WO1998031820A1 - PROTEINE DE FUSION CTLA-4 Ig, A TITRE ELEVE - Google Patents

PROTEINE DE FUSION CTLA-4 Ig, A TITRE ELEVE Download PDF

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Publication number
WO1998031820A1
WO1998031820A1 PCT/KR1998/000009 KR9800009W WO9831820A1 WO 1998031820 A1 WO1998031820 A1 WO 1998031820A1 KR 9800009 W KR9800009 W KR 9800009W WO 9831820 A1 WO9831820 A1 WO 9831820A1
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WIPO (PCT)
Prior art keywords
ctla4
fusion protein
iggl
cys
igm
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PCT/KR1998/000009
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English (en)
Inventor
Yong-Hoon Chung
Original Assignee
Boryung Pharmaceutical Co., Ltd.
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Publication date
Application filed by Boryung Pharmaceutical Co., Ltd. filed Critical Boryung Pharmaceutical Co., Ltd.
Priority to AU56814/98A priority Critical patent/AU5681498A/en
Publication of WO1998031820A1 publication Critical patent/WO1998031820A1/fr

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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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70521—CD28, CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • 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

Definitions

  • the present invention relates to a CTLA4-Ig fusion protein having high titer, and more particularly, to a fusion protein connecting an extracellular region of CTLA4 and C ⁇ of IgM or C ⁇ 1 region of IgG.
  • T-cell plays an important role.
  • the reaction of T-cell starts with two kinds of signals, an antigen- sensitive stimulatory and a costimulatory signals.
  • a large number of ligand/receptor bonds including ICAM-l/LFA-1, B7/CD28 and CTLA4 and LFA-3/CD2 participate in the costimulatoion.
  • CD28 plays an important role in the reaction of the T-cell, making stable mRNA of a T-cell cytokinin by binding to the B7.1 and B7.2(June, C. H. et al, Mol.
  • interleukin-2 interleukin-2
  • IFN- ⁇ interferon- ⁇
  • TNF- a tumor necrosis factor- a
  • GM-CSF granulocyte macrophage-colony stimulating factor
  • IL-3 interleukin-3
  • CTLA4 has 67% homology with the CD28, binding to the B7(B7.1 and B7.2) of an antigen presenting cell(APC) like CD28.
  • APC antigen presenting cell
  • Yamada et al. recently reported that they manufactured a pentameric CTLA4-IgM fusion protein and that the protein extended lives of patients after the organ transplant (Yamada, A. et al, Microbio. Immunol, 40, 513-518, 1996)
  • CTLA4-Ig fusion protein since its too much dosage of 600 mg per once for a 60 kg adult and high manufacturing cost, is hardly commercially viable.
  • a CTLA4-Ig fusion protein in which an extracellular region is connected with CH 2 , CH 3 , and CH 4 region of IgM, or with a hinge, CH 2 , and CH 3 of IgGl Cys 30 8(IgGl having Cys 3 os), and which has a hexameric structure.
  • the hexameric structure of the CTLA4-Ig fusion protein is caused by forming multimer between adjoining IgMs or between IgGl Cys 3 osS forced by disulfide bonds of cy steins.
  • Cys 4 j and Cys 5 67 ⁇ f the IgM make a disulfide bond and, in case of IgGl Cys 3 osS of IgG Is make a disulfide bond.
  • the IgGl Cys 308 ⁇ f the present invention is the one that Leu 3 os of the IgGl CH 2 region, the correspondent site of Cys ⁇ of IgM, is converted to cystein in order to form polymeric IgGl like IgM.
  • DNA base sequence coding amino acid sequence correspondent to the CTLA4-Ig fusion protein is provided.
  • the expression vectors pHIGH3neo and pHIGHgpt manufactured by inserting to vectors of pSV2neo and pSV2gpt an enhancer, a promoter, CTLA4 leader sequence of which N-terminal is cut, and DNA sequence coding amino acid sequence correspondent to the CTLA4-Ig fusion protein.
  • the CTLA4 leader sequence of which N- terminal is cut makes the CTLA-Ig fusion protein secreted to the outside of cell.
