ATE382053T1 - System zur antikörperexpression und- synthese - Google Patents

System zur antikörperexpression und- synthese

Info

Publication number
ATE382053T1
ATE382053T1 AT02763536T AT02763536T ATE382053T1 AT E382053 T1 ATE382053 T1 AT E382053T1 AT 02763536 T AT02763536 T AT 02763536T AT 02763536 T AT02763536 T AT 02763536T AT E382053 T1 ATE382053 T1 AT E382053T1
Authority
AT
Austria
Prior art keywords
expression
antibodies
synthesis
systems
recombinant
Prior art date
Application number
AT02763536T
Other languages
English (en)
Inventor
Dana Andersen
Laura Simmons
Original Assignee
Genentech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Genentech Inc filed Critical Genentech Inc
Application granted granted Critical
Publication of ATE382053T1 publication Critical patent/ATE382053T1/de

Links

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
    • C07K16/36—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood coagulation factors
    • 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
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • C07K16/2845—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta2-subunit-containing molecules, e.g. CD11, CD18
    • 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
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/54—F(ab')2
AT02763536T 2001-08-27 2002-08-26 System zur antikörperexpression und- synthese ATE382053T1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US31520901P 2001-08-27 2001-08-27

Publications (1)

Publication Number Publication Date
ATE382053T1 true ATE382053T1 (de) 2008-01-15

Family

ID=23223369

Family Applications (1)

Application Number Title Priority Date Filing Date
AT02763536T ATE382053T1 (de) 2001-08-27 2002-08-26 System zur antikörperexpression und- synthese

Country Status (11)

Country Link
US (6) US20030077739A1 (de)
EP (1) EP1427744B1 (de)
JP (1) JP4461210B2 (de)
KR (1) KR100968664B1 (de)
CN (1) CN100513414C (de)
AT (1) ATE382053T1 (de)
CA (1) CA2454731C (de)
DE (1) DE60224291T2 (de)
MX (1) MXPA04001566A (de)
NZ (1) NZ530852A (de)
WO (1) WO2003018771A2 (de)

Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009618A2 (en) 2002-07-18 2004-01-29 Crucell Holland B.V. Recombinant production of mixtures of antibodies
US6979556B2 (en) * 2000-12-14 2005-12-27 Genentech, Inc. Separate-cistron contructs for secretion of aglycosylated antibodies from prokaryotes
ATE382053T1 (de) * 2001-08-27 2008-01-15 Genentech Inc System zur antikörperexpression und- synthese
USRE47770E1 (en) 2002-07-18 2019-12-17 Merus N.V. Recombinant production of mixtures of antibodies
WO2004065417A2 (en) 2003-01-23 2004-08-05 Genentech, Inc. Methods for producing humanized antibodies and improving yield of antibodies or antigen binding fragments in cell culture
US7605235B2 (en) 2003-05-30 2009-10-20 Centocor, Inc. Anti-tissue factor antibodies and compositions
US20100069614A1 (en) 2008-06-27 2010-03-18 Merus B.V. Antibody producing non-human mammals
US9708410B2 (en) 2003-05-30 2017-07-18 Janssen Biotech, Inc. Anti-tissue factor antibodies and compositions
CA2527694C (en) 2003-05-30 2015-07-14 Hendricus Renerus Jacobus Mattheus Hoogenboom Fab library for the preparation of anti vegf and anti rabies virus fabs
KR100570422B1 (ko) * 2003-10-16 2006-04-11 한미약품 주식회사 대장균 분비서열을 이용하여 항체 단편을 분비·생산하는 발현벡터 및 이를 이용하여 항체 단편을 대량 생산하는 방법
CN100475965C (zh) * 2005-07-22 2009-04-08 上海高科联合生物技术研发有限公司 一种大肠杆菌高效外分泌表达溶葡萄球菌酶的方法
WO2009021548A1 (en) * 2007-08-10 2009-02-19 Wacker Chemie Ag Expression of full length igg and secretion into the culture medium of prokaryotic cells
JP2011514161A (ja) * 2008-02-29 2011-05-06 ラモット・アット・テル・アビブ・ユニバーシテイ・リミテッド 免疫グロブリン組成物およびその製造方法
JP5463528B2 (ja) * 2009-02-25 2014-04-09 味の素株式会社 Ｌ−システイン生産菌及びｌ−システインの製造法
JP6132551B2 (ja) 2009-09-24 2017-05-24 ユセベ ファルマ ソシエテ アノニム シャペロン活性を保持するプロテアーゼ欠損ＤｅｇＰ並びにノックアウトＴｓｐ及びｐｔｒ遺伝子を持つ、組換えタンパク質発現のための細菌株
EP2496601B1 (de) * 2009-11-05 2017-06-07 F. Hoffmann-La Roche AG Methoden und zusammensetzung zur sekretion heterologer polypeptide
GB201000587D0 (en) 2010-01-14 2010-03-03 Ucb Pharma Sa Bacterial hoist strain
GB201000590D0 (en) 2010-01-14 2010-03-03 Ucb Pharma Sa Bacterial host strain
GB201000591D0 (en) 2010-01-14 2010-03-03 Ucb Pharma Sa Bacterial hoist strain
GB201000588D0 (en) * 2010-01-14 2010-03-03 Ucb Pharma Sa Bacterial host strain
GB201012599D0 (en) 2010-07-27 2010-09-08 Ucb Pharma Sa Process for purifying proteins
US8722044B2 (en) 2011-03-15 2014-05-13 Janssen Biotech, Inc. Human tissue factor antibody and uses thereof
EP2692911B1 (de) 2011-03-31 2017-02-22 Kunimine Industries Co., Ltd. Gebrauch eines mittels zum suchen nach proteinkristallisationsbedingungen und verfahren zum suchen nach proteinkristallisationsbedingungen
LT2731973T (lt) 2011-07-13 2018-02-26 Ucb Biopharma Sprl Bakterijų padermė, ekspresuojanti rekombinantinį dsbc
KR20230091201A (ko) 2012-04-20 2023-06-22 메뤼스 엔.페. Ig-유사 분자의 제조방법 및 제조수단
GB201208367D0 (en) 2012-05-14 2012-06-27 Ucb Pharma Sa Biological product
