A CD38xCD28 Costimulatory Bispecific Antibody Demonstrates Potent Preclinical Combinatorial Activity with a BCMAxCD3 T Cell-Engager

Improving therapies for relapsed/refractory multiple myeloma (RRMM) remains an unmet medical need, as despite improvements in treatment management, there is still no curative therapy and relapse remains a persistent problem. The emergence of T cell targeted immunotherapies, including BCMAxCD3 bispecific antibodies (bsAbs), has marked a significant advancement in patient outcomes. Among these, the BCMAxCD3 bispecific antibody, linvoseltamab, has emerged as a potential best-in-class option for RRMM; however, deeper and more durable responses in this patient population are still required. In RRMM, linvoseltamab activates T cells by engaging the T cell receptor (TCR)/CD3 complex in the presence of BCMA-expressing MM tumor cells leading to tumor cell killing. However, for optimal activation, T cells require engagement of costimulatory receptor signaling (e.g., CD28) in addition to the TCR/CD3 complex. CD28-targeting bsAbs, including REGN5668 (MUC16xCD28) and REGN5837 (CD22xCD28), are an emerging class of therapeutics capable of providing targeted costimulation and enhancing T cell effector function in combination with CD3-targeted bsAbs. In MM, CD38 is a cell-surface, multifunctional ectoenzyme that is highly expressed on MM blasts, making it a good candidate for a CD28-targeted bsAb. Thus, here we examine whether providing CD28 costimulatory signaling via a novel CD38xCD28 bsAb in the context of BCMAxCD3 bsAb therapy (linvoseltamab) can drive enhanced antitumor activity in preclinical models. We explored combining a novel CD38xCD28 bsAb antibody, REGN7945, with linvoseltamab. This combination potently enhanced linvoseltamab's anti-tumor activity by delivering a critical costimulatory signal to CD28-expressing T cells, augmenting T cell activation, cytokine production, and cytotoxicity in vitro. We demonstrated strong enhancement of linvoseltamab's anti-tumor activity with REGN7945 in multiple in vivo murine xenograft MM models. Further, in immunocompetent mice genetically engineered to express human CD3, CD28, BCMA, and CD38, we demonstrated potent combinatorial efficacy of linvoseltamab and REGN7945 to treat syngeneic murine tumors. Based on these promising preclinical results, a Phase 1 clinical trial is planned to evaluate the safety, tolerability, and preliminary efficacy of the CD38xCD28 bsAb REGN7945 and the BCMAxCD3 bsAb linvoseltamab in patients with RRMM. This innovative approach, leveraging the combinatorial potential of CD38xCD28 costimulation with linvoseltamab's targeted cytolytic activity, represents a novel therapeutic strategy with the potential to improve RRMM treatment outcomes.