title: Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu.
abstract: 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.
authors: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. yu-tzu_tai@dfci.harvard.edu
authors: Yu-Tzu
authors: YT
authors: Tai
authors: Myles
authors: M
authors: Dillon
authors: Weihua
authors: W
authors: Song
authors: Merav
authors: M
authors: Leiba
authors: Xian-Feng
authors: XF
authors: Li
authors: Peter
authors: P
authors: Burger
authors: Alfred I
authors: AI
authors: Lee
authors: Klaus
authors: K
authors: Podar
authors: Teru
authors: T
authors: Hideshima
authors: Audie G
authors: AG
authors: Rice
authors: Anne
authors: A
authors: van Abbema
authors: Lynne
authors: L
authors: Jesaitis
authors: Ingrid
authors: I
authors: Caras
authors: Debbie
authors: D
authors: Law
authors: Edie
authors: E
authors: Weller
authors: Wanling
authors: W
authors: Xie
authors: Paul
authors: P
authors: Richardson
authors: Nikhil C
authors: NC
authors: Munshi
authors: Claire
authors: C
authors: Mathiot
authors: Hervé
authors: H
authors: Avet-Loiseau
authors: Daniel E H
authors: DE
authors: Afar
authors: Kenneth C
authors: KC
authors: Anderson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000951:Antigens, Neoplasm; D001853:Bone Marrow; D002448:Cell Adhesion / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D000071176:Signaling Lymphocytic Activation Molecule Family; D017154:Stromal Cells; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family