M9657 / EMD Serono - LARVOL DELTA

M9657, a tumor-targeted anti-CD137 agonist, induced significant antitumor immunity in combination with anti-PD-1 antibody (AACR 2024) - "Anti-PD-(L)-1 antibodies can reverse the suppressive immune signals, and CD137 agonists can boost T cell activation, improving antigen presentation and cytokine release. The antitumor immunity of M9657 + pembrolizumab (anti-PD-1 antibody) combination therapy was assessed using in-vitro luciferase and ex-vivo functional assays. The combination of M9657 with anti-PD-(L)1 could overcome primary ICI therapy resistance and improve the antitumor efficacy of current anti-PD-(L)1 therapy in the clinic. Our findings support a combination strategy to combine M9657 with anti-PD-(L)1 in a clinical setting, potentially leading to enhanced antitumor immunity and improved patient outcomes. Future studies should investigate the safety and efficacy of this combination therapy in human patients."

Combination therapy • Oncology • CD8 • MSLN

M9657 is a bispecific tumor-targeted anti-CD137 agonist that induces MSLN-dependent antitumor immunity without liver inflammation. (PubMed, Cancer Immunol Res) - "Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by FcγR ligand-dependent CD137 activation, respectively. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity."

IO biomarker • Journal • Hepatology • Oncology • CD8 • MSLN

Anti-tumor immunity of M9657, a conditional CD137 immune agonist, is correlated with mesothelin expression on tumor cells (AACR 2023) - "M9657 exhibits promising and potent MSLN-dependent conditional immune agonism, supporting its clinical investigation."

IO biomarker • Tumor cell • Oncology • CD8 • IFNG • MSLN • TNFRSF9

M9657, a novel tumor-targeted conditional anti-CD137 agonist displays MSLN-dependent anti-tumor immunity (SITC 2021) - "In clinical trials, the systemic administration of the 1st generation CD137 agonist monotherapies, utomilumab and urelumab, were suspended due to either low anti-tumor efficacy or hepatotoxicity mediated by recognized epitope on CD137 and FcγR ligand-dependent clustering. Comparing with 3H3, a Urelumab surrogate Ab, FS122m displayed an improved therapeutic window with significantly lower for on-target /off-tumor toxicity. Conclusions Taken together, M9657 exhibits a promising developability profile as a tumor-targeted immune agonist with potent anti-cancer activity, but without systemic immune activation."

IO biomarker • Oncology • BCL2L1 • MSLN