Abstract 2134: KA-2886-LD38: a bispecific antibody-drug conjugate (ADC) targeting both EGFR and MET, incorporating a novel linker-payload that inhibits DNA topoisomerase I

Abstract Epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) are frequently co-expressed in multiple solid cancers, and over-activation of MET signaling is one of the major mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs). Antagonistic bispecific antibodies targeting both EGFR and MET have been shown to overcome this resistance. KA-2886-LD38 is a bispecific ADC targeting both EGFR and MET. It is a bispecific common light chain IgG1 , conjugated with LD-38, an Escugen proprietary ADC platform composed of TopIi payload and highly hydrophilic stable cleavable linker. It binds to MET with an affinity of 0.02 nM and to EGFR with an affinity of 1 nM. KA-2886-LD38 blocks the binding of HGF to MET with an IC50 of about 0.3 nM and the interaction of EGF with EGFR with an IC50 of about 2 nM. Compared to the benchmark ADC AZD9592, KA-2886-LD38 exhibits a similar internalization rate when binding to tumor cells but demonstrates significantly stronger cytotoxicity and bystander killing activity across different tumor cell lines in vitro. Additionally, in xenograft mouse tumor models with various tumor types, including NSCLC, head and neck squamous cell carcinoma, colorectal cancer, esophageal squamous cell carcinoma, and triple-negative breast cancer, KA-2886-LD38 showed much stronger in vivo efficacy compared to AZD9592. Moreover, KA-2886-LD38, when combined with osimertinib, also demonstrated a combination inhibitory effect on H1975 tumor growth. KA-2886-LD38 is well-tolerated at doses up to 30 mg/kg in EGFR and MET humanized genetically modified mice, and toxicity studies in monkeys are ongoing. These results suggest that KA-2886-LD38 has remarkable potential in the landscape of anti-EGFR/cMet therapies. Citation Format: Guojin Wu, Chuanying Xu, Weihong Nian, Zhengcheng Guo, Jiabei Liang, Feng He, Qing Zhou, Jinying Ning. KA-2886-LD38: a bispecific antibody-drug conjugate (ADC) targeting both EGFR and MET, incorporating a novel linker-payload that inhibits DNA topoisomerase I [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 2134.