  • a transformed body manufactured by inserting to a mouse SP2/0-Agl4 cell the expression vectors pHIGH3neo and pHIGH3gpt which is manufactured by inserting to the vectors pSV2neo and pSV2gpt an enhancer, a promoter, CTAL4 leader sequence of which N-terminal is cut, and the DNA sequence coding amino acid sequence correspondent to the CTLA4-Ig fusion protein.
  • an immunosuppressant containing the CTLA4-Ig fusion protein.
  • the CTLA4-Ig fusion protein of the present invention a soluble protein, binds to the B7 of the antigen presenting cell to inhibit binding of the CTLA4 and the CD28 of T-cell at the B7, to block costimulatory signal needed for the activation of T-cell and, in the result, the immunoreaction is suppressed.
  • the titer of the CTLA4-Ig fusion protein according to the present invention is 32-356 times of an existing CTLA4-Ig fusion protein.
  • the dosage of the CTLA4-Ig fusion protein according to the present invention is 2—13 mg per once for a 60 kg adult, and it's effective titer is 45-260 times of the existing CTLA4-Ig fusion protein's.
  • Fig.l is a structure of a CTLA4 gene cloned by a reverse transcription-polymerase chain reaction(RT-PCR) of example 1.
  • Fig.2 is a expression ratio of a fusion protein of example 2.
  • Fig. 3a, 3b are base sequences of a CTLA4-IgM fusion gene of example 2 and an correspondent amino acid sequence thereof.
  • Fig. 4a, 4b are base sequence of a CTLA4-IgGl Cys 3 o 8 fusion gene of example 3 and a correspondent amino acid sequence thereof.
  • Fig. 5a, 5b are a manufacturing method for the expression vectors of p QGH3neo and pFQGH3gpt of the CTLA4-IgM fusion gene and the CTLA4-IgGl Cys 3 o8 fusion gene.
  • Fig. 6a, 6b are western blots of the CTLA4-IgM fusion protein and the CTLA4-IgGl Cys 30 8 fusion protein.
  • Fig. 7 is a structure of 600kD of the CTLA4-IgM fusion protein or the CTLA4-IgG Cys 30 8 fusion protein.
  • Fig. 8 is a graph showing the immunosuppression effect of the CTLA4-IgM fusion protein and the CTLA4-IgGl Cys 30 s fusion protein.
  • Example 1 Cloning of human CTLA4, IgGl, and IgM genes
  • CTLA4, IgGl , and IgM genes were cloned respectively by the method of a reverse transcription-polymerase chain reaction(RT-PCR).
  • RT-PCR reverse transcription-polymerase chain reaction
  • the polymerase used in the reverse transcription-polymerase chain reaction was pfu(Stratagene Corp.).
  • the primers used in the reverse transcription-polymerase chain reaction are five forward primers(Ll ⁇ 5) and a reverseward primer, as follows;
  • CTLA4 without cutting, for the L2 primer as a form that 6 amino acids of it were cut from N-terminal, 11 amino acids cut for the L3, 16 amino acids cut for the L4, and 22 amino acids cut for the L5 from N-terminal
  • Inventing the forward primers to be expressed as cutting form of amino acids from N-terminal is for a part of leader sequence to be cut and expressed , and for the CTLA4 protein to be secreted to an extracellular region.
  • 5 primers were invented in order that the leader sequence is cut and expressed one by one for the determination of a leader sequence which makes the most CTLA4 proteins secreted to extracellular region.
  • CTLA4 gene obtained by the reverse transcription-polymerase reaction was cloned to pUC 18.
  • the cloned CTLA4 gene has confirmed which base No.49 was converted from adenine to guanine, and base No.331 was converted from guanine to adenine.
  • an amino acid No.17 of CTLA4 protein was converted from threonine to alanine
  • an amino acid No.111 of CTLA4 protein was converted from alanine to threonine. 2.
  • the cloning method was same with the method of the above 1 of the example 1 except template and primer.
  • the template used here was mRNA of B-cell at peripheral blood lymph node obtained from a recovering ill-defined fever patient.
  • the primer was invented in order to clone a counterbalancing of IgGl as follows;
  • the primer was invented in order to clone a counterbalancing of the IgM as follows;
  • the five CTLA4 genes obtained by serial deletion of N-terminal amino acids were fused with IgGl respectively, inserted to a vector pHIGH3, and transfected to a mouse bone marrow SP2/0-Agl4 cell(ATCC#: CRL 1581) to be expressed. And after an incubation for 48 hours, the expression ratio was analyzed by a cell circulation assay.
