CN103275216B - 单链抗体的基于序列的工程改造和最优化 - Google Patents
单链抗体的基于序列的工程改造和最优化 Download PDFInfo
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- CN103275216B CN103275216B CN201310170015.8A CN201310170015A CN103275216B CN 103275216 B CN103275216 B CN 103275216B CN 201310170015 A CN201310170015 A CN 201310170015A CN 103275216 B CN103275216 B CN 103275216B
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- 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
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/241—Tumor Necrosis Factors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/567—Framework region [FR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- 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)
-
- 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
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
Description
Claims (14)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US90636507P | 2007-03-12 | 2007-03-12 | |
US60/906,365 | 2007-03-12 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2008800079463A Division CN101668771B (zh) | 2007-03-12 | 2008-03-12 | 单链抗体的基于序列的工程改造和最优化 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103275216A CN103275216A (zh) | 2013-09-04 |
CN103275216B true CN103275216B (zh) | 2015-05-06 |
Family
ID=39586970
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310170015.8A Active CN103275216B (zh) | 2007-03-12 | 2008-03-12 | 单链抗体的基于序列的工程改造和最优化 |
CN2008800079463A Active CN101668771B (zh) | 2007-03-12 | 2008-03-12 | 单链抗体的基于序列的工程改造和最优化 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2008800079463A Active CN101668771B (zh) | 2007-03-12 | 2008-03-12 | 单链抗体的基于序列的工程改造和最优化 |
Country Status (12)
Country | Link |
---|---|
US (2) | US8280711B2 (zh) |
EP (2) | EP2118138A1 (zh) |
JP (1) | JP5622397B2 (zh) |
CN (2) | CN103275216B (zh) |
AU (1) | AU2008226067B2 (zh) |
CA (1) | CA2680564C (zh) |
HK (1) | HK1138602A1 (zh) |
IL (1) | IL200710A (zh) |
IN (1) | IN2009DN05758A (zh) |
NZ (1) | NZ579594A (zh) |
RU (2) | RU2009137582A (zh) |
WO (1) | WO2008110348A1 (zh) |
Families Citing this family (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ579594A (en) | 2007-03-12 | 2012-03-30 | Esbatech Alcon Biomed Res Unit | Sequence based engineering and optimization of single chain antibodies |
CA2689941C (en) | 2007-06-25 | 2019-10-29 | Esbatech Ag | Methods of modifying antibodies, and modified antibodies with improved functional properties |
DK2164961T3 (en) | 2007-06-25 | 2015-03-02 | Esbatech Alcon Biomed Res Unit | Sequence based forward position and optimization of single chain antibodies |
CN102164958A (zh) | 2008-06-25 | 2011-08-24 | 艾斯巴技术,爱尔康生物医药研究装置有限责任公司 | 使用通用抗体构架进行的兔抗体的人源化 |
US8349322B2 (en) | 2008-06-25 | 2013-01-08 | ESBATech, an Alcon Biomedical Research Unit, LLC | Stable and soluble antibodies inhibiting VEGF |
CA2728829C (en) | 2008-06-25 | 2018-01-02 | Esbatech, An Alcon Biomedical Research Unit Llc | Solubility optimization of immunobinders |
ES2687259T5 (es) | 2008-06-25 | 2022-10-14 | Novartis Ag | Anticuerpos estables y solubles que inhiben TNF |
MX347291B (es) | 2009-03-20 | 2017-04-17 | Amgen Inc | Inmunoglobulinas portadoras y usos de las mismas. |
US8399624B1 (en) | 2009-06-25 | 2013-03-19 | Esbatech, An Alcon Biomedical Research Unit Llc | Acceptor framework for CDR grafting |
TW201129379A (en) | 2009-11-20 | 2011-09-01 | Amgen Inc | Anti-Orai1 antigen binding proteins and uses thereof |
EA201370076A1 (ru) | 2010-09-22 | 2013-08-30 | Амген Инк. | Иммуноглобулины-переносчики и их применение |
UY33679A (es) | 2010-10-22 | 2012-03-30 | Esbatech | Anticuerpos estables y solubles |
GB201310859D0 (en) * | 2013-06-18 | 2013-07-31 | Cambridge Entpr Ltd | Rational method for solubilising proteins |
JP6580570B2 (ja) * | 2013-09-06 | 2019-09-25 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | 抗体安定性を向上させるための方法 |
