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

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: He...

Full description

Saved in:
Bibliographic Details
Published in:Clinical cancer research 2007-10, Vol.13 (19), p.5903-5909
Main Authors: NERI, Paola, KUMAR, Shaji, MUNSHI, Nikhil C, HIDESHIMA, Teru, ANDERSON, Kenneth C, RAJE, Noopur, FULCINITI, Maria Teresa, VALLET, Sonia, CHHETRI, Shweta, MUKHERJEE, Sidhartha, YUTZUTAI, CHAUHAN, Dharminder, TASSONE, Pierfrancesco, VENUTA, Salvatore
Format: Article
Language:English
Subjects:
Acid Phosphatase - metabolism
Animals
Antibodies - chemistry
antibody
Antineoplastic agents
B-Cell Activating Factor - immunology
B-Cell Activating Factor - physiology
BAFF
Biological and medical sciences
Cell Line, Tumor
Cell Survival
Gene Expression Profiling
Hematologic and hematopoietic diseases
Humans
Immunodeficiencies. Immunoglobulinopathies
Immunoglobulinopathies
Immunopathology
Interleukin-6 - metabolism
Isoenzymes - metabolism
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical sciences
Mice
Mice, SCID
multiple myeloma
Multiple Myeloma - genetics
Multiple Myeloma - immunology
Osteoclasts - metabolism
Pharmacology. Drug treatments
Recombinant Proteins - chemistry
SCID-hu
Tartrate-Resistant Acid Phosphatase
Treatment Outcome
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-07-0753