Abstract 2132: KA-3123-LD38: a novel bispecific antibody-drug conjugate (ADC) targeting EGFR and B7H3 with a DNA topoisomerase I inhibitor payload

Abstract KA-3123-LD38 is a novel bispecific antibody-drug conjugate (ADC) designed to target both EGFR and B7H3, two markers that are highly expressed in various tumor cells but have limited expression in normal tissues. The co-expression of EGFR and B7H3 in tumor cells is particularly high, making them promising therapeutic targets. By targeting both of these markers simultaneously, KA-3123-LD38 aims to reduce the risk of "on-target/off-tumor" cytotoxicity, a common side effect in cancer therapies. This ADC is a IgG1 with a common light chain, conjugated with LD-38, an Escugen proprietary ADC platform composed of TopIi payload and highly hydrophilic stable cleavable linker. KA-3123-LD38 binds to B7H3 with high affinity, with a Kd of less than 0.01 nM, while its affinity for EGFR is weaker, with a Kd greater than 10 nM. When compared to monoclonal antibodies targeting B7H3, KA-3123-LD38 exhibits a significantly faster internalization rate in tumor cells that co-express EGFR and B7H3. In vitro assays show that KA-3123-LD38 effectively induces cytotoxicity in tumor cells expressing either EGFR and B7H3 together or B7H3 alone. However, the cytotoxic effect is notably stronger in cells co-expressing both targets. Furthermore, KA-3123-LD38 demonstrates strong bystander killing activity, further enhancing its therapeutic potential. In xenograft mouse models, KA-3123-LD38 strongly inhibits the growth of a variety of tumor types, including NSCLC, esophageal squamous cell carcinoma, colorectal cancer, and gastric cancer. Ongoing toxicity studies suggest that KA-3123-LD38 has a favorable safety profile, with low toxicity observed. These promising results highlight KA-3123-LD38 as a potentially powerful treatment for a broad range of solid tumors. Citation Format: Guojin Wu, Chuanying Xu, Weihong Nian, Zhengcheng Guo, Jiabei Liang, Feng He, Qing Zhou. KA-3123-LD38: a novel bispecific antibody-drug conjugate (ADC) targeting EGFR and B7H3 with a DNA topoisomerase I inhibitor payload [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 2132.