The Novel Trifunctional Anti-BCMA NK Cell Engager SAR'514 Has Potent in-Vitro and in-Vivo Anti-Myeloma Effect through Dual NK Cell Engagement

Abstract

Multiple Myeloma (MM) is the second most prevalent hematopoietic malignancy, representing 10% of total blood cancers. Despite the emergence of new therapies in the recent years, it is still an incurable disease, with a 5-year overall survival of 56% in patients (https://cancerstatisticscenter.cancer.org/). Thus, innovative approaches that would be safe, potent and with long lasting beneficial effects are required. BCMA (B Cell Maturation Antigen) is a cell surface receptor highly and selectively expressed on normal and malignant plasma cells and which function is to promote cell proliferation and survival upon binding of its ligands APRIL (A PRoliferation Inducing Ligand) and BAFF (B cell Activating Factor). BCMA has a very high prevalence among MM patients and its expression on tumor cells is maintained after treatments with standard of care such as anti-CD38 therapies, or even BCMA-targeting agents (Cohen AD et al. J Clin Invest 2019). The ability of NK cells to intrinsically kill tumor cells, leaving healthy cells unharmed, with minimal pro-inflammatory cytokine release induction as compared to T cell-based therapies makes NK cells ideal immune cells for a safe and efficacious therapeutic approach. We developed a NK Cell Engager (NKCE) SAR'514 that activates NK cells through a dual engagement of NKp46 and CD16a, two major NK cell activating receptors highly expressed on NK cells in MM patients, and which redirects the activated NK cells to engage and kill BCMA+ tumor cells. The trifunctional NK cell engager molecule SAR'514 was designed to specifically and efficiently activate NK cells to induce potent cytotoxic activity against BCMA+ MM cells. SAR'514 exhibits high affinity for the 3 targets BCMA, CD16 and NKp46. The ability of SAR'514 to induce NK cell-mediated cytotoxicity in vitro was tested against a panel of MM cell lines with low, medium and high BCMA expression levels and compared to an afucosylated reference compound. SAR'514 exhibited a strong and similar potency against all tested cell lines and a better potency compared to this comparator (EC50 0.4 pM vs 7.8 pM) demonstrating the superiority of a dual targeting NK cell engager molecule as compared to an antibody approach. An optimized NK cell activation was obtained with a dual engagement of both NKp46 and CD16a compared to single CD16a or NKp46 engagement or the combination of two molecules engaging CD16a or NKp46. Binding of SAR'514 on NK cells promoted a strong NK cell activation and induced cytotoxic activity only in the presence of MM target cells with no fratricide effect on NK cells. This antitumor activity is associated with very low IL-1b, IL-6, TNFa and IFNg cytokine release (in the low pg/mL range) in human PBMC and whole blood settings in the presence of BCMA+ tumor target cells, and a good safety profile. In addition, the in vivo anti-tumor activity of an anti-murine NKp46 surrogate NK cell engager molecule at 0.05, 0.5 and 5 mg/kg was investigated versus a control isotype in huFcgR transgenic mice engrafted with the EL4-huBCMA murine thymoma model. As compared to the control group in which only 20% of mice survived with a median survival day of 44.5 days, SAR'514 induced a significant mouse survival from 0.5 mg/kg to 5 mg/kg with an overall survival of 90% and a median survival day over 90 days. In summary, these results demonstrate the efficacy of SAR'514 for controlling MM tumors in vivo and provide consistent support for its clinical development.