Abstract 5461: BG-C477, a novel topoisomerase 1 inhibitor-based ADC, exhibits antitumor activity in carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-expressing preclinical models

作者：Daochuan He, Yiren Xiao, Zhuo Li, Jie Li, Hongyu Chen, Weijie Li, Yan Huang, Kunji Liu, Yang Lyu, Qingsong Hu, Mengjia Wang, Lai Xu, Zhitao Wan, Xiaomin Song, Yu Shen, Lai Wang · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/1538-7445.am2025-5461 · 被引用次数：4 · 研究领域：Radiopharmaceutical Chemistry and Applications、Cancer therapeutics and mechanisms、Monoclonal and Polyclonal Antibodies Research

Abstract CEACAM5 (CEA) is a cell surface glycoprotein highly expressed in many cancers, including colorectal cancer (CRC), gastric cancer (GC), lung and pancreatic cancers. BG-C477 is a novel ADC that is composed of a CEACAM5-specific antibody conjugated to Top1i payloads (drug-to-antibody ratio = 8) via a cleavable linker. It remains stable in human plasma and mice blood circulation. BG-C477 showed specific binding to CEA-expressing MKN45 cells and stronger internalization activity compared to anti-CEA DM4 ADC. BG-C477 exhibited robust and CEA-dependent cytotoxicity in cell lines with different CEA expression levels. A potent bystander effect of BG-C477 was observed in co-culture killing assay with mixed CEA-positive MKN45 and -negative HCT116 cells, indicating the potential to treat tumors with heterogeneous CEA expression. In the animal studies, BG-C477 demonstrated potent and dose-associated single-agent efficacy in multiple CEA-expressing cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Moreover, BG-C477 exhibited superior antitumor efficacy in GC and CRC PDX models that anti-CEA DM4 ADC was ineffective. In summary, BG-C477 is a promising CEA targeting ADC with great anti-tumor activity across multiple types of tumors. The first in human study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of BG-C477 is ongoing (NCT06596473). Citation Format: Daochuan He, Yiren Xiao, Zhuo Li, Jie L...