Abstract 6325: A novel EGFR x MUC1 bispecific antibody-drug conjugate, BSA01, targets MUC1 transmembrane cleavage products and improves tumor selectivity

Abstract Epidermal growth factor receptor (EGFR) and mucin 1 (MUC1) are tumor-associated antigens that are highly co-expressed in esophageal squamous cell carcinomas, non-small cell lung cancers (NSCLC), and triple negative breast cancers, among others. MUC1, a glycoprotein essential for the formation of the epithelial mucous barrier, is hypoglycosylated and dimerizes with EGFR, a potent oncoprotein, in transformed cells. Dual-targeting of both tumor-associated antigens (TAAs) represents a promising therapeutic strategy to treat common malignancies. We generated a fully human anti-EGFR/MUC1 bispecific antibody-drug conjugate (BSA01) from RenLite® humanized, common light chain mice. BSA01 is conjugated with Monomethyl auristatin E (MMAE). BSA01 targets the extracellular domain of MUC1-C (C-terminal domain of MUC1), which is the membrane-bound MUC1 cleavage product that remains after MUC1 is cleaved, providing more access to the tumor antigen in situ. In addition, we generated affinity and internalization optimized binders targeting EGFR that increases the tumor selectivity, to avoid potential skin toxicity due to ubiquitous basal EGFR expression. Internalization assays demonstrate that the anti-EGFR/MUC1 bispecific antibody used to generate BSA01 was endocytosed in tumor cells co-expressing EGFR/MUC1 more efficiently than mono- or bivalent antibodies targeting EGFR or MUC1 alone. When conjugated with payload, BSA01 also exhibited strong anti-tumor efficacy in vitro against gastric, NSCLC and pancreatic cancer cell lines. Moreover, BSA01 showed similar activity in vivo, effectively inhibiting tumor growth in multiple cell-derived xenograft and patient-derived xenograft models. These results suggest that BSA01 has great clinical potential for treating tumors co-expressing EGFR and MUC1. Citation Format: Yifu Zhang, Chenzhang Shang, Anqi Wang, Jia Zhang, Yuji Liu, Hao Li, Xiaopeng Li, Gao An, Li Hui, Frank An, Yi Yang. A novel EGFR x MUC1 bispecific antibody-drug conjugate, BSA01, targets MUC1 transmembrane cleavage products and improves tumor selectivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6325.