Abstract 4793: BCG033: a first-in-class PTK7×TROP2 bispecific ADC demonstrating potent and broad efficacy in various preclinical models

Abstract TROP2 is frequently overexpressed in a number of epithelial cancers, and therapeutics targeting TROP2 has demonstrated clinical efficacy in multiple indications, including triple-negative breast cancer (TNBC), HR+/HER2- breast cancer, and non-small cell lung cancer (NSCLC). However, its broad expression in normal tissues raises the risk of on-target and off-tumor toxicity, potentially limiting the therapeutic effectiveness. PTK7 has emerged as an alternative target, exhibiting high prevalence and overexpression in a variety of tumors, such as TNBC, NSCLC, ovarian, oesophageal and colorectal cancers. BCG033 is a bispecific antibody-drug conjugate (ADC) that targets both PTK7 and TROP2, enhancing the therapeutic efficacy while reducing the off-target effects. Developed using Biocytogen’s fully human common light chain RenLite® mice, BCG033 is conjugated with BLD1102--a novel linker/payload containing a DNA Topoisomerase I inhibitor paired with a highly hydrophilic, protease-cleavable linker, achieving an optimal drug-to-antibody ratio (DAR) of 8. Structurally, the backbone of BCG033 consists of a bivalent antibody with two monovalent components that separately target PTK7 and TROP2, which are engineered to minimize internalization and improve tumor selectivity. BCG033 backbone antibody demonstrates strong binding activity under varying PTK7 and TROP2 expression levels in tumors, and exhibits promising developability under stress force degradation. In proof of concept studies, BCG033 AB-vcMMAE showed synergistic effect and enhanced activity compared to the parental ADCs in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of TNBC, even with low PTK7 expression. When conjugated with Biocytogen’s linker/payload BLD1102, BCG033 demonstrated superior efficacy across varying PTK7 and TROP2 expression levels in PDX models and consistently outperformed benchmark ADCs in multiple tumor models, including NSCLC, TNBC, gastric cancer, and colorectal cancer. In summary, BCG033 demonstrates promising potential for delivering potent and broad anti-tumor activity across a range of solid tumors, offering broad clinical application opportunities. Citation Format: Lillian Ma, Na Zhang, Chengzhang Shang, Yi Yang. BCG033: a first-in-class PTK7×TROP2 bispecific ADC demonstrating potent and broad efficacy in various preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4793.