WO2003018836A2 - Model of autoimmune disease and methods for identifying agents against autoimmune disease - Google Patents

Model of autoimmune disease and methods for identifying agents against autoimmune disease Download PDF

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Publication number
WO2003018836A2
WO2003018836A2 PCT/EP2002/009365 EP0209365W WO03018836A2 WO 2003018836 A2 WO2003018836 A2 WO 2003018836A2 EP 0209365 W EP0209365 W EP 0209365W WO 03018836 A2 WO03018836 A2 WO 03018836A2
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cells
protein
aiolos
obf
oct
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French (fr)
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WO2003018836A3 (en
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Patrick Daniel Matthias
Jian Sun
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Novartis Forschungsstiftung Zweigniederlassung Friedrich Miescher Institute for Biomedical Research
Novartis Forschungsstiftung
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Novartis Forschungsstiftung Zweigniederlassung Friedrich Miescher Institute for Biomedical Research
Novartis Forschungsstiftung
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Priority to JP2003523683A priority Critical patent/JP2005500854A/ja
Priority to EP02772184A priority patent/EP1421218A2/en
Priority to US10/487,116 priority patent/US20040191756A1/en
Priority to AU2002336999A priority patent/AU2002336999A1/en
Publication of WO2003018836A2 publication Critical patent/WO2003018836A2/en
Publication of WO2003018836A3 publication Critical patent/WO2003018836A3/en
Anticipated expiration legal-status Critical
Priority to US11/501,626 priority patent/US20070020673A1/en
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6897—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids involving reporter genes operably linked to promoters
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5023—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on expression patterns
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5047—Cells of the immune system
    • G01N33/5052—Cells of the immune system involving B-cells
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A01K2267/0325—Animal model for autoimmune diseases
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders
    • G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
    • G01N2800/104—Lupus erythematosus [SLE]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders

Definitions

  • autoimmune diseases are thought to result from a breakdown in control of the immune system and its inherent tolerance to self antigens.
  • autoimmune diseases There are several different autoimmune diseases and they affect millions of people worldwide.
  • One or more tissues of the body is generally attacked by the immune system in autoimmune diseases.
  • MS multiple sclerosis
  • myasthenia gravis and autoimmune ureitis the nervous system is attacked.
  • Crohn's disease and ulcerative colitis the gastrointestinal system is attacked, and in psoriasis, pemphigus vulgaris and vitiligo, the skin is affected.
  • Several autoimmune diseases attack multiple organs, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis and scleroderma.
  • SLE systemic lupus erythematosus
  • Aiolos homozygous knock-out mice Surprisingly, when Aiolos -/- mice also lack the transcriptional co-activator OBF-1 , all the signs of SLE are eliminated. Moreover, at the molecular level, B cells from the double knock-out mice are no longer hyperactive, suggesting that the execution of the pathway that is triggered in an uncontrolled manner in the absence of Aiolos requires OBF-1 function. Thus, Aiolos dysfunction (mutation) in mice and other animals is expected to be involved in the pathogenesis of at least some cases of SLE. Moreover, it is also expected that the OBF-1 pathway is involved in the pathogenesis of SLE (whether Aiolos-related or not).
  • Fusion proteins including full length OBF-1 or an active fragment or variant thereof are also envisaged as being useful in the methods of the invention.
  • tags for the targeted delivery or detection of OBF-1 can be fused to the protein, fragment or derivative.
  • any OBF-1 protein, fragment or variant thereof can be derivatised in any way which does not abolish its biological activity.
  • peptides having modified amino acids/peptide linkages, and peptides containing non-naturally occurring amino acids and/or cyclic peptides, which may have improved properties such as stability or activity are included.
  • the Aiolos protein is a repressor of gene expression.
  • the reporter gene is expected to be repressed under normal conditions.
  • a test agent which causes an increase in expression of the reporter gene is concluded to be an antagonist of Aiolos.
  • An active agent which further represses the expression of the reporter gene is concluded to be an agonist of the Aiolos protein.
  • the cells can contain a mutated Aiolos protein which is normally inactive or exhibits lower repression activity than wild type Aiolos. In these cells expression from a reporter gene would be expected to be higher than in cells containing wild type Aiolos protein and this facilitates a screen for an agonist of Aiolos since an enhanced repression is easier to detect.
  • the lack of Aiolos protein in the cells results in normal high transcription of the reporter gene.
  • the reporter gene should be expressed under a constitutive promoter for example a viral constitutive promoter, e.g. the SV40 promoter, in any suitable cell as readily determined by a person skilled in the art.
  • Test agents which result in a repression of the reporter gene in the absence of Aiolos protein are concluded to mimic the activity of the Aiolos protein and are therefore candidates for agents active against an autoimmune disease, for example SLE.
  • agonists of the Aiolos protein are candidate active agents active against autoimmune diseases.
  • the invention provides a method of identifying an agent active against an autoimmune disease, for example SLE comprising providing cells containing OBF-1 protein or a fragment, variant or derivative thereof and an oct protein selected from: oct-1 protein, oct-2 protein, the POU domain of oct-1 protein or the POU domain of oct-2 protein.
  • An extract e.g. a nuclear extract
  • a labelled nucleic acid probe containing an oct-1 or oct-2 protein binding site, e.g. an octamer site, in the presence or absence of a test agent, and the formation of a complex between the OBF-1 protein, the oct protein and the nucleic acid probe is determined in the presence of absence of the test agent.
  • compositions of the invention may be accomplished orally or parenterally.
  • Methods of parenteral delivery include topical, intra-arterial, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration.
  • these pharmaceutical compositions can contain suitable pharmaceutically acceptable carriers comprising excipients and other compounds that facilitate processing of the active compounds into preparations which can be used pharmaceutically. Further details on techniques for formulation and administration can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co, Easton PA).
  • Example 2 - Aiolosf -/- mice have significantly increased levels of creatinine and/or urea in their serum
  • Aiolos -/- mice were crossed with OBF-1 -/- mice and autoantibodies against dsDNA, ssDNA, histone and ANA were detected in the serum of double mutant mice.
  • the double knockout mice completely lacked autoantibodies, even at the lowest serum dilution (1 :5) tested.
  • This result indicates that OBF-1 is essential for development of the autoimmune responses observed in Aiolos -/- mice.
  • no immune complex deposits were found in the glomeruli of Aiolos -/- OBF-1 -/- mice (Fig. 1a) and histological examination of kidney morphology showed normal glomeruli in these mice (Fig. 1b). All these results support the conclusion that lack of OBF-1 prevents the development of SLE in Aiolos -/- mice.
  • CD23+B cells which represent mature B cells in bone marrow, were also drastically reduced in the double mutant mice (Fig 3a).
  • the strongly reduced number of B220+lgM+ cells in bone marrow is not the result of impaired ⁇ chain gene transcription because cytoplasmic ⁇ chain expression was not affected in the double mutant mice.
  • the number of splenic B220+ cells was found to be reduced about 2 fold in the double mutant mice (Fig. 3b).
  • Our data indicate that efficient transition from the pre-B to the immature B cell stage requires either Aiolos or OBF-1.
  • Example 8 Mice lacking Aiolos and OBF-1 fail to form germinal centres

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PCT/EP2002/009365 2001-08-22 2002-08-21 Model of autoimmune disease and methods for identifying agents against autoimmune disease Ceased WO2003018836A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2003523683A JP2005500854A (ja) 2001-08-22 2002-08-21 自己免疫疾患に対する薬剤を同定するための、自己免疫疾患のモデルおよび方法
EP02772184A EP1421218A2 (en) 2001-08-22 2002-08-21 Model of autoimmune disease and methods for identifying agents against autoimmune disease
US10/487,116 US20040191756A1 (en) 2001-08-22 2002-08-21 Model of autoimmune disease and methods for identifying agents against autoimmune disease
AU2002336999A AU2002336999A1 (en) 2001-08-22 2002-08-21 Model of autoimmune disease and methods for identifying agents against autoimmune disease
US11/501,626 US20070020673A1 (en) 2001-08-22 2006-08-08 Model of autoimmune disease and methods for identifying agents against autoimmune disease

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GB0120441.1 2001-08-22
GBGB0120441.1A GB0120441D0 (en) 2001-08-22 2001-08-22 Model of autoimmune disease and methods for identifying anti autoimmune disease disorders