  • IgGl Cys 3 o8 was manufactured by converting Leu 3 08 of IgGl to cysteine using a polymerase chain reaction.
  • the primers used in the polymerase chain reaction are as follows;
  • the primary polymerase chain reaction using the forward primer and reverseward primer was performed, and then using the product of the above reaction and reverseward primer, secondary polymerase chain reaction was performed.
  • the amplified product of the secondary polymerase chain reaction was cloned in pUC 18 vector.
  • Genome DNA of SP2/0-Agl4 cell was extracted, cut with restriction enzymes of BamH I and Hind HI, transferred to a nitrocellulose membrane, and performed Southern blot with 5 -ATT TGC ATA TTT GCA TAT TTG CAT-3 ' fragment and 5 -CTC ATG ACT CAT GAC TCA-3 fragment marked with isotope to clone 5.3kb promoter.
  • genome DNA of SP2/0-Agl4 cell was cut by restriction enzymes of EcoR I and BamH I and performed the southern blot with 5 -TGA ATT GAG CAA TGT TGA ATT GAG CAA TGT-3' fragment and 5 -TAT TTG GGG AAG GGT ATT TGG GGA AGG-3 ' fragment marked with isotope to clone lkb enhancer.
  • Ig fusion gene was cloned to pUC 18 by fusing the lkb enhancer and 5.3 kb promoter in pUC 19, and inserting the fused product to the site of Sal I, the front part of CTLA4- Ig fusion gene cloned in pUC 18(CTLA4-
  • Example 5 Expression of CTLA4-Ig fusion gene and purification of CTLA4-Ig fusion protein
  • SP2/0-Agl4 cell of mouse was incubated in 10%> FCS-DMEM medium, and diluted to 5X10 6 ceWslmi by adding PBS.
  • the above suspension 0.2ml was put to cuvette(BioRad Corp.) for electroporation and the purified expression vector 15 g of the CTLA4-Ig fusion gene of example 4 was added. And then electroporation (BT 820) was performed under the condition of 480V, 99 ⁇ sec, 2cycle.
  • the above cells were incubated for 3 weeks in the FCS-DMEM medium containing 1500 g/m# of geneticin G418(Gibco Corp.). And then colonies were separated, collected, and incubated for amplifying.
  • the CTLA4-Ig fusion gene expression was examined by the a cell circulation analyzer and enzyme linked immunosorbent assay (ELI S A) method.
  • CTLA4-Ig fusion protein was purified.
  • Ig fusion protein of 600kD is 6 times as large as the existing CTL
  • Ig fusion protein(lOOkD) is a hexamer which was six of CTL
  • the existing CTLA4-Ig fusion protein is a comparative example 1
  • the pentameric CTLA4-Ig fusion protein is a comparative example 2
  • the hexameric CTLA4-Ig fusion protein is an example, and the Immunosuppression effects of them were examined as follows;
  • peripheral blood lymphocytes were separated, and on the cells of the one person 300 rad of 60 Co radiation was irradiated.
  • the cells of the two persons were spread into a 96-well plate with
  • the incubated cells were adsorbed to a glass filter by using titertek(Flow lab), put into a test tube, and after adding 5 ⁇ & of Scintillation cocktail a radioactivity was measured by using ⁇ -liquid scintillation counter. The all tests were performed three for every times under the same condition and an average of them was determined.
  • the percent value gained by adding the fusion protein of the present invention was calculated on the basis of the radiation value(100%>) gained without an addition. And when the value reaches to 50%>, the value was defined as a line of 50% division suppression and the titer between fusion proteins was compared on the basis of the concentration of the adding fusion protein.
  • the 50%> division suppression concentration of the CTLA4-Ig fusion protein of this example is 0.009-0.022 gM(the average is 0.016 ⁇ g Imi). This value is lower than 0.7-3.2 g/m£(the average is 1.4 ⁇ g/ l) of the comparative example 1 and lower than 0.031-0.056 ⁇ glml (the average is 0.44 ⁇ g/ml) the comparative example 2 (Fig.8).
  • CTLA4-Ig fusion protein of this example has high titer, 32-356 times (the average is 88 times) comparing to the existing CTLA4-Ig fusion protein of the comparative example 1 .