JP6956631B2 (ja) | 2014-09-15 | 2021-11-02 | アムジェン インコーポレイテッド | 二重特異性抗cgrp受容体/pac1受容体抗原結合タンパク質及びその使用 |
AU2016323440B2 (en) | 2015-09-15 | 2023-07-13 | Amgen Inc. | Tetravalent bispecific and tetraspecific antigen binding proteins and uses thereof |
MA43567A (fr) | 2015-12-15 | 2018-11-14 | Amgen Inc | Anticorps pacap et leurs utilisations |
AU2017356317A1 (en) | 2016-11-14 | 2019-05-30 | Amgen Inc. | Bispecific or biparatopic antigen binding proteins and uses thereof |
JP7339262B2 (ja) | 2018-01-12 | 2023-09-05 | アムジェン インコーポレイテッド | Pac1抗体及びその使用 |
CN112292394A (zh) * | 2018-06-08 | 2021-01-29 | 文塔纳医疗系统公司 | 用于改善的功能性和可制造性的通用或归一化抗体框架 |
KR20220016139A (ko) | 2019-05-30 | 2022-02-08 | 암젠 인크 | 항체 이량체화를 유도하기 위한 경첩 영역 조작 |
JP2022538232A (ja) | 2019-06-28 | 2022-09-01 | アムジエン・インコーポレーテツド | 抗cgrp受容体/抗pac1受容体二重特異性抗原結合タンパク質 |
US20220389119A1 (en) | 2019-11-08 | 2022-12-08 | Amgen Inc. | ENGINEERING CHARGE PAIR MUTATIONS FOR PAIRING OF HETERO-IgG MOLECULES |
JP2023501717A (ja) | 2019-11-19 | 2023-01-18 | アムジエン・インコーポレーテツド | 新規の多重特異性抗体フォーマット |
MX2022007688A (es) | 2019-12-20 | 2022-07-19 | Amgen Inc | Constructos de anticuerpo multiespecificos agonistas de cd40 dirigidos a mesotelina para el tratamiento de tumores solidos. |
EP4200338A1 (en) | 2020-08-20 | 2023-06-28 | Amgen Inc. | Antigen binding proteins with non-canonical disulfide in fab region |
US20230374162A1 (en) | 2020-10-07 | 2023-11-23 | Amgen Inc. | Rational selection of building blocks for the assembly of multispecific antibodies |
AU2021379598A1 (en) | 2020-11-10 | 2023-06-08 | Amgen Inc. | Novel linkers of multispecific antigen binding domains |
AU2022219517A1 (en) | 2021-02-12 | 2023-07-13 | Boehringer Ingelheim International Gmbh | Complement c3 antigen binding proteins |
WO2022190007A1 (en) | 2021-03-09 | 2022-09-15 | Cdr-Life Ag | Rabbit-derived antigen binding protein nucleic acid libraries |
KR20230169944A (ko) | 2021-03-09 | 2023-12-18 | 씨디알-라이프 아게 | Mage-a4 펩티드-mhc 항원 결합 단백질 |
WO2022225921A1 (en) | 2021-04-20 | 2022-10-27 | Amgen Inc. | Balanced charge distribution in electrostatic steering of chain pairing in multi-specific and monovalent igg molecule assembly |
WO2023110918A1 (en) | 2021-12-14 | 2023-06-22 | Cdr-Life Ag | Dual mhc-targeting t cell engager |
US20240091262A1 (en) | 2022-09-14 | 2024-03-21 | Cdr-Life Ag | Mage-a4 peptide dual t cell engagers |
Family Cites Families (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69233482T2 (de) | 1991-05-17 | 2006-01-12 | Merck & Co., Inc. | Verfahren zur Verminderung der Immunogenität der variablen Antikörperdomänen |
US5824307A (en) | 1991-12-23 | 1998-10-20 | Medimmune, Inc. | Human-murine chimeric antibodies against respiratory syncytial virus |
US5714350A (en) | 1992-03-09 | 1998-02-03 | Protein Design Labs, Inc. | Increasing antibody affinity by altering glycosylation in the immunoglobulin variable region |
US5736137A (en) | 1992-11-13 | 1998-04-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
DK0669836T3 (da) | 1992-11-13 | 1996-10-14 | Idec Pharma Corp | Terapeutisk anvendelse af kimære og radioaktivt mærkede antistoffer og humant B-lymfocytbegrænset differentieringsantigen til behandling af B-cellelymfom |
DK0698097T3 (da) | 1993-04-29 | 2001-10-08 | Unilever Nv | Produktion af antistoffer eller (funktionaliserede) fragmenter deraf afledt af Camelidae-immunoglobuliner med tung kæde |
US6740734B1 (en) | 1994-01-14 | 2004-05-25 | Biovitrum Ab | Bacterial receptor structures |
HU230048B1 (hu) | 1996-02-09 | 2015-06-29 | Abbvie Biotechnology Ltd | Humán TNFalfa-kötő antitestek alkalmazása |
CN1062312C (zh) * | 1996-11-29 | 2001-02-21 | 中国科学院微生物研究所 | 抗ⅳ型胶原酶单链抗体 |
US6884879B1 (en) | 1997-04-07 | 2005-04-26 | Genentech, Inc. | Anti-VEGF antibodies |
