Abstract 2960: The novel trifunctional anti-BCMA NK cell engager SAR’514 has potent in-vitro , in-vivo and ex-vivo anti-myeloma effect through dual NK cell engagement

Multiple Myeloma (MM) is the second most prevalent hematopoietic malignancy, representing 10% of total blood cancers. Despite the emergence of new therapies, it is still an incurable disease. Safe, potent and innovative approaches with long lasting beneficial effects are required. BCMA (B Cell Maturation Antigen) is a cell surface receptor selectively expressed on normal and malignant plasma cells and promote cell proliferation and survival upon binding of its ligands APRIL (A PRoliferation Inducing Ligand) and BAFF (B cell Activating Factor). BCMA expression is highly prevalent on myeloma tumor cells and is maintained after standard of care treatments 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 SAR’514, a trifunctional NK Cell Engager (NKCE) 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. We demonstrated that SAR’514 NK dual engagement was more potent than the single NK engagement with NKp46 or CD16a as well as the combination of NKp46 and CD16a engagement. SAR’514 leads to NK cell activation, degranulation and release of effector cytokines only in the presence of BCMA+ tumor cells. This antitumor activity is associated with very low IL-1β, IL-6, TNFα and IFNγ cytokine release as compared to a T cell engager targeting the same BCMA antigen, in PBMC and in whole blood settings in the presence of BCMA+ tumor target cells. In addition, the in vivo anti-tumor activity of an anti-murine NKp46 surrogate NKCE molecule was investigated in huFcgR transgenic mice engrafted with the EL4-huBCMA murine thymoma model. SAR’514 induced a significant mouse survival at 0.5 to 5 mg/kg with an overall survival of 90% as compared to the control group in which only 20% of mice survived. Importantly, SAR’514 exhibits ex vivo efficacy using bone marrow mononuclear cells (BMMC) from MM patients in an autologous setting showing an active and efficient primary MM cell killing against MM cells from patients that have failed diverse therapies, including standard of care t