CA2877009C (en) * 2012-07-05 2023-10-03 Devin TESAR Expression and secretion system
DK3187586T3 (da) * 2012-08-05 2019-10-14 Absci Llc Inducerbar co-ekspressionssystem
US20150353940A1 (en) * 2013-08-05 2015-12-10 Absci, Llc Vectors for use in an inducible coexpression system
CN103468735B (zh) * 2013-09-18 2016-01-20 山西大学 重组华溪蟹金属硫蛋白(rcMT)及其单克隆抗体的制备
US10435694B2 (en) 2014-03-14 2019-10-08 Genentech, Inc. Methods and compositions for secretion of heterologous polypeptides
BR112016021383A2 (pt) 2014-03-24 2017-10-03 Genentech Inc Método para identificar um paciente com câncer que é susceptível ou menos susceptível a responder ao tratamento com um antagonista de cmet, método para identificar um paciente apresentando câncer previamente tratado, método para determinar a expressão do biomarcador hgf, antagonista anti-c-met e seu uso, kit de diagnóstico e seu método de preparo
KR102307278B1 (ko) 2014-04-29 2021-09-30 노파르티스 아게 신규 척추동물 세포 및 관심 폴리펩티드의 재조합적 발현 방법
SI3164492T1 (sl) * 2014-07-03 2020-02-28 F. Hoffmann-La Roche Ag Sistem polipeptidne ekspresije
EP3167065B1 (de) 2014-07-09 2020-03-25 Lupin Limited Duales system zur cistronischen bakteriellen expression
US10066002B2 (en) * 2014-11-05 2018-09-04 Genentech, Inc. Methods of producing two chain proteins in bacteria
CA2966558C (en) 2014-11-05 2024-03-12 Genentech, Inc. Methods of producing two chain proteins in bacteria
MA45489A (fr) 2015-10-22 2018-08-29 Juno Therapeutics Gmbh Procédés de culture de cellules, kits et appareil associés
CN105505884B (zh) * 2016-01-26 2017-10-03 郑州师范学院 进行抗体表达和组装的重组系统及应用
CN111032850A (zh) 2017-04-27 2020-04-17 朱诺治疗学有限公司 寡聚粒子试剂及其使用方法
WO2019038338A1 (en) 2017-08-23 2019-02-28 Sandoz Ag PROTEIN EXPRESSION SYSTEM WITH MULTIPLE GENIC COPIES
WO2019120635A1 (en) 2017-12-18 2019-06-27 Ventana Medical Systems, Inc. Peptide nucleic acid conjugates
MX2020008470A (es) * 2018-02-14 2020-09-25 Generation Bio Co Vectores de adn no virales y usos de estos para la produccion de anticuerpos y proteinas de fusion.
TW202031899A (zh) * 2018-11-05 2020-09-01 美商建南德克公司 在原核宿主細胞中產生二鏈蛋白質之方法
US11352445B2 (en) * 2018-12-31 2022-06-07 Jecho Laboratories Inc. Method for preparing recombinant protein from bacterium and composition containing the same
CA3124515A1 (en) * 2019-01-23 2020-07-30 Genentech, Inc. Methods of producing multimeric proteins in eukaryotic host cells
AU2020243460A1 (en) 2019-03-18 2021-10-07 Bio-Rad Abd Serotec Gmbh Protection of SpyTag-containing periplasmic fusion proteins from protease Tsp and ompT degradation
SE544001C2 (en) * 2020-03-17 2021-10-26 Xbrane Biopharma Ab Novel combination of tis sequences, signal peptide sequences and nucleic acid sequences encoding heavy and light chains of an antibody
SE544000C2 (en) * 2020-03-17 2021-10-26 Xbrane Biopharma Ab Novel combination of tis sequence, signal peptide sequence and nucleic acid sequence encoding a recombinant protein