Abstract

La présente invention concerne une protéine de fusion CTLA4-Ig, dans laquelle une région extracellulaire de CTLA4 est connectée à CH2, CH3 et CH4 d'une IgM ou à une charnière, CH2 et CH3 de IgC1 Cys308 et dont six monomères sont polymérisés pour constituer une structure hexamère. Selon la présente invention, on fournit une protéine de fusion CTLA4-Ig ayant un titre élevé et permettant une administration à faible dose.
PCT/KR1998/000009 1997-01-18 1998-01-19 PROTEINE DE FUSION CTLA-4 Ig, A TITRE ELEVE WO1998031820A1 (fr)

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Application Number Priority Date Filing Date Title
AU56814/98A AU5681498A (en) 1997-01-18 1998-01-19 A ctla4-ig fusion protein having high titer

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KR1997/1360 1997-01-18
KR1019970001360A KR19980066046A (ko) 1997-01-18 1997-01-18 고역가의 CTLA4-Ig 융합단백질

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000009560A2 (fr) * 1998-08-17 2000-02-24 Abgenix, Inc. Production de molecules modifiees avec demi-vie serique prolongee
WO2000064327A2 (fr) * 1999-04-26 2000-11-02 Duke University Inhibition de l'action du complement
WO2001083525A2 (fr) * 2000-05-03 2001-11-08 Amgen Inc. Peptides modifies utilises comme agents therapeutiques
WO2000024782A3 (fr) * 1998-10-23 2002-06-06 Amgen Inc Peptides modifies utilises comme agents therapeutiques
US7026326B2 (en) 2002-05-21 2006-04-11 Amgen Inc. Substituted heterocyclic compounds and methods of use
US7094874B2 (en) 2000-05-26 2006-08-22 Bristol-Myers Squibb Co. Soluble CTLA4 mutant molecules
US7105166B1 (en) 1991-06-27 2006-09-12 Bristol-Myers Squibb Company Soluble CTLA4 mutant molecules and uses thereof
US7229962B2 (en) 2001-07-26 2007-06-12 Medexgen Co., Ltd. Tetravalent etanercept
US7304033B2 (en) 2001-05-23 2007-12-04 Bristol-Myers Squibb Company Methods for protecting allogeneic islet transplant using soluble CTLA4 mutant molecules
US7455835B2 (en) 2000-07-03 2008-11-25 Bristol-Myers Squibb Company Methods for treating immune system diseases using a soluble CTLA4 molecule
US7488590B2 (en) 1998-10-23 2009-02-10 Amgen Inc. Modified peptides as therapeutic agents
US8148332B2 (en) 2000-07-03 2012-04-03 Bristol-Myers Squibb Company Method for treating a rheumatic disease using a soluble TLA4 molecule
US20140010809A1 (en) * 2001-01-17 2014-01-09 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
US9114175B2 (en) 2005-08-12 2015-08-25 Amgen Inc. Modified Fc molecules
US9145450B2 (en) 1998-10-23 2015-09-29 Amgen Inc. Thrombopoietic compounds
US9493564B2 (en) 2008-10-02 2016-11-15 Aptevo Research And Development Llc CD86 antagonist multi-target binding proteins
US10143748B2 (en) 2005-07-25 2018-12-04 Aptevo Research And Development Llc B-cell reduction using CD37-specific and CD20-specific binding molecules

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US5434131A (en) * 1991-06-27 1995-07-18 Bristol Myers Squibb Co. Chimeric CTLA4 receptor and methods for its use
EP0682039A1 (fr) * 1994-04-15 1995-11-15 Bristol-Myers Squibb Company Des molécules CTLA4 et des molécules liant à IL4, et leurs utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5434131A (en) * 1991-06-27 1995-07-18 Bristol Myers Squibb Co. Chimeric CTLA4 receptor and methods for its use
EP0682039A1 (fr) * 1994-04-15 1995-11-15 Bristol-Myers Squibb Company Des molécules CTLA4 et des molécules liant à IL4, et leurs utilisations