ES2301198T3 (es) | 1997-06-12 | 2008-06-16 | Novartis International Pharmaceutical Ltd. | Polipeptidos artificiales de anticuerpos. |
DE19742706B4 (de) | 1997-09-26 | 2013-07-25 | Pieris Proteolab Ag | Lipocalinmuteine |
EP1946775A3 (en) | 1998-08-11 | 2008-08-06 | Biogen Idec Inc. | Combination therapies for B-cell lymphomas comprising administration of anti-CD20 antibody |
US6818418B1 (en) | 1998-12-10 | 2004-11-16 | Compound Therapeutics, Inc. | Protein scaffolds for antibody mimics and other binding proteins |
ATE270905T1 (de) | 1998-12-14 | 2004-07-15 | Osteotech Inc | Knochentransplantat aus knochenpartikel |
CN1232039A (zh) * | 1999-04-02 | 1999-10-20 | 中国人民解放军海军总医院 | 一种基因工程双特异抗体及其应用 |
SE9901379D0 (sv) | 1999-04-19 | 1999-04-19 | Pharmacia & Upjohn Ab | Receptor structures |
US6602977B1 (en) | 1999-04-19 | 2003-08-05 | Biovitrum Ab | Receptor structures |
EP1242457B1 (en) | 1999-12-28 | 2004-08-11 | Esbatech AG | Intrabodies with defined framework that is stable in a reducing environment and applications thereof |
ES2376725T3 (es) | 2000-05-10 | 2012-03-16 | Mayo Foundation For Medical Education And Research | Anticuerpos IgM humanos con la capacidad de inducir remielinización y usos diagnósticos y terapéuticos de los mismos, particularmente en el sistema nervioso central |
DE60140474D1 (de) | 2000-09-08 | 2009-12-24 | Univ Zuerich | Sammlung von proteinen mit sich wiederholenden sequenzen (repeat proteins), die repetitive sequenzmodule enthalten |
US7396917B2 (en) | 2000-12-05 | 2008-07-08 | Alexion Pharmaceuticals, Inc. | Rationally designed antibodies |
DK1390535T3 (da) | 2001-04-26 | 2010-12-06 | Amgen Mountain View Inc | Kombinatoriske biblioteker af monomer-domæner |
US20030157561A1 (en) | 2001-11-19 | 2003-08-21 | Kolkman Joost A. | Combinatorial libraries of monomer domains |
US20060127893A1 (en) * | 2001-07-19 | 2006-06-15 | Stefan Ewert | Modification of human variable domains |
ES2399617T3 (es) * | 2002-05-22 | 2013-04-02 | Esbatech - A Novartis Company Llc | Regiones de marco de inmunoglobulina que demuestran estabilidad potenciada en el entorno intracelulcar y métodos de identificación de las mismas |
US20050033029A1 (en) | 2003-06-30 | 2005-02-10 | Jin Lu | Engineered anti-target immunoglobulin derived proteins, compositions, methods and uses |
EP1658308A1 (en) | 2003-08-25 | 2006-05-24 | Pieris ProteoLab AG | Muteins of a bilin-binding protein with affinity for a given target |
RU2006122946A (ru) | 2003-11-28 | 2008-01-10 | Астразенека Аб (Se) | Антитела |
EP1773872B1 (en) | 2004-05-21 | 2017-03-15 | The Uab Research Foundation | Variable lymphocyte receptors, related polypeptides and nucleic acids, and uses thereof |
GB0416651D0 (en) | 2004-07-26 | 2004-08-25 | Proteo Target Aps | Polypeptide |
WO2006040153A2 (en) * | 2004-10-13 | 2006-04-20 | Ablynx N.V. | Single domain camelide anti -amyloid beta antibodies and polypeptides comprising the same for the treatment and diagnosis of degenarative neural diseases such as alzheimer's disease |
US7462697B2 (en) | 2004-11-08 | 2008-12-09 | Epitomics, Inc. | Methods for antibody engineering |
WO2006131013A2 (en) | 2005-06-07 | 2006-12-14 | Esbatech Ag | STABLE AND SOLUBLE ANTIBODIES INHIBITING TNFα |
PT1963368E (pt) | 2005-12-13 | 2012-09-14 | Lilly Co Eli | Anticorpos anti-il-17 |
JP2009542232A (ja) | 2006-07-10 | 2009-12-03 | エスバテック・アーゲー | 上皮および/または内皮層を通過するscFv抗体 |
NZ579594A (en) | 2007-03-12 | 2012-03-30 | Esbatech Alcon Biomed Res Unit | Sequence based engineering and optimization of single chain antibodies |
DK2164961T3 (en) * | 2007-06-25 | 2015-03-02 | Esbatech Alcon Biomed Res Unit | Sequence based forward position and optimization of single chain antibodies |
CA2689941C (en) | 2007-06-25 | 2019-10-29 | Esbatech Ag | Methods of modifying antibodies, and modified antibodies with improved functional properties |
-
2008
