Killing of Drug-Sensitive and Resistant Myeloma Cells and Disruption of Their Bone Marrow Stromal Interaction by HuLuc63, a Novel Humanized Anti-CS1 Monoclonal Antibody.
Authors: Tai Yu-Tzu , Song Weihua , Li Xian-Feng , Burger Peter , Schlossman Robert , Rice Audie , van Abbema Anne , Richardson Paul , Munshi Nikhil C. , Afar Daniel , Anderson Kenneth C. 
Published: October 2019

Introduction: Current monoclonal antibody (mAb) therapies for multiple myeloma (MM) have had limited success due to narrow target expression across MM patient samples. A preferred strategy would be to develop cytotoxic human mAbs against novel antigens that are highly expressed in MM cells yet have limited expression in other cell types. CS1 (CD2 subset 1, CRACC, SLAMF7), a member of the CD2 family of cell surface glycoproteins, was found to be highly expressed in myeloma cells. In this study, we investigated the anti-myeloma activity of HuLuc63, a novel humanized anti-CS1 mAb.

Methods: Microarray expression profiling was used to determine the CS1 mRNA levels in CD138-expressing myeloma cells from 101 MM patient samples. For detection of CS1 protein, flow cytometry was performed using the anti-CS1 mAb HuLuc63. Functional characterization of HuLuc63 was performed by assessing antibody-dependent cellular cytotoxicity (ADCC) and by assessing MM and bone marrow stromal cell (BMSC) interactions.

Results: CS1 mRNA was expressed in CD138 cells from more than 96% (97/101) of MM patients. Flow cytometric analysis confirmed that protein expression mirrors the mRNA profile. Importantly, CS1 is also present in 12 MM cell lines that are either drug-sensitive or resistant. HuLuc63, but not an isotype control antibody, induced ADCC in a CS1-specific, dose-dependent manner against CD138-expressing MM lines and patient MM cells including dexamethasone (dex)-sensitive MM1S and dex-resistant MM1R cells. Significantly, HuLuc63 triggered autologous ADCC against CS1-expressing CD138-purified tumor cells from 11 MM patients resistant to conventional or novel therapies such as bortezomib (Velcade®) and an HSP90 inhibitor. Since CS1 may regulate cell adhesion, we next studied whether HuLuc63 alters MM cell adhesion to BMSCs. HuLuc63 inhibited MM cell adhesion to BMSCs in a dose-dependent manner, whereas human control IgG did not. However, the presence of BMSC appeared to reduce HuLuc63-induced cell lysis against MM1S and MM1R cells. Since the immunomodulatory drug lenalidomide (Revlimid®) enhances NK cell function, we further tested whether HuLuc63-induced ADCC against MM cells is augmented by lenalidomide. Pretreatment with lenalidomide markedly enhanced NK-cell-mediated lysis of autologous patient MM cells triggered by HuLuc63.

Conclusions: We show that the new MM antigen, CS1, is expressed in myeloma cells from more than 96% of MM patients. The novel humanized anti-CS1 mAb, HuLuc63, induced significant cytotoxicity against MM cells including drug-resistant cells, and inhibited their interaction with BMSCs. These data suggest that HuLuc63 may have clinical utility in a spectrum of MM patients including those newly diagnosed with the disease as well as patients with late stage refractory disease.