JP6687526B2 - ＮＧＦアンタゴニストドメインおよびＴＮＦαアンタゴニストドメインから構成されるキメラタンパク質 - Google Patents
ＮＧＦアンタゴニストドメインおよびＴＮＦαアンタゴニストドメインから構成されるキメラタンパク質 Download PDFInfo
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Classifications
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C07K14/475—Growth factors; Growth regulators
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
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- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
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- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
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- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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- C07K2317/565—Complementarity determining region [CDR]
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- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/32—Fusion polypeptide fusions with soluble part of a cell surface receptor, "decoy receptors"
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/35—Fusion polypeptide containing a fusion for enhanced stability/folding during expression, e.g. fusions with chaperones or thioredoxin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
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- Biophysics (AREA)
- Molecular Biology (AREA)
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- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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| US201461934828P | 2014-02-02 | 2014-02-02 | |
| US61/934,828 | 2014-02-02 | ||
| PCT/EP2015/052098 WO2015114150A1 (en) | 2014-02-02 | 2015-02-02 | Chimeric protein composed of ngf antagonist domain and a tnfa antagonist domain |
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| JP2020065513A Division JP7074792B2 (ja) | 2014-02-02 | 2020-04-01 | ＮＧＦアンタゴニストドメインおよびＴＮＦαアンタゴニストドメインから構成されるキメラタンパク質 |
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| JP2020065513A Active JP7074792B2 (ja) | 2014-02-02 | 2020-04-01 | ＮＧＦアンタゴニストドメインおよびＴＮＦαアンタゴニストドメインから構成されるキメラタンパク質 |
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| JP2024109298A Pending JP2024133644A (ja) | 2014-02-02 | 2024-07-08 | ＮＧＦアンタゴニストドメインおよびＴＮＦαアンタゴニストドメインから構成されるキメラタンパク質 |
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| JP2022077858A Active JP7520070B2 (ja) | 2014-02-02 | 2022-05-11 | ＮＧＦアンタゴニストドメインおよびＴＮＦαアンタゴニストドメインから構成されるキメラタンパク質 |
| JP2024109298A Pending JP2024133644A (ja) | 2014-02-02 | 2024-07-08 | ＮＧＦアンタゴニストドメインおよびＴＮＦαアンタゴニストドメインから構成されるキメラタンパク質 |
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Cited By (1)
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| JP2022106951A (ja) * | 2014-02-02 | 2022-07-20 | メドイミューン・リミテッド | ＮＧＦアンタゴニストドメインおよびＴＮＦαアンタゴニストドメインから構成されるキメラタンパク質 |
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| US9862760B2 (en) * | 2015-09-16 | 2018-01-09 | Novartis Ag | Polyomavirus neutralizing antibodies |
| SG11202001772SA (en) | 2017-09-21 | 2020-04-29 | Merck Patent Gmbh | Fusion protein comprising an fgf-18 moiety |
| WO2021142573A1 (zh) * | 2020-01-13 | 2021-07-22 | 丁邦 | 一种融合蛋白及其制法和用途 |
| KR20230084199A (ko) * | 2020-09-28 | 2023-06-12 | 메디뮨 리미티드 | 통증 치료를 위한 화합물 및 방법 |
| CN114574444B (zh) * | 2020-12-01 | 2024-05-03 | 达达生物技术(北京)有限公司 | 自体纤维母细胞在制备抗类风湿关节炎药物中的应用 |
| TWI821881B (zh) * | 2021-01-29 | 2023-11-11 | 醫研生物科技有限公司 | 腫瘤壞死因子α重組抗體及其用途 |
| CN116179667A (zh) * | 2022-09-21 | 2023-05-30 | 福建中妆技术研究有限公司 | 基于斑马鱼模型中trpv1信号通路筛选皮肤疼痛舒缓原料的试剂盒及应用 |
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| US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
| DE10399023I2 (de) | 1989-09-12 | 2006-11-23 | Ahp Mfg B V | TFN-bindende Proteine |
| US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
| US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
