Neutralizing B-cell-activating factor antibody improves survival and inhibits osteoclastogenesis in a severe combined Immunodeficient human multiple myeloma model

被引:98
作者
Neri, Paola
Kumar, Shaji
Fulciniti, Maria Teresa
Vallet, Sonia
Chhetri, Shweta
Mukherjee, Sidhartha
Tai, YuTzu
Chauhan, Dharminder
Tassone, Pierfrancesco
Venuta, Salvatore
Munshi, Nikhil C.
Hideshima, Teru
Anderson, Kenneth C.
Raje, Noopur
机构
[1] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA
[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, VA Boston Hlthcare Syst, Boston, MA USA
[4] Magna Graecia Univ Catanzaro, Ctr Canc, Catanzaro, Italy
关键词
D O I
10.1158/1078-0432.CCR-07-0753
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 antiBAFF 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 dexa methasone-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 W Importantly, the in vivo antitumor activity of neutralizing anti-BAFF antibody provide the preclinical rationale for its evaluation in the treatment of MM.
引用
收藏
页码:5903 / 5909
页数:7
相关论文
共 48 条
[1]   BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACl-Fc treatment in patients with multiple myeloma [J].
Abe, M. ;
Kido, S. ;
Hiasa, M. ;
Nakano, A. ;
Oda, A. ;
Amou, H. ;
Matsumoto, T. .
LEUKEMIA, 2006, 20 (07) :1313-1315
[2]  
Anderson K, 1999, SEMIN ONCOL, V26, P10
[3]   BAFF selectively enhances the survival of plasmablasts generated from human memory B cells [J].
Avery, DT ;
Kalled, SL ;
Ellyard, JI ;
Ambrose, C ;
Bixler, SA ;
Thien, M ;
Brink, R ;
Mackay, F ;
Hodgkin, PD ;
Tangye, SG .
JOURNAL OF CLINICAL INVESTIGATION, 2003, 112 (02) :286-297
[4]  
Burger R, 2001, Hematol J, V2, P42, DOI 10.1038/sj.thj.6200075
[5]   Myeloma bone disease [J].
Callander, NS ;
Roodman, GD .
SEMINARS IN HEMATOLOGY, 2001, 38 (03) :276-285
[6]   Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B [J].
Chauhan, D ;
Uchiyama, H ;
Akbarali, Y ;
Urashima, M ;
Yamamoto, K ;
Libermann, TA ;
Anderson, KC .
BLOOD, 1996, 87 (03) :1104-1112
[7]   THE HUMAN HEMATOPOIETIC COLONY-STIMULATING FACTORS [J].
CLARK, SC ;
KAMEN, R .
SCIENCE, 1987, 236 (4806) :1229-1237
[8]   TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease [J].
Gross, JA ;
Johnston, J ;
Mudri, S ;
Enselman, R ;
Dillon, SR ;
Madden, K ;
Xu, WF ;
Parrish-Novak, J ;
Foster, D ;
Lofton-Day, C ;
Moore, M ;
Littau, A ;
Grossman, A ;
Haugen, H ;
Foley, K ;
Blumberg, H ;
Harrison, K ;
Kindsvogel, W ;
Clegg, CH .
NATURE, 2000, 404 (6781) :995-999
[9]   APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth [J].
Hahne, M ;
Kataoka, T ;
Schröter, M ;
Hofmann, K ;
Irmler, M ;
Bodmer, JL ;
Schneider, P ;
Bornard, T ;
Holler, N ;
French, LE ;
Sordat, B ;
Rimoldi, D ;
Tschopp, J .
JOURNAL OF EXPERIMENTAL MEDICINE, 1998, 188 (06) :1185-1190
[10]   Lymphoma B cells evade apoptosis through the TNF family members BAFF/BLyS and APRIL [J].
He, B ;
Chadburn, A ;
Jou, E ;
Schattner, EJ ;
Knowles, DM ;
Cerutti, A .
JOURNAL OF IMMUNOLOGY, 2004, 172 (05) :3268-3279