The Combination of the Novel Trifunctional BCMA NK Cell Engager SAR445514 with IMiDs and Celmods Enhances Cytotoxicity Against Multiple Myeloma Cells As Compared to Single Agents

Introduction:

SAR445514 (SAR'514) is a trifunctional anti-BCMA NK Cell Engager (NKCE), currently in a phase 1/2 trial in patients with relapsed/refractory (R/R) multiple myeloma (MM) (NCT05839626). SAR'514 acts by targeting BCMA antigen expressed on MM cells and by co-engaging NKp46 and CD16a activating receptors on NK cells, facilitating the formation of an immunological synapse between NK and BCMA-positive tumor cells. This leads to NK cell activation, degranulation and tumor cell killing. The anti-tumor activity of SAR'514 in preclinical models has been previously described (Tang et al. “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” American Association for Cancer Research 2023). Herein, we further document SAR'514 in vitro anti-myeloma effects in combination with pomalidomide (IMiD), iberdomide and mezigdomide (CELMoDs), which have established or emerging therapeutic roles in MM.

Methods:

The cytotoxic activity of SAR'514 was evaluated in vitro as a single agent alongside pomalidomide, iberdomide or mezigdomide and also as a combination with each of these IMiD/CELMoDs against the fluorescent BCMA-positive H929-RFP MM cells, in the presence of healthy donor NK cells at an effector to target ratio set at 1:2 during 4 days by live-cell imaging analysis (Incucyte system).

Results:

SAR'514 and the different IMiD/CELMoDs demonstrated potent MM cell killing in a concentration-dependent manner as single agents against H929 cells as compared to an isotype control that does not bind to BCMA. When SAR'514 was combined with either pomalidomide, iberdomide or mezigdomide, a higher cytotoxic activity was observed as compared to single agent pomalidomide (p=0.1197) and significantly higher as compared to single agent iberdomide (p=0.0035) or mezigdomide (p=0.0026). SAR'514 shows the highest potency in combination with mezigdomide.

Conclusion:

In summary, these results demonstrate that the combinations of SAR'514 with pomalidomide IMiD or iberdomide and mezigdomide CELMoDs potentiate MM tumor cell killing in vitro and provide consistent support for the evaluation of this combination in patients with multiple myeloma.

Tang:Sanofi: Current Employment, Current equity holder in publicly-traded company. Zaghi:Sanofi: Current Employment. Perlat:Sanofi: Current Employment. Boisrobert-D'heilly:Sanofi: Current Employment. Van de Velde:Sanofi: Current Employment. Desjonqueres:Sanofi: Current Employment. Fantin:Sanofi: Current Employment. Chiron:Sanofi: Current Employment. Virone-Oddos:Sanofi: Current Employment.