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US10487116 A-371-Of-International 2002-08-21
US11/501,623 Continuation US7642903B2 (en) 2006-08-08 2006-08-08 Trailer tire alert system
US11/501,626 Continuation US20070020673A1 (en) 2001-08-22 2006-08-08 Model of autoimmune disease and methods for identifying agents against autoimmune disease

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WO2003018836A3 WO2003018836A3 (en) 2003-10-30

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Cited By (7)

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EP1589030A1 (en) * 2004-04-14 2005-10-26 Friedrich-Alexander-Universität Erlangen-Nürnberg Bob-1 specific T cells and methods to use
EP1650299A4 (en) * 2003-06-19 2006-12-20 Olympus Corp METHOD FOR DETECTING A REACTION BETWEEN DNA AND DNA BINDING PROTEINS
US9857359B2 (en) 2012-06-29 2018-01-02 Celgene Corporation Methods for determining drug efficacy using cereblon-associated proteins
US10245266B2 (en) 2014-05-19 2019-04-02 Celgene Corporation 3-(4-((4-morpholinomethyl-benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione for the treatment of systemic lupus erythematosus
WO2019212752A1 (en) 2018-05-03 2019-11-07 University Of Utah Research Foundation Oca-b peptide conjugates and methods of treatment
US10919883B2 (en) 2012-08-09 2021-02-16 Celgene Corporation Treatment of immune-related and inflammatory diseases
US11524950B2 (en) 2012-08-09 2022-12-13 Celgene Corporation Treatment of immune-related and inflammatory diseases

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EP2359139B1 (en) * 2008-11-07 2018-03-07 National Jewish Health Diagnosis and treatment of autommune diseases by targeting autommune-related b cells ("abcs")
CN106788941B (zh) * 2011-02-10 2020-10-13 三菱电机株式会社 通信系统
US11480568B2 (en) 2017-09-28 2022-10-25 Yeda Research And Development Co. Ltd. Diagnosis of autoimmune diseases
BR112022002365A2 (pt) 2019-08-09 2022-04-26 Nutcracker Therapeutics Inc Métodos e aparelhos para fabricar e para remover material de uma composição terapêutica
CN116114656B (zh) * 2022-10-11 2024-06-11 上海交通大学医学院附属瑞金医院 一种红斑狼疮小鼠模型的构建方法及应用

Family Cites Families (3)

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Publication number Priority date Publication date Assignee Title
US6890534B1 (en) * 1995-10-18 2005-05-10 The General Hospital Corporation Aiolos gene
WO1995032284A1 (en) * 1994-05-24 1995-11-30 Ciba-Geigy Ag Factor interacting with nuclear proteins
WO1997014714A1 (en) * 1995-10-18 1997-04-24 The General Hospital Corporation The aiolos gene

Cited By (18)

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EP1650299A4 (en) * 2003-06-19 2006-12-20 Olympus Corp METHOD FOR DETECTING A REACTION BETWEEN DNA AND DNA BINDING PROTEINS
US7560235B2 (en) 2003-06-19 2009-07-14 Olympus Corporation Method of detecting reaction of DNA and DNA-binding protein
EP1589030A1 (en) * 2004-04-14 2005-10-26 Friedrich-Alexander-Universität Erlangen-Nürnberg Bob-1 specific T cells and methods to use
WO2005100390A3 (en) * 2004-04-14 2006-04-27 Univ Friedrich Alexander Er Bob-1 specific t cells and methods to use
EP3489682A1 (en) * 2012-06-29 2019-05-29 Celgene Corporation Methods for determining drug efficacy using ikzf3 (aiolos)
US20180209961A1 (en) * 2012-06-29 2018-07-26 Celgene Corporation Methods for determining drug efficacy using cereblon-associated proteins
EP2867671B1 (en) * 2012-06-29 2018-10-24 Celgene Corporation Methods for determining drug efficacy using cereblon-associated proteins
EP3904875A1 (en) * 2012-06-29 2021-11-03 Celgene Corporation Methods for determining drug efficacy using ikzf3 (aiolos)
US9857359B2 (en) 2012-06-29 2018-01-02 Celgene Corporation Methods for determining drug efficacy using cereblon-associated proteins
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