TY - JOUR
T1 - Neutralizing B-cell-activating factor antibody improves survival and inhibits osteoclastogenesis in a severe combined immunodeficient human multiple myeloma model
AU - Neri, Paola
AU - Kumar, Shaji
AU - Fulciniti, Maria Teresa
AU - Vallet, Sonia
AU - Chhetri, Shweta
AU - Mukherjee, Sidhartha
AU - Tai, Yu Tzu
AU - Chauhan, Dharminder
AU - Tassone, Pierfrancesco
AU - Venuta, Salvatore
AU - Munshi, Nikhil C.
AU - Hideshima, Teru
AU - Anderson, Kenneth C.
AU - Raje, Noopur
PY - 2007/10/1
Y1 - 2007/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=35348915408&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-07-0753
DO - 10.1158/1078-0432.CCR-07-0753
M3 - Journal article
C2 - 17908986
AN - SCOPUS:35348915408
SN - 1078-0432
VL - 13
SP - 5903
EP - 5909
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -