Abstract 5530: Preclinical validation of the antitumor activity and safety of M0324, a novel MUC-1 conditional CD40 agonist, and its combination with immune checkpoint inhibitors (ICIs), for selective immune activation

Le résumé fourni par la source

Abstract Background: MUC-1, a glycoprotein commonly overexpressed in various cancers, plays a pivotal role in tumor progression and immune evasion. M0324 is a novel MUC-1-conditional CD40 agonist designed to activate antigen-presenting cells in the presence of MUC-1-overexpressing tumor cells. Targeted CD40 activation could minimize systemic toxicity observed with first-generation unconditional CD40 antibodies. Methods: The effect of M0324 on the activation of CD40 expressed on human dendritic cells (DCs) was assessed in vitro and benchmarked against anti-CD40 antibodies, using MUC-1 expressing HCC827 tumor cell line co-cultured with primary human monocyte-derived DCs. Co-culture of human primary B cells with human tumor cell lines with various MUC-1 expression was analyzed to further characterize MUC-1 dependent M0324 activity. In vivo efficacy was evaluated using M0324m, a mouse surrogate for M0324, as monotherapy or in combination with anti-PD-L1, in hMUC-1 expressing tumor models. Results: In vitro, M0324 significantly enhanced DC activation in the presence of MUC-1 expressing tumor cells; no activity was observed in the absence of MUC-1 expressing cells. M0324 led to higher activation of IL-12p40 expression in DC HCC827 tumor cell co-cultures versus other agonistic anti-CD40 antibodies. Co-culture of human primary B cells with tumor cell lines with various levels of MUC-1 expression demonstrated that M0324-induced B cell activation was linked to MUC-1 expression levels on tumor cells. In vivo, a single dose of M0324m demonstrated robust tumor eradication in hMUC-1high immune competent mouse tumor models (orthotopic Panc02-MUC-1 model: 93%; MC38-MUC-1 model: 100% tumor-free mice). The lack of body weight loss in mice after M0324m dosing indicated minimal off-tumor effects and increased therapeutic index due to the conditional activation of CD40 in the presence of MUC-1. In contrast, anti-mouse CD40 benchmark antibody induced body weight loss, and its marginally tolerable dose failed to control tumor growth. M0324m also demonstrated robust antitumor activity in hMUC-1int tumor models (MC38, 4T1). Combination of M0324m with anti-PD-L1 in hMUC-1int tumor model further improved tumor growth inhibition. Conclusions: M0324 was shown to selectively activate DC and B cells only in the presence of MUC-1 expressing tumor cells, demonstrating superior in vitro and in vivo activity compared to anti-CD40 agonistic antibodies. M0324m further improved tumor control when combined with anti-PD-L1. M0324m was also well-tolerated in vivo. Overall, the preclinical data suggest that combination of M0324 with ICIs may maximize the rigor of de novo or pre-existing T cell responses. A Phase 1 study of M0324 as monotherapy and in combination with pembrolizumab and chemotherapy is ongoing (NCT07166601). Citation Format: Weixiao Sha, Jing Ni, Anika Bergmann, Nathalie Duncan, Bo Marelli, Feng Jiang, Julia Marie Mueller, Sina Junkers, Christina Hubl, Ivana Durutovic, Sonia Jaramillo, Paul D. Lyne, Laura Helming. Preclinical validation of the antitumor activity and safety of M0324, a novel MUC-1 conditional CD40 agonist, and its combination with immune checkpoint inhibitors (ICIs), for selective immune activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5530.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.