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

Department of Immunology, Genentech, South San Francisco, CA 94080, USA.
Blood (Impact Factor: 10.45). 01/2008; 110(12):3959-67. DOI: 10.1182/blood-2007-04-088088
Source: PubMed


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.

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Available from: Suhasini Iyer, Mar 31, 2014
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    • "The first is an anti-BAFF neutralizing antibody (LymphoStat-B, Belimumab) [158]. The second is anti-BAFF-R [159], which blocks the interaction of BAFF with the BAFF-R and also kills BAFF-R expressing cells. The third is the decoy receptor BR3-Fc, which is a humanized fusion protein of the extracellular domain of human BAFF-R with the Fc portion of human IgG1 [160]. "
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    • "TACI-Ig is being evaluated in RA and SLE, and preliminary studies suggest that there is a significant decrease in serum immunoglobulins. Anti-BR3 antibodies with cell depletion activity and BR3-Fc are being developed for similar indications [21,23]. The respective merits of strategies involving BLyS and APRIL are difficult to compare because their respective roles in humans are not yet fully understood. "
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    • "Since BAFF is the only known ligand for BAFF-R these studies strongly suggest that peripheral B cells require BAFF for their survival. In one of these studies a more detailed analysis of the extent of depletion of the various mature B cell subpopulations is reported [25]. This analysis revealed that after such a treatment the B-2 and MZB compartments were largely reduced whereas the B-1 cell numbers were practically not affected. "
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