Neutralizing B-cell activating factor antibody improves survival and inhibits osteoclastogenesis in a severe combined immunodeficient human multiple myeloma model - PubMed (original) (raw)
. 2007 Oct 1;13(19):5903-9.
doi: 10.1158/1078-0432.CCR-07-0753.
Shaji Kumar, Maria Teresa Fulciniti, Sonia Vallet, Shweta Chhetri, Sidhartha Mukherjee, Yutzu Tai, Dharminder Chauhan, Pierfrancesco Tassone, Salvatore Venuta, Nikhil C Munshi, Teru Hideshima, Kenneth C Anderson, Noopur Raje
Affiliations
- PMID: 17908986
- DOI: 10.1158/1078-0432.CCR-07-0753
Neutralizing B-cell activating factor antibody improves survival and inhibits osteoclastogenesis in a severe combined immunodeficient human multiple myeloma model
Paola Neri et al. Clin Cancer Res. 2007.
Abstract
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.
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