 및 이것의 사용 |
| GB201615844D0 (en) * | 2016-09-16 | 2016-11-02 | Genagon Therapeutics Ab | Agents for use in therapy |
| US20200069774A1 (en) * | 2016-12-06 | 2020-03-05 | St Vincent's Hospital Sydney Limited | Treatment of obesity and eating disorders |
| GB201700567D0 (en) | 2017-01-12 | 2017-03-01 | Genagon Therapeutics Ab | Therapeutic agents |
| GB201700553D0 (en) * | 2017-01-12 | 2017-03-01 | Genagon Therapeutics Ab | Therapeutic agents |
| JP2020517657A (ja) | 2017-04-20 | 2020-06-18 | ノヴォ ノルディスク アー／エス | アルブミン融合タンパク質の精製方法 |
| TWI710377B (zh) | 2017-05-23 | 2020-11-21 | 丹麥商諾佛 儂迪克股份有限公司 | Ｍｉｃ－１化合物及其用途 |
| CN111163795A (zh) | 2017-09-10 | 2020-05-15 | 诺沃挪第克公司 | 用于治疗肥胖症的mic-1和glp-1 |
| US11913039B2 (en) | 2018-03-30 | 2024-02-27 | Alexion Pharmaceuticals, Inc. | Method for producing recombinant alkaline phosphatase |
| TWI724392B (zh) | 2018-04-06 | 2021-04-11 | 美商美國禮來大藥廠 | 生長分化因子15促效劑化合物及其使用方法 |
| CR20200510A (es) | 2018-04-09 | 2020-11-26 | Amgen Inc | Protreínas de fusión del factor de diferenciación de crecimiento 15 |
| EP3833974A2 (en) | 2018-08-10 | 2021-06-16 | Novartis AG | Gfral extracellular domains and methods of use |
| US12268733B2 (en) | 2018-08-10 | 2025-04-08 | Alexion Pharmaceuticals, Inc. | Methods of treating neurofibromatosis type 1 and related conditions with alkaline phosphatase |
| EA202191105A1 (ru) | 2018-10-22 | 2021-08-03 | Янссен Фармацевтика Нв | Слитые белки, полученные из глюкагоноподобного пептида 1 (glp1) и ростового фактора дифференцировки 15 (gdf15), и их применение |
| EP4041281B1 (en) | 2019-10-04 | 2025-11-26 | Amgen Inc. | Use of gdf15 for treating cardiometabolic syndrome and other conditions |
| CA3161302A1 (en) * | 2019-11-26 | 2021-06-03 | Yuhan Corporation | Long-acting gdf15 fusion protein and pharmaceutical composition comprising same |
| CA3161266A1 (en) * | 2019-12-09 | 2021-06-17 | Alexion Pharmaceuticals, Inc. | Alkaline phosphatase polypeptides and methods of use thereof |
| CA3159979A1 (en) * | 2019-12-11 | 2021-06-17 | Yeonchul Kim | Fusion polypeptide comprising gdf15 and polypeptide region capable of o-glycosylation |
| CN115379850A (zh) * | 2019-12-24 | 2022-11-22 | 裘美娜治疗公司 | 再生性多肽及其用途 |
| EP4085077A4 (en) * | 2019-12-31 | 2024-01-17 | Beijing QL Biopharmaceutical Co., Ltd. | Fusion proteins of glp-1 and gdf15 and conjugates thereof |
| WO2021194257A1 (ko) * | 2020-03-25 | 2021-09-30 | (주) 업테라 | 세포 투과성 펩티드 이량체, 이의 제조방법 및 이를 이용한 카고 전달 시스템 |
| KR102195740B1 (ko) * | 2020-03-25 | 2020-12-28 | 서울대학교산학협력단 | 세포 투과성 펩티드 이량체, 이의 제조방법 및 이를 이용한 카고 전달 시스템 |
| AU2021337652B2 (en) | 2020-09-04 | 2025-01-30 | Alexion Pharmaceuticals, Inc. | Methods for treating bone mineralization disorders |
| EP4237438A4 (en) | 2020-10-27 | 2024-11-27 | Beijing QL Biopharmaceutical Co., Ltd. | GDF15 FUSION PROTEINS AND THEIR USE |
| CN112694520B (zh) * | 2020-12-02 | 2023-01-17 | 图凌(杭州)生物医药有限公司 | 一种人工多肽hm、其抗体及在病理检测中的应用 |
