AFM26 is a novel, highly potent BCMA/CD16A-directed bispecific antibody for high affinity NK-cell engagement in multiple myeloma.

8045 Background: Despite recent advances in the treatment of multiple myeloma (MM), novel therapies are needed to achieve long-lasting remissions in a greater number of patients. Natural killer (NK) cells play a key role in the immune response to MM and have been implicated in the clinical efficacy of current standard of care interventions, including IMiDs, proteasome inhibitors, recently approved immunotherapies and autologous stem cell transplantation (ASCT). Numerous strategies are being developed to enhance the natural NK-cell cytotoxicity against myeloma cells, which is frequently dysregulated in MM. Approaches include modulation of activity, through cytokine stimulation or immune checkpoint targeting, and adoptive transfer of culture expanded NK-cells in ASCT-eligible MM. While highly attractive, these approaches are non-targeted, as they rely on the natural cytotoxicity of NK-cells, and may benefit from antigen-specific retargeting and effector activation. AFM26 is a novel tetravalent, bispecific antibody designed to specifically enhance NK-cell anti-MM activity by redirecting NK-cell lysis to BCMA, an antigen expressed on MM cells. Methods: NK-cell engagement and cytotoxicity of AFM26 towards MM cell lines and freshly isolated tumor cells from MM patients was characterized in vitro and compared with classical antibody formats. Results: AFM26 engages NK-cells with superior avidity ( K D : 1-2nM) through bivalent interaction with CD16A (FcγRIIIa) and demonstrates extended cell surface retention that is not affected by high level IgG, as is particularly relevant in MM. Importantly, AFM26 does not induce NK-cell depletion but selectively induces potent and efficacious lysis of MM cells in vitro. Conclusions: In summary, AFM26 is a promising candidate to enhance NK-cell activity and confer tumor-specificity to NK-cells in MM. Differentiation of AFM26 from classical antibody formats and its potential for combination with cellular NK-cell therapies is highlighted.