Family Cites Families (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE30985E (en) * 1978-01-01 1982-06-29 Serum-free cell culture media
US4560655A (en) * 1982-12-16 1985-12-24 Immunex Corporation Serum-free cell culture medium and process for making same
US4657866A (en) * 1982-12-21 1987-04-14 Sudhir Kumar Serum-free, synthetic, completely chemically defined tissue culture media
US4816567A (en) * 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4767704A (en) * 1983-10-07 1988-08-30 Columbia University In The City Of New York Protein-free culture medium
DE3572982D1 (en) 1984-03-06 1989-10-19 Takeda Chemical Industries Ltd Chemically modified lymphokine and production thereof
GB8516415D0 (en) 1985-06-28 1985-07-31 Celltech Ltd Culture of animal cells
US5618920A (en) * 1985-11-01 1997-04-08 Xoma Corporation Modular assembly of antibody genes, antibodies prepared thereby and use
US4927762A (en) * 1986-04-01 1990-05-22 Cell Enterprises, Inc. Cell culture medium with antioxidant
IL85035A0 (en) * 1987-01-08 1988-06-30 Int Genetic Eng Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same
EP0307434B2 (de) * 1987-03-18 1998-07-29 Scotgen Biopharmaceuticals, Inc. Geänderte antikörper
CA1341235C (en) 1987-07-24 2001-05-22 Randy R. Robinson Modular assembly of antibody genes, antibodies prepared thereby and use
DE3744595A1 (de) * 1987-12-31 1989-07-13 Andreas Dr Plueckthun Verfahren zur gentechnischen herstellung von antikoerpern
AU632065B2 (en) 1988-09-23 1992-12-17 Novartis Vaccines And Diagnostics, Inc. Cell culture medium for enhanced cell growth, culture longevity and product expression
EP0401384B1 (de) 1988-12-22 1996-03-13 Kirin-Amgen, Inc. Chemisch modifizierte granulocytenkolonie erregender faktor
DE3920358A1 (de) 1989-06-22 1991-01-17 Behringwerke Ag Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung
US5208020A (en) * 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
US5122469A (en) * 1990-10-03 1992-06-16 Genentech, Inc. Method for culturing Chinese hamster ovary cells to improve production of recombinant proteins
US5508192A (en) * 1990-11-09 1996-04-16 Board Of Regents, The University Of Texas System Bacterial host strains for producing proteolytically sensitive polypeptides
US5264365A (en) * 1990-11-09 1993-11-23 Board Of Regents, The University Of Texas System Protease-deficient bacterial strains for production of proteolytically sensitive polypeptides
EP0580737B1 (de) * 1991-04-10 2004-06-16 The Scripps Research Institute Bibliotheken heterodimerer rezeptoren mittels phagemiden
JP4124480B2 (ja) * 1991-06-14 2008-07-23 ジェネンテック・インコーポレーテッド 免疫グロブリン変異体
JP3951062B2 (ja) * 1991-09-19 2007-08-01 ジェネンテック・インコーポレーテッド 少なくとも遊離のチオールとして存在するシステインを有する抗体フラグメントの大腸菌での発現、２官能性Ｆ（ａｂ’）２抗体の産生のための使用
WO1993008300A1 (en) 1991-10-18 1993-04-29 The University Of Calgary Expression-secretion vectors for the production of biologically active fv fragments
US20020037558A1 (en) 1991-10-23 2002-03-28 Kin-Ming Lo E.coli produced immunoglobulin constructs
EP0617706B1 (de) 1991-11-25 2001-10-17 Enzon, Inc. Multivalente antigen-bindende proteine
DE69332948T2 (de) 1992-03-05 2003-11-27 Univ Texas Verwendung von Immunokonjugate zur Diagnose und/oder Therapie der vaskularisierten Tumoren
GB9206422D0 (en) 1992-03-24 1992-05-06 Bolt Sarah L Antibody preparation
GB9215541D0 (en) * 1992-07-22 1992-09-02 Celltech Ltd Protein expression system
AU691811B2 (en) 1993-06-16 1998-05-28 Celltech Therapeutics Limited Antibodies
FR2715664B1 (fr) * 1994-01-31 1996-04-12 Proteine Performance Sa Baculovirus recombinant et son utilisation pour la production d'anticorps monoclonaux.
FR2724182B1 (fr) * 1994-09-02 1996-12-13 Pasteur Institut Obtention d'un anticorps monoclonal recombinant a partir d'un anticorps monoclonal humain anti-rhesus d, sa production en cellules d'insecte, et ses utilisations
