HuLuc63 in Combination Regimens with Conventional and Targeted Therapies Has Additive and Synergistic Anti-Tumor Activity in Pre-Clinical Models of Myeloma.

Introduction: HuLuc63 is a humanized monoclonal antibody that targets CS1 (CD2 subset 1, CRACC, SLAMF7, CD319), a cell surface glycoprotein that is highly and universally expressed on myeloma cells. In preclinical studies, we have shown that HuLuc63 treatment of mice with multiple myeloma (MM) xenograft tumors resulted in significant in vivo anti-tumor activity that is mediated at least in part by an antibody-dependent cellular cytotoxicity (ADCC) mechanism of action. The purpose of this study was to examine whether using HuLuc63 in combination with a panel of drugs having distinct modes of action (dexamethasone, thalidomide, bevacizumab (Avastin®), bortezomib (Velcade®)) could result in additional therapeutic benefit and provide a rationale for the design of future clinical trials.

Methods: HuLuc63 in combination with other agents was tested in vivo for anti-tumor activity using the human L363 and OPM2 xenograft models. SCID mice were implanted subcutaneously with myeloma cells and randomized into different groups (10–15 mice per treatment group) when the average tumor volume reached ∼100 mm³. HuLuc63 was administered via intra-peritoneal injection twice per week at doses of 1–10 mg/kg. Dosing for dexamethasone was 10 mg/kg twice weekly, thalidomide 50 mg/kg daily, bevacizumab twice weekly at 0.5 mg/kg, and bortezomib 1 mg/kg for two dosing cycles, each cycle consisting of twice weekly dosing for 2 weeks followed by a week of rest.

Results: The combination of dexamethasone with HuLuc63 showed a statistically significant increase in anti-tumor activity over either agent alone (p < 0.04). Combination with thalidomide only showed a slight enhancement of tumor inhibition when dosed in combination with HuLuc63 but its anti-tumor activity did not reach a statistically significant increase in over that of HuLuc63 alone. Co-treatment of the anti-VEGF anti-angiogenic monoclonal antibody bevacizumab with HuLuc63 resulted in a significant increase in tumor inhibition (p < 0.05) over that observed with either antibody when used as a single agent. The strongest anti-myeloma activity was observed when HuLuc63 was combined with bortezomib, which appeared to result in a synergistic inhibition of tumor cell growth. None of the agents tested changed the CS1 expression level on the myeloma cells or diminished the anti-myeloma activity of HuLuc63.

Conclusions: These results suggest that HuLuc63 may be combined with different classes of drugs to enhance its anti-myeloma effects. In particular, agents that may induce apoptosis of myeloma cells (dexamethasone and bortezomib) and anti-angiogenics (bevacizumab) may be of particular interest for future clinical testing. Further preclinical studies using HuLuc63 in combination with other agents are in progress. HuLuc63 is currently being evaluated in a phase I clinical study as monotherapy for the treatment of relapsed/refractory multiple myeloma.