Anti-BR3 antibodies: a new class of B-cell immunotherapy combining cellular depletion and survival blockade

Author:

Lin Wei Yu1,Gong Qian1,Seshasayee Dhaya1,Lin Zhonghua1,Ou Qinglin1,Ye Shiming1,Suto Eric1,Shu Jean1,Pun Lee Wyne1,Lee Ching-Wei V.2,Fuh Germaine2,Leabman Maya3,Iyer Suhasini3,Howell Kathy3,Gelzleichter Thomas3,Beyer Joseph3,Danilenko Dimitry4,Yeh Sherry5,DeForge Laura E.5,Ebens Allen6,Thompson Jeffrey S.7,Ambrose Christine7,Balazs Mercedesz1,Starovasnik Melissa A.2,Martin Flavius1

Affiliation:

1. Departments ofImmunology,

2. Protein Engineering,

3. Development Sciences,

4. Pathology,

5. Assay and Automation Technology, and

6. Translational Oncology, Genentech, South San Francisco, CA; and

7. Department of Gene Discovery, Biogen IDEC, Cambridge Center, Cambridge, MA

Abstract

Abstract Removal of pathogenic B lymphocytes by depletion of monoclonal antibodies (mAbs) or deprivation of B-cell survival factors has demonstrated clinical benefit in both oncologic and immunologic diseases. Partial clinical responses and emerging data demonstrating incomplete B-cell depletion after immunotherapy fuels the need for improved therapeutic modalities. Lessons from the first generation of therapeutics directed against B-cell-specific antigens (CD20, CD22) are being applied to develop novel antibodies with additional functional attributes. We describe the generation of a novel class of B-cell-directed therapy (anti-BR3 mAbs) that combines the depleting capacity of a therapeutic mAb and blockade of B-cell-activating factor (BAFF)–BR3 B-cell survival. In mice, treatment with antagonistic anti-BR3 antibodies results in quantitatively greater reduction in some B-cell subsets and qualitatively different effects on bone marrow plasma cells compared with BR3-Fc BAFF blockade or with anti-CD20 treatment. Comparative analysis of BR3-Fc and anti-BR3 mAb reveals a lower B-cell dependence for BAFF-mediated survival in nonhuman primates than in mice. This novel class of B-cell-targeted therapies shows species characteristics in mice and primates that will guide translation to treatment of human disease.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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