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 Blood, 15 August 2008, Vol. 112, No. 4, pp. 1329-1337.
Prepublished online as a Blood First Edition Paper on October 9, 2007; DOI 10.1182/blood-2007-08-107292.

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NEOPLASIA

Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu

Yu-Tzu Tai1, Myles Dillon2, Weihua Song1, Merav Leiba1, Xian-Feng Li1, Peter Burger1, Alfred I. Lee1, Klaus Podar1, Teru Hideshima1, Audie G. Rice2, Anne van Abbema2, Lynne Jesaitis2, Ingrid Caras2, Debbie Law2, Edie Weller3, Wanling Xie3, Paul Richardson1, Nikhil C. Munshi1,4, Claire Mathiot5, Hervé Avet-Loiseau6, Daniel E. H. Afar2, and Kenneth C. Anderson1

1 Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 2 Department of Research, PDL BioPharma, Fremont, CA; 3 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; 4 Veterans Administration Boston Health Care System, Harvard Medical School, Boston, MA; 5 Hematology Laboratory, Institut Curie, Paris, France; and 6 Laboratoire d'Hématologie Institut de Biologie, Nantes, France

Currently, no approved monoclonal antibody (mAb) therapies exist for human multiple myeloma (MM). Here we characterized cell surface CS1 as a novel MM antigen and further investigated the potential therapeutic utility of HuLuc63, a humanized anti-CS1 mAb, for treating human MM. CS1 mRNA and protein was highly expressed in CD138-purified primary tumor cells from the majority of MM patients (more than 97%) with low levels of circulating CS1 detectable in MM patient sera, but not in healthy donors. CS1 was expressed at adhesion-promoting uropod membranes of polarized MM cells, and short interfering RNA (siRNA) targeted to CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs). HuLuc63 inhibited MM cell binding to BMSCs and induced antibody-dependent cellular cytotoxicity (ADCC) against MM cells in dose-dependent and CS1-specific manners. HuLuc63 triggered autologous ADCC against primary MM cells resistant to conventional or novel therapies, including bortezomib and HSP90 inhibitor; and pretreatment with conventional or novel anti-MM drugs markedly enhanced HuLuc63-induced MM cell lysis. Administration of HuLuc63 significantly induces tumor regression in multiple xenograft models of human MM. These results thus define the functional significance of CS1 in MM and provide the preclinical rationale for testing HuLuc63 in clinical trials, either alone or in combination.


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Y.-T. Tai, E. Soydan, W. Song, M. Fulciniti, K. Kim, F. Hong, X.-F. Li, P. Burger, M. J. Rumizen, S. Nahar, et al.
CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells
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