US5639635A (en) 1994-11-03 1997-06-17 Genentech, Inc. Process for bacterial production of polypeptides
US5840523A (en) * 1995-03-01 1998-11-24 Genetech, Inc. Methods and compositions for secretion of heterologous polypeptides
US5747662A (en) * 1995-03-01 1998-05-05 Genentech, Inc. Methods and compositions for secretion of heterologous polypeptides
US5641870A (en) * 1995-04-20 1997-06-24 Genentech, Inc. Low pH hydrophobic interaction chromatography for antibody purification
DE19513676A1 (de) * 1995-04-11 1996-10-17 Behringwerke Ag Cytoplasmatische Expression von Antikörpern, Antikörperfragmenten und Antikörperfragmentfusionsmolekülen in E.coli
WO1997038123A1 (en) * 1996-04-05 1997-10-16 Board Of Regents, The University Of Texas System Methods for producing soluble, biologically-active disulfide bond-containing eukaryotic proteins in bacterial cells
GB9614700D0 (en) 1996-07-12 1996-09-04 Medical Res Council Over-expression of proteins in E.Coli
WO1998049198A1 (en) 1997-04-30 1998-11-05 Enzon, Inc. Single-chain antigen-binding proteins capable of glycosylation, production and uses thereof
US6083715A (en) * 1997-06-09 2000-07-04 Board Of Regents, The University Of Texas System Methods for producing heterologous disulfide bond-containing polypeptides in bacterial cells
DK0999853T3 (da) 1997-06-13 2003-04-22 Genentech Inc Stabiliseret antostofformulering
US6171586B1 (en) * 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
EP1025246A1 (de) * 1997-10-23 2000-08-09 Plückthun, Andreas, Prof. Dr. Verfahren zur identifizierung von nukleinsäureseqeunzen und (poly)peptide die die funktionelle periplasmatische proteinexpression erhöhen
EP1068241B1 (de) 1998-04-02 2007-10-10 Genentech, Inc. Antikörper varianten und fragmente davon
WO2000024873A1 (en) * 1998-10-28 2000-05-04 Genentech, Inc. Process for recovering heterologous polypeptides from bacterial cells
US6208020B1 (en) * 1999-02-24 2001-03-27 Matsushita Electronics Corporation Leadframe for use in manufacturing a resin-molded semiconductor device
DE60025829T2 (de) * 1999-07-12 2006-11-02 Genentech, Inc., South San Francisco Expressionsvektoren und anwendungsmethoden
US20050005310A1 (en) * 1999-07-12 2005-01-06 Genentech, Inc. Expression vectors and methods
EP1077263A1 (de) * 1999-07-29 2001-02-21 F.Hoffmann-La Roche Ag Verfahren zur Herstellung von natürlich gefalteten und sekretierten Proteinen durch Co-Sekretion von Chaperonen
US6703494B2 (en) * 2000-03-16 2004-03-09 Genentech, Inc. Anti-tissue factor antibodies with enhanced anticoagulant potency
MXPA03001645A (es) * 2000-08-24 2004-05-14 Genentech Inc Composiciones y metodos para el diagnostico y tratamiento de tumores.
DE60117601T2 (de) * 2000-12-14 2006-11-16 Genentech Inc., San Francisco Bakterielle wirtstämme
DK1356052T3 (da) * 2000-12-14 2008-12-08 Genentech Inc Produktion af hele antistoffer i prokaryotiske celler
US6979556B2 (en) * 2000-12-14 2005-12-27 Genentech, Inc. Separate-cistron contructs for secretion of aglycosylated antibodies from prokaryotes
ATE382053T1 (de) * 2001-08-27 2008-01-15 Genentech Inc System zur antikörperexpression und- synthese

Also Published As

Publication number Publication date
WO2003018771A2 (en) 2003-03-06
US20030077739A1 (en) 2003-04-24
CN1549821A (zh) 2004-11-24
US20060246542A1 (en) 2006-11-02
WO2003018771A3 (en) 2004-03-11
KR100968664B1 (ko) 2010-07-06
US20110244517A1 (en) 2011-10-06
US9688775B2 (en) 2017-06-27
US20070015244A1 (en) 2007-01-18
CA2454731A1 (en) 2003-03-06
EP1427744A2 (de) 2004-06-16
CA2454731C (en) 2010-11-02
JP2005517385A (ja) 2005-06-16
US20070224664A1 (en) 2007-09-27
EP1427744B1 (de) 2007-12-26
EP1427744A4 (de) 2005-12-07
DE60224291D1 (de) 2008-02-07
NZ530852A (en) 2006-11-30
MXPA04001566A (es) 2004-05-17
US20140120580A1 (en) 2014-05-01
DE60224291T2 (de) 2008-12-11
CN100513414C (zh) 2009-07-15
KR20040031011A (ko) 2004-04-09
JP4461210B2 (ja) 2010-05-12

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