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Preclinical Analysis of Candidate Anti-Human CD79 Therapeutic Antibodies Using a Humanized CD79 Mouse Model.
Wemlinger, Scott M; Parker Harp, Chelsea R; Yu, Bo; Hardy, Ian R; Seefeldt, Matthew; Matsuda, Jennifer; Mingueneau, Michael; Spilker, Kerri A; Cameron, Thomas O; Larrick, James W; Getahun, Andrew; Cambier, John C.
Afiliação
  • Wemlinger SM; Department of Immunology and Microbiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO.
  • Parker Harp CR; Multiple Sclerosis and Neurorepair Research Unit, Biogen, Cambridge, MA.
  • Yu B; Panorama Research Institute, Sunnyvale, CA.
  • Hardy IR; Miltenyi Biotec, Bergisch Gladbach, Germany.
  • Seefeldt M; The Charles Gates Biomanufacturing Facility, Aurora, CO.
  • Matsuda J; Department of Biomedical Research, National Jewish Health, Denver, CO; and.
  • Mingueneau M; Multiple Sclerosis and Neurorepair Research Unit, Biogen, Cambridge, MA.
  • Spilker KA; Biologics Drug Discovery, Biogen, Cambridge, MA.
  • Cameron TO; Biologics Drug Discovery, Biogen, Cambridge, MA.
  • Larrick JW; Panorama Research Institute, Sunnyvale, CA.
  • Getahun A; Department of Immunology and Microbiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO.
  • Cambier JC; Department of Immunology and Microbiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO; John.Cambier@cuanschutz.edu.
J Immunol ; 208(7): 1566-1584, 2022 04 01.
Article em En | MEDLINE | ID: mdl-35321883
The BCR comprises a membrane-bound Ig that is noncovalently associated with a heterodimer of CD79A and CD79B. While the BCR Ig component functions to sense extracellular Ag, CD79 subunits contain cytoplasmic ITAMs that mediate intracellular propagation of BCR signals critical for B cell development, survival, and Ag-induced activation. CD79 is therefore an attractive target for Ab and chimeric Ag receptor T cell therapies for autoimmunity and B cell neoplasia. Although the mouse is an attractive model for preclinical testing, due to its well-defined immune system, an obstacle is the lack of cross-reactivity of candidate therapeutic anti-human mAbs with mouse CD79. To overcome this problem, we generated knockin mice in which the extracellular Ig-like domains of CD79A and CD79B were replaced with human equivalents. In this study, we describe the generation and characterization of mice expressing chimeric CD79 and report studies that demonstrate their utility in preclinical analysis of anti-human CD79 therapy. We demonstrate that human and mouse CD79 extracellular domains are functionally interchangeable, and that anti-human CD79 lacking Fc region effector function does not cause significant B cell depletion, but induces 1) decreased expression of plasma membrane-associated IgM and IgD, 2) uncoupling of BCR-induced tyrosine phosphorylation and calcium mobilization, and 3) increased expression of PTEN, consistent with the levels observed in anergic B cells. Finally, anti-human CD79 treatment prevents disease development in two mouse models of autoimmunity. We also present evidence that anti-human CD79 treatment may inhibit Ab secretion by terminally differentiated plasmablasts and plasma cells in vitro.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos B / Ativação Linfocitária Limite: Animals Idioma: En Revista: J Immunol Ano de publicação: 2022 Tipo de documento: Article País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos B / Ativação Linfocitária Limite: Animals Idioma: En Revista: J Immunol Ano de publicação: 2022 Tipo de documento: Article País de publicação: Estados Unidos