| BR112023016048A2 (pt) | 2021-02-12 | 2023-11-14 | Alexion Pharma Inc | Polipeptídeos de fosfatase alcalina e métodos de uso dos mesmos |
| WO2022219495A1 (en) | 2021-04-12 | 2022-10-20 | Novartis Ag | 2-((4-((s)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((s)-oxetan-2-yl)methyl)-1h-imidazole derivatives as activators of the glp1 receptor for the treatment of obesity |
| EP4476212A1 (en) | 2022-02-10 | 2024-12-18 | Novartis AG | 2-((4-((s)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((s)-oxetan-2-yl)methyl)-1h-imidazole derivatives as activators of the glp1 receptor for the treatment of obesity |
| EP4389762A1 (en) | 2022-12-23 | 2024-06-26 | Ospedale San Raffaele S.r.l. | Inhibitors of dux4 activity and their use in therapy. |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2213743A1 (en) | 2000-04-12 | 2010-08-04 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| CN1241946C (zh) | 2002-07-01 | 2006-02-15 | 美国福源集团 | 对多种细胞具刺激增生作用的人血清白蛋白重组融合蛋白 |
| EP2441466B1 (en) | 2004-04-13 | 2014-07-23 | St Vincent's Hospital Sydney Limited | MIC-1 inhibiting agent |
| EP2194064A1 (en) * | 2004-05-13 | 2010-06-09 | Eli Lilly & Company | FGF-21 fusion proteins |
| EP1771467A2 (en) * | 2004-07-26 | 2007-04-11 | Asterion Limited | Linkers |
| JP2010536341A (ja) | 2007-08-15 | 2010-12-02 | アムニクス， インコーポレイテッド | 生物学的に活性なポリペプチドの特性を改変するための組成物および方法 |
| EP3683228A3 (en) * | 2012-01-26 | 2020-07-29 | Amgen Inc. | Growth differentiation factor 15 (gdf-15) polypeptides |
| CA2862516C (en) | 2012-03-27 | 2023-02-14 | Ngm Biopharmaceuticals, Inc. | Compositions and methods of use for treating metabolic disorders |
| KR101993714B1 (ko) | 2013-01-30 | 2019-06-28 | 엔지엠 바이오파마슈티컬스, 아이엔씨. | 대사 장애를 치료하는데 이용하기 위한 조성물과 방법 |
| US9862752B2 (en) | 2013-07-31 | 2018-01-09 | Amgen Inc. | Growth differentiation factor 15 (GDF-15) constructs |
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- 2015-06-17 EP EP15730140.9A patent/EP3160496B1/en not_active Withdrawn - After Issue
- 2015-06-17 CA CA2952293A patent/CA2952293A1/en not_active Withdrawn
- 2015-06-17 AU AU2015279525A patent/AU2015279525A1/en not_active Withdrawn
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| RU2017101436A (ru) | 2018-07-24 |
| TW201613958A (en) | 2016-04-16 |
| CA2952293A1 (en) | 2015-12-30 |
| JP2017528419A (ja) | 2017-09-28 |
| BR112016029848A2 (pt) | 2017-10-24 |
| CN106459222A (zh) | 2017-02-22 |
| WO2015197446A1 (en) | 2015-12-30 |
| MX2016016063A (es) | 2017-03-10 |
| RU2017101436A3 (enExample) | 2019-02-13 |
| EP3160496B1 (en) | 2021-03-03 |
| EP3160496A1 (en) | 2017-05-03 |
| AU2015279525A1 (en) | 2016-12-15 |
| US9956264B2 (en) | 2018-05-01 |
| US20160129083A1 (en) | 2016-05-12 |
| US20160015784A1 (en) | 2016-01-21 |
| US9272019B2 (en) | 2016-03-01 |
| ZA201608214B (en) | 2018-11-28 |
| KR20170020383A (ko) | 2017-02-22 |
| AR100945A1 (es) | 2016-11-09 |
| IL249327A0 (en) | 2017-02-28 |
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