WO1998047531A3 - Fc receptor non-binding anti-cd3 monoclonal antibodies deliver a partial tcr signal and induce clonal anergy - Google Patents

Fc receptor non-binding anti-cd3 monoclonal antibodies deliver a partial tcr signal and induce clonal anergy Download PDF

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Publication number
WO1998047531A3
WO1998047531A3 PCT/US1998/008029 US9808029W WO9847531A3 WO 1998047531 A3 WO1998047531 A3 WO 1998047531A3 US 9808029 W US9808029 W US 9808029W WO 9847531 A3 WO9847531 A3 WO 9847531A3
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WIPO (PCT)
Prior art keywords
receptor non
binding anti
binding
receptor
signaling
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PCT/US1998/008029
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French (fr)
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WO1998047531A2 (en
Inventor
Judith A Smith
J Yun Tso
Marcus R Clark
Michael S Cole
Jeffrey A Bluestone
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Arch Dev Corp
Judith A Smith
J Yun Tso
Marcus R Clark
Michael S Cole
Jeffrey A Bluestone
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Application filed by Arch Dev Corp, Judith A Smith, J Yun Tso, Marcus R Clark, Michael S Cole, Jeffrey A Bluestone filed Critical Arch Dev Corp
Priority to AU74678/98A priority Critical patent/AU7467898A/en
Publication of WO1998047531A2 publication Critical patent/WO1998047531A2/en
Publication of WO1998047531A3 publication Critical patent/WO1998047531A3/en

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    • 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
    • C07K16/2803—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 immunoglobulin superfamily
    • C07K16/2809—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 immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • 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
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07K2317/77—Internalization into the cell

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  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Anti-CD3 mAbs are potent immunosuppressive agents used in clinical transplantation. However, the activation-related adverse side effects associated with these mAbs have prompted the development of less toxic Fc receptor non-binding anti-CD3 mAb therapies. At present, the functional and biochemical consequences of T cell exposure to Fc receptor non-binding anti-CD3 is unclear. In this study, the inventors have examined the early signaling events triggered by a Fc receptor non-binding anti-CD3 mAb. Like the mitogenic anti-CD3 mAb, Fc receptor non-binding anti-CD3 triggered changes in the TCR complex, including z chain tyrosine phosphorylation and ZAP-70 association. However, unlike the mitogenic anti-CD3 stimulation, Fc receptor non-binding anti-CD3 was ineffective at inducing the highly phosphorylated form of z (p23) and tyrosine phosphorylation of the associated ZAP-70 tyrosine kinase. This proximal signaling deficiency correlated with minimal PLCη-1 phosphorylation and failure to mobilize detectable Ca2+. Not only did biochemical signals delivered by Fc receptor non-binding anti-CD3 resemble altered peptide ligand signaling, but exposure of Th1 clones to Fc receptor non-binding anti-CD3 also resulted in functional anergy. Finally, a bispecific anti-CD3 x anti-CD4 F(ab)'¿2? reconstituted early signal transduction events and induced proliferation, suggesting that defective association of 1ck with the TCR complex may underlie the observed signaling differences between the mitogenic and Fc receptor non-binding anti-CD3.
PCT/US1998/008029 1997-04-21 1998-04-21 Fc receptor non-binding anti-cd3 monoclonal antibodies deliver a partial tcr signal and induce clonal anergy WO1998047531A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU74678/98A AU7467898A (en) 1997-04-21 1998-04-21 Fc receptor non-binding anti-cd3 monoclonal antibodies deliver a partial cr signal and induce clonal anergy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4408497P 1997-04-21 1997-04-21
US60/044,084 1997-04-21

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WO1998047531A2 WO1998047531A2 (en) 1998-10-29
WO1998047531A3 true WO1998047531A3 (en) 1999-04-15

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AU (1) AU7467898A (en)
WO (1) WO1998047531A2 (en)

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Publication number Priority date Publication date Assignee Title
US9011852B2 (en) 2010-04-30 2015-04-21 Alexion Pharmaceuticals, Inc. Anti-C5a antibodies

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WO1998047531A2 (en) 1998-10-29
AU7467898A (en) 1998-11-13

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