- 2008-03-12 NZ NZ579594A patent/NZ579594A/en not_active IP Right Cessation
- 2008-03-12 WO PCT/EP2008/001958 patent/WO2008110348A1/en active Application Filing
- 2008-03-12 JP JP2009553071A patent/JP5622397B2/ja active Active
- 2008-03-12 RU RU2009137582/10A patent/RU2009137582A/ru unknown
- 2008-03-12 CN CN201310170015.8A patent/CN103275216B/zh active Active
- 2008-03-12 AU AU2008226067A patent/AU2008226067B2/en not_active Ceased
- 2008-03-12 IN IN5758DEN2009 patent/IN2009DN05758A/en unknown
- 2008-03-12 CN CN2008800079463A patent/CN101668771B/zh active Active
- 2008-03-12 CA CA2680564A patent/CA2680564C/en not_active Expired - Fee Related
- 2008-03-12 EP EP08716464A patent/EP2118138A1/en not_active Withdrawn
- 2008-03-12 US US12/530,756 patent/US8280711B2/en active Active
- 2008-03-12 EP EP17159837.8A patent/EP3202786A3/en not_active Withdrawn
-
2009
- 2009-09-03 IL IL200710A patent/IL200710A/en active IP Right Grant
-
2010
- 2010-04-21 HK HK10103877.0A patent/HK1138602A1/xx unknown
-
2012
- 2012-08-23 US US13/592,885 patent/US9938336B2/en active Active
-
2014
- 2014-07-03 RU RU2014127308A patent/RU2014127308A/ru not_active Application Discontinuation
Non-Patent Citations (3)
Title |
---|
Altering the fine specificity of an anti-legionella single chain antibody by a single amino acid insertion;Barry J McCarthy et al;《Journal of Immunological Methods》;20011231;第251卷;137-149 * |
Disrupting the hydrophobic patches at the antibody variable/constant domain interface:improved in vivo folding and physical characterization of an engineered scFv fragment;Lars Nieba et al;《Protein Engineering》;19971231;第10卷(第4期);435-444 * |
Stability improvement of antibodies for extracellular and intracellular applications:CDR grafting to stable frameworks and structure-based framework engineering;Stefan Ewert et al;《Methods》;20040715;第34卷;184-199 * |
Also Published As
Publication number | Publication date |
---|---|
IL200710A (en) | 2014-07-31 |
US8280711B2 (en) | 2012-10-02 |
US20100137150A1 (en) | 2010-06-03 |
CA2680564A1 (en) | 2008-09-18 |
WO2008110348A1 (en) | 2008-09-18 |
US20130053259A1 (en) | 2013-02-28 |
IN2009DN05758A (zh) | 2015-07-24 |
CA2680564C (en) | 2018-05-01 |
RU2014127308A (ru) | 2016-02-10 |
AU2008226067A1 (en) | 2008-09-18 |
EP3202786A3 (en) | 2017-10-11 |
EP3202786A2 (en) | 2017-08-09 |
US9938336B2 (en) | 2018-04-10 |
IL200710A0 (en) | 2010-05-17 |
CN101668771A (zh) | 2010-03-10 |
AU2008226067B2 (en) | 2012-11-08 |
JP5622397B2 (ja) | 2014-11-12 |
RU2009137582A (ru) | 2011-04-20 |
HK1138602A1 (en) | 2010-08-27 |
CN101668771B (zh) | 2013-08-21 |
NZ579594A (en) | 2012-03-30 |
CN103275216A (zh) | 2013-09-04 |
JP2010523077A (ja) | 2010-07-15 |
EP2118138A1 (en) | 2009-11-18 |
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CB02 | Change of applicant information |
Address after: Swiss Shi Lilun Applicant after: Esbatech Alcon Biomed Res Unit Address before: Swiss Shi Lilun Applicant before: Esbatech Alcon Biomed Res Unit |
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COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: ESBATECH, ESBATECH ALCON BIOMEDICAL RESEARCH UNIT LLC TO: ESBATECH-NOVARTIS COMPANY LLC |
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Application publication date: 20130904 Assignee: Delenex Therapeutics AG Assignor: Esbatech Alcon Biomed Res Unit Contract record no.: 2014990000590 Denomination of invention: Sequence based engineering and optimization of single chain antibodies License type: Common License Record date: 20140724 |
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Effective date of registration: 20210804 Address after: Basel, SUI Patentee after: NOVARTIS AG Address before: Swiss Shi Lilun Patentee before: ESBATech, an Alcon Biomedical Research Unit LLC |
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