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(American Journal of Pathology. 2006;168:476-489.)
© 2006 American Society for Investigative Pathology

A Soluble BAFF Antagonist, BR3-Fc, Decreases Peripheral Blood B Cells and Lymphoid Tissue Marginal Zone and Follicular B Cells in Cynomolgus Monkeys

Yulia Vugmeyster^*, Dhaya Seshasayee^*, Wesley Chang^*, Anahid Storn^*, Kathy Howell^*, Susan Sa^*, Tenea Nelson^*, Flavius Martin^*, Iqbal Grewal^*, Ellen Gilkerson^*, Ben Wu^*, Jeff Thompson, Barbara N. Ehrenfels, Song Ren^*, An Song^*, Thomas R. Gelzleichter^* and Dimitry M. Danilenko^*

From Genentech, Inc.,^* South San Francisco, California; and Biogen Idec, Inc., Cambridge, Massachusetts

BAFF (also known as BLyS), a member of the tumor necrosis factor superfamily, plays a critical role in the maturation and development of B cells. BAFF has three receptors on B cells, the most crucial of which is BR3. In this study, we demonstrate the biological outcome of BAFF blockade in cynomolgus monkeys using a soluble fusion protein consisting of human BR3 and human IgG1 Fc. In vitro, BR3-Fc blocked BAFF-mediated survival and proliferation of cynomolgus monkey B cells. Weekly treatment of cynomolgus monkeys with BR3-Fc for 13 to 18 weeks resulted in significant B-cell reduction in the peripheral blood and in lymphoid organs. CD21^high B cells in lymphoid tissues, a subset analogous to human marginal zone B cells, expressed nearly twofold higher BR3 levels than did CD21^med B cells. Lymphoid tissue flow cytometric analysis showed that BR3-Fc reduced this CD21^high B-cell subset to a greater extent than it reduced CD21^med B cells. Dual-label immunohistochemistry and morphometric image analysis supported these results by demonstrating that BR3-Fc reduced a significant proportion of the B cells within the splenic inner and outer marginal zones. These findings should prove very useful in guiding the desired therapeutic use of BR3-Fc for autoimmune diseases in the clinic.

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