Abstract 6931: Preclinical study of BCG044, a novel bispecific ADC targeting EpCAM and HER3 for the treatment of colorectal and other tumors

Abstract Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths. Unfortunately, current therapies have limited effectiveness on long-term survival. Antibody-drug conjugates (ADCs) represent an emerging class of treatments with potential in oncology, but their efficacy in colorectal cancer has been limited thus far. Therefore, identifying new drug targets and developing ADCs are essential for improving treatment outcomes. Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein widely expressed in various cancers, notably colorectal, gastric, ovarian, and lung cancers. However, its presence in normal tissues has led to adverse effects from previous biologic therapies, including gastrointestinal toxicity and pancreatitis associated with systemic administration. In this study, we developed an innovative approach to generate a bispecific ADC targeting both EpCAM and HER3, another antigen that is widely overexpressed in various solid tumors, including gastrointestinal cancers, breast cancer, and NSCLC. By employing a "1+1" format, we aimed to mitigate EpCAM-related toxicity while enhancing tumor selectivity. The BCG044 bispecific antibody (bsAb) effectively bound to a diverse range of gastrointestinal tumor cell lines. Notably, the monovalent form of EpCAM and HER3 resulted in decreased internalization within tumor cells. In contrast, simultaneous engagement of both targets by bsAbs maximized internalization. This suggests that bsAb requires targeting of tumor cells with bivalency. When conjugated with BLD1102, a novel TOP1 inhibitor linker-payload, BCG044 exhibited potent efficacy comparable to the EpCAM benchmark ADC and demonstrated stronger effects than the HER3 benchmark ADC in colorectal, breast, and NSCLC PDX models. Subsequently, we utilized humanized EpCAM mice to test a surrogate ADC that contained the same EpCAM arm, along with a HER3 arm that cross-reacted with mouse HER3. The surrogate ADC demonstrated better tolerance compared to both the parent EpCAM ADC. In summary, BCG044 exhibited the potential to enhance tumor selectivity while maintaining potent efficacy against colorectal and other solid tumors. Citation Format: Jeremy Lee, Zhuolin Li, Chengzhang Shang, Yi Yang, . Preclinical study of BCG044, a novel bispecific ADC targeting EpCAM and HER3 for the treatment of colorectal and other tumors 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 6931.