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Blood, 1 December 2007, Vol. 110, No. 12, pp. 3959-3967.
Prepublished online as a Blood First Edition Paper on August 8, 2007; DOI 10.1182/blood-2007-04-088088.
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Submitted April 30, 2007
Accepted July 31, 2007
Anti-BR3 antibodies - a new class of B cell immunotherapy combining cellular depletion and survival blockade
Wei Yu Lin, Qian Gong, Dhaya Seshasayee, Zhonghua Lin, Qinglin Ou, Shiming Ye, Eric Suto, Jean Shu, Wyne Pun Lee, Ching-Wei V Lee, Germaine Fuh, Maya Leabman, Suhasini Iyer, Kathy Howell, Thomas Gelzleichter, Joseph Beyer, Dimitry Danilenko, Sherry Yeh, Laura E DeForge, Allen Ebens, Jeffrey S Thompson, Christine Ambrose, Mercedesz Balazs, Melissa A Starovasnik, and Flavius Martin*
Department of Immunology, Genentech, Inc., South San Francisco, CA
Department of Protein Engineering, Genentech, Inc., South San Francisco, CA
Department of Development Sciences, Genentech, Inc., South San Francisco, CA
Department of Pathology, Genentech, Inc., South San Francisco, CA
Department of Assay and Automation Technology, Genentech, Inc., South San Francisco, CA
Department of Translational Oncology, Genentech, Inc., South San Francisco, CA
Department of Gene Discovery, Biogen Idec, Inc., Cambridge, MA
* Corresponding author; email: flavius{at}gene.com.
Removal of pathogenic B lymphocytes by depleting monoclonal antibodies (mAbs) or deprivation of B cell survival factors have demonstrated clinical benefit in both oncological and immunological diseases. Partial clinical responses and emerging data demonstrating incomplete B cell depletion following 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 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 non-human primates (NHP) then 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.
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