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| US20040220103A1 (en) | 1999-04-19 | 2004-11-04 | Immunex Corporation | Soluble tumor necrosis factor receptor treatment of medical disorders |
| DE19926068C1 (de) * | 1999-06-08 | 2001-01-11 | Arne Skerra | Muteine des Bilin-Bindungsproteins |
| CN1684708A (zh) | 2001-05-30 | 2005-10-19 | 基因技术股份有限公司 | 抗ngf抗体用于治疗各种疾病 |
| GB0216648D0 (en) | 2002-07-18 | 2002-08-28 | Lonza Biologics Plc | Method of expressing recombinant protein in CHO cells |
| ZA200502612B (en) | 2002-10-08 | 2007-07-25 | Rinat Neuroscience Corp | Methods for treating post-surgical pain by administering a nerve crowth factor antagonist and compositions containing the same |
| US7569364B2 (en) * | 2002-12-24 | 2009-08-04 | Pfizer Inc. | Anti-NGF antibodies and methods using same |
| WO2005075514A2 (en) | 2004-03-10 | 2005-08-18 | Lonza Ltd. | Method for producing antibodies |
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| RU2406728C2 (ru) | 2005-01-24 | 2010-12-20 | Медиммун Лимитэд | Партнеры специфического связывания с ngf |
| CN105837690A (zh) | 2006-06-12 | 2016-08-10 | 新兴产品开发西雅图有限公司 | 具有效应功能的单链多价结合蛋白 |
| GB0624500D0 (en) * | 2006-12-07 | 2007-01-17 | Istituto Superiore Di Sanito | A novel passive vaccine for candida infections |
| US7691980B2 (en) | 2007-01-09 | 2010-04-06 | Bio-Rad Laboratories, Inc. | Enhanced capacity and purification of antibodies by mixed mode chromatography in the presence of aqueous-soluble nonionic organic polymers |
| MX2009012343A (es) * | 2007-05-14 | 2010-02-10 | Biogen Idec Inc | Regiones fc (sc fc) de cadena sencilla, polipeptidos de enlace que comprenden las mismas, y metodos relacionados con ello. |
| WO2009092014A1 (en) | 2008-01-18 | 2009-07-23 | Gagnon Peter S | Enhanced purification of antibodies and antibody fragments by apatite chromatography |
| SG191639A1 (en) | 2008-06-03 | 2013-07-31 | Abbott Lab | Dual variable domain immunoglobulins and uses thereof |
| MX2010014574A (es) * | 2008-07-08 | 2011-04-27 | Abbott Lab | Inmunoglobulinas de dominio variable dual para prostaglandina e2 y usos de las mismas. |
| JP2011016676A (ja) * | 2009-07-07 | 2011-01-27 | Sumitomo Electric Ind Ltd | 窒化物半導体基板の製造方法 |
| AR078651A1 (es) * | 2009-10-15 | 2011-11-23 | Abbott Lab | Inmunoglobulinas con dominio variable dual y usos de las mismas |
| RU2012127383A (ru) | 2009-12-02 | 2014-01-10 | Акселерон Фарма Инк. | Композиции и способы для увеличения времени полужизни fc-слитых белков в сыворотке |
| JP2013523153A (ja) * | 2010-04-07 | 2013-06-17 | アッヴィ・インコーポレイテッド | ＴＮＦ−α結合タンパク質 |
| DK2714738T3 (en) * | 2011-05-24 | 2019-01-28 | Zyngenia Inc | MULTIVALENT AND MONOVALENT MULTISPECIFIC COMPLEXES AND THEIR APPLICATIONS |
| CA2854806A1 (en) | 2011-11-07 | 2013-05-16 | Medimmune, Llc | Multispecific and multivalent binding proteins and uses thereof |
| US20130171059A1 (en) | 2011-12-30 | 2013-07-04 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
| WO2014106001A2 (en) * | 2012-12-28 | 2014-07-03 | Abbvie, Inc. | Dual specific binding proteins having a receptor sequence |
| RU2015143833A (ru) | 2013-03-15 | 2017-04-21 | Эббви Инк. | СВЯЗЫВАЮЩИЕ БЕЛКИ С ДВОЙНОЙ СПЕЦИФИЧНОСТЬЮ, НАПРАВЛЕННЫЕ ПРОТИВ TNFα |
| CA2938066C (en) | 2014-02-02 | 2025-05-06 | Medimmune Limited | CHIMERIC PROTEIN COMPOSED OF NERVE GROWTH FACTOR ANTAGONIST DOMAIN AND TUMOR NECROSIS FACTOR-ANTAGONIST DOMAIN-A |
| CA2874083C (en) * | 2014-12-05 | 2024-01-02 | Universite Laval | Tdp-43-binding polypeptides useful for the treatment of neurodegenerative diseases |
| US20210009671A1 (en) | 2019-05-10 | 2021-01-14 | Medimmune Limited | Compounds and methods for treating pain |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2022106951A (ja) * | 2014-02-02 | 2022-07-20 | メドイミューン・リミテッド | ＮＧＦアンタゴニストドメインおよびＴＮＦαアンタゴニストドメインから構成されるキメラタンパク質 |
| JP7520070B2 (ja) | 2014-02-02 | 2024-07-22 | メドイミューン・リミテッド | ＮＧＦアンタゴニストドメインおよびＴＮＦαアンタゴニストドメインから構成されるキメラタンパク質 |
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