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Neutralizing B-Cell–Activating Factor Antibody Improves Survival and Inhibits Osteoclastogenesis in a Severe Combined Immunodeficient Human Multiple Myeloma Model

Authors' Affiliations: ¹ Dana-Farber Cancer Institute, ² VA Boston Healthcare System, ³ Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts and ⁴ University of "Magna Græcia" and Cancer Center, Catanzaro, Italy

Requests for reprints: Noopur Raje, Massachusetts General Hospital, P.O. Box 218, 55 Fruit Street, Boston, MA 02114. Phone: 617-726-0711; Fax: 617-724-6801; E-mail: nraje{at}partners.org.

Purpose: B-cell–activating factor (BAFF) is a tumor necrosis factor superfamily member critical for the maintenance and homeostasis of normal B-cell development. It has been implicated in conferring a survival advantage to B-cell malignancies, including multiple myeloma (MM).

Experimental Design: Here, we validate the role of BAFF in the in vivo pathogenesis of MM examining BAFF and its receptors in the context of patient MM cells and show activity of anti-BAFF antibody in a severe combined immunodeficient model of human MM.

Results: Gene microarrays and flow cytometry studies showed increased transcripts and the presence of all three receptors for BAFF in CD138⁺ patient MM cells, as well as an increase in plasma BAFF levels in 51 MM patients. Functional studies show that recombinant BAFF protects MM cells against dexamethasone-induced apoptosis accompanied by an increase in survival proteins belonging to the BCL family. These in vitro studies led to the evaluation of a clinical grade–neutralizing antibody to BAFF in a severe combined immunodeficient human MM model. Anti-BAFF–treated animals showed decreased soluble human interleukin 6 receptor levels, a surrogate marker of viable tumor, suggesting direct anti-MM activity. This translated into a survival advantage of 16 days (P < 0.05), a decrease in tartrate-resistant acid phosphatase–positive osteoclasts, and a reduction in radiologically evident lytic lesions in anti-BAFF–treated animals.

Conclusions: Our data show a role for BAFF as a survival factor in MM. Importantly, the in vivo antitumor activity of neutralizing anti-BAFF antibody provide the preclinical rationale for its evaluation in the treatment of MM.