Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu
| Autor: | Weihua Song, Daniel E. H. Afar, Peter Burger, Yu-Tzu Tai, Hervé Avet-Loiseau, Wanling Xie, Paul G. Richardson, Claire Mathiot, Audie G. Rice, Anne van Abbema, Xian Feng Li, Kenneth C. Anderson, Lynne Jesaitis, Edie Weller, Ingrid Caras, Alfred Ian Lee, Klaus Podar, Teru Hideshima, Nikhil C. Munshi, Myles B.C. Dillon, Merav Leiba, Debbie A. Law |
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| Rok vydání: | 2008 |
| Předmět: |
Stromal cell
medicine.drug_class Immunology Biology Monoclonal antibody Biochemistry Mice Antigen Antigens Neoplasm Bone Marrow Signaling Lymphocytic Activation Molecule Family Cell Adhesion Tumor Cells Cultured medicine Animals Humans RNA Messenger Receptors Immunologic Cell adhesion Antibody-dependent cell-mediated cytotoxicity Neoplasia Bortezomib SLAMF7 Antibody-Dependent Cell Cytotoxicity Antibodies Monoclonal Cell Biology Hematology Xenograft Model Antitumor Assays Molecular biology medicine.anatomical_structure Bone marrow Stromal Cells Multiple Myeloma medicine.drug |
| Zdroj: | Blood. 112:1329-1337 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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