Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu.
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.
Tai
Yu-Tzu
YT
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
Dillon
Myles
M
Song
Weihua
W
Leiba
Merav
M
Li
Xian-Feng
XF
Burger
Peter
P
Lee
Alfred I
AI
Podar
Klaus
K
Hideshima
Teru
T
Rice
Audie G
AG
van Abbema
Anne
A
Jesaitis
Lynne
L
Caras
Ingrid
I
Law
Debbie
D
Weller
Edie
E
Xie
Wanling
W
Richardson
Paul
P
Munshi
Nikhil C
NC
Mathiot
Claire
C
Avet-Loiseau
Hervé
H
Afar
Daniel E H
DE
Anderson
Kenneth C
KC
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
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family