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7105166B1 (en) 1991-06-27 2006-09-12 Bristol-Myers Squibb Company Soluble CTLA4 mutant molecules and uses thereof
WO2000009560A3 (fr) * 1998-08-17 2000-05-18 Abgenix Inc Production de molecules modifiees avec demi-vie serique prolongee
WO2000009560A2 (fr) * 1998-08-17 2000-02-24 Abgenix, Inc. Production de molecules modifiees avec demi-vie serique prolongee
US9534032B2 (en) 1998-10-23 2017-01-03 Amgen Inc. Thrombopoietic compounds
US9145450B2 (en) 1998-10-23 2015-09-29 Amgen Inc. Thrombopoietic compounds
US7488590B2 (en) 1998-10-23 2009-02-10 Amgen Inc. Modified peptides as therapeutic agents
WO2000024782A3 (fr) * 1998-10-23 2002-06-06 Amgen Inc Peptides modifies utilises comme agents therapeutiques
US7189827B2 (en) 1998-10-23 2007-03-13 Amgen Inc. Modified peptides as therapeutic agents
US6660843B1 (en) 1998-10-23 2003-12-09 Amgen Inc. Modified peptides as therapeutic agents
EA005404B1 (ru) * 1998-10-23 2005-02-24 Амген Инк. Модифицированные пептиды как терапевтические агенты
US7169905B2 (en) 1998-10-23 2007-01-30 Amgen Inc. Modified peptides as therapeutic agents
US7166707B2 (en) 1998-10-23 2007-01-23 Amgen Inc. Modified peptides as therapeutic agents
US7049282B2 (en) 1999-04-26 2006-05-23 Duke University Inhibition of complement action
WO2000064327A2 (fr) * 1999-04-26 2000-11-02 Duke University Inhibition de l'action du complement
WO2000064327A3 (fr) * 1999-04-26 2001-03-08 Univ Duke Inhibition de l'action du complement
WO2001083525A3 (fr) * 2000-05-03 2002-07-18 Amgen Inc Peptides modifies utilises comme agents therapeutiques
WO2001083525A2 (fr) * 2000-05-03 2001-11-08 Amgen Inc. Peptides modifies utilises comme agents therapeutiques
US7700556B2 (en) 2000-05-26 2010-04-20 Bristol-Myers Squibb Company Methods of treatment using CTLA4 mutant molecules
US10370428B2 (en) 2000-05-26 2019-08-06 Bristol-Myers Squibb Company Methods of treatment using CTLA4 mutant molecules
US9758565B2 (en) 2000-05-26 2017-09-12 Bristol-Myers Squibb Company Methods of treatment using CTLA4 mutant molecules
US7439230B2 (en) 2000-05-26 2008-10-21 Bristol-Myers Squibb Company Methods of treatment using CTLA4 mutant molecules
US7094874B2 (en) 2000-05-26 2006-08-22 Bristol-Myers Squibb Co. Soluble CTLA4 mutant molecules
US8497247B2 (en) 2000-07-03 2013-07-30 Bristol-Myers Squibb Company Methods for treating type I diabetes mellitus by administering a soluble CTLA4 molecule
US8722632B2 (en) 2000-07-03 2014-05-13 Bristol-Myers Squibb Company Methods for treating Sjogrens syndrome by administering a soluble CTLA4 molecule
US8148332B2 (en) 2000-07-03 2012-04-03 Bristol-Myers Squibb Company Method for treating a rheumatic disease using a soluble TLA4 molecule
US8227420B2 (en) 2000-07-03 2012-07-24 Bristol-Myers Squibb Company Method for treating an autoimmune disease using a soluble CTLA4 molecule and a DMARD or NSAID
US10052360B2 (en) 2000-07-03 2018-08-21 Bristol-Myers Squibb Company Methods for treating dermatomyositis or polymyositis by administering a soluble CTLA4 molecule
US9296808B2 (en) 2000-07-03 2016-03-29 Bristol-Myers Squibb Company Methods for treating scleroderma by administering a soluble CTLA4 molecule
US7455835B2 (en) 2000-07-03 2008-11-25 Bristol-Myers Squibb Company Methods for treating immune system diseases using a soluble CTLA4 molecule
US8703718B2 (en) 2000-07-03 2014-04-22 Bristol-Myers Squibb Company Methods for treating juvenile rheumatoid arthritis by administering a soluble CTLA4 molecule
US20140010809A1 (en) * 2001-01-17 2014-01-09 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
US7829534B2 (en) 2001-05-23 2010-11-09 Bristol-Myers Squibb Company Methods for protecting allogeneic islet transplant using soluble CTLA4 mutant molecules
US7304033B2 (en) 2001-05-23 2007-12-04 Bristol-Myers Squibb Company Methods for protecting allogeneic islet transplant using soluble CTLA4 mutant molecules
US7670602B2 (en) 2001-07-26 2010-03-02 Medexgen Co., Ltd Concatameric immunoadhesion molecule
US7229962B2 (en) 2001-07-26 2007-06-12 Medexgen Co., Ltd. Tetravalent etanercept
US8372961B2 (en) 2001-07-26 2013-02-12 Medexgen Co., Ltd. Polynucleotides encoding concatameric immunoadhesion molecules
US7026326B2 (en) 2002-05-21 2006-04-11 Amgen Inc. Substituted heterocyclic compounds and methods of use
US10143748B2 (en) 2005-07-25 2018-12-04 Aptevo Research And Development Llc B-cell reduction using CD37-specific and CD20-specific binding molecules
US10307481B2 (en) 2005-07-25 2019-06-04 Aptevo Research And Development Llc CD37 immunotherapeutics and uses thereof
US9114175B2 (en) 2005-08-12 2015-08-25 Amgen Inc. Modified Fc molecules
US10188740B2 (en) 2005-08-12 2019-01-29 Amgen Inc. Modified Fc molecules
US11266744B2 (en) 2005-08-12 2022-03-08 Amgen Inc. Modified Fc molecules
US9493564B2 (en) 2008-10-02 2016-11-15 Aptevo Research And Development Llc CD86 antagonist multi-target binding proteins

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KR19980066046A (ko) 1998-10-15
AU5681498A (en) 1998-08-07

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