Abstract 2621: Preclinical Efficacy of DM002, a bispecific HER3 × MUC1 antibody-drug conjugate with a novel DNA topoisomerase I inhibitor, in solid tumor models

Abstract MUC1 is a known tumor-associated antigen (TAA), but previous anti-MUC1 agents have shown limited clinical efficacy due to neutralization by the soluble N-terminal autoproteolytic product of MUC1. More recently, HER3-targeted ADCs, such as Patritumab deruxtecan, have shown encouraging early clinical activity in a variety of tumors. However, the majority of patients did not exhibit response to paritumab deruxtecan treatment. Therefore, improved therapies targeting these TAAs are needed. As HER3 and MUC1 are co-expressed in a wide range of cancer types, we hypothesized that simultaneous targeting of HER3 and MUC1 with a bispecific antibody-drug conjugate (bsADC) could potentially lead to increased efficacy, reduced resistance and improved safety in the clinical setting. We generated an anti-HER3 × MUC1 bispecific antibody using the fully human common light chain antibody transgenic mice (RenLite®). The HER3 × MUC1 bsAb showed improved cell binding and internalization in vitro compared to the parental mAb, suggesting synergy between the two arms. We then conjugated the HER3xMUC1 bsAb with vcMMAE for proof-of-concept studies, or with our novel DNA topoisomerase I inhibitor linker/payload conjugates (BLD1102) to make DM002-BLD1102 bsADC. Both bsADCs potently inhibited the growth of HER3+MUC1+ PDX tumors. DM002-vcMMAE also showed greater in vivo efficacy than its parental mAb ADCs, consistent with their in vitro internalization activity. DM002-BLD1102 also showed strong anti-tumor activity in DM002-vcMMAE resistant PDX models, suggesting the superiority of this new DNA topoisomerase I inhibitor linker/payload over the classical vcMMAE linker/payload. In conclusion, the HER3 × MUC1 bsAb is a promising agent for the treatment of HER3 and MUC1 positive tumors. Citation Format: Yifu Zhang, Chengzhang Shang, Nannan Wang, Gao An, Chaoshe Guo, W. Frank An, Yi Yang. Preclinical Efficacy of DM002, a bispecific HER3 × MUC1 antibody-drug conjugate with a novel DNA topoisomerase I inhibitor, in solid tumor models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2621.