Abstract 2133: KA-2887-LD38: a novel bispecific antibody-drug conjugate (ADC) targeting both EGFR and PD-L1

Abstract PD-L1 is widely expressed across various cancer types and suppresses immune responses against tumor cells. EGFR is also highly expressed in many solid tumors and plays a key role in driving tumor growth. Targeting the PD-1/PD-L1 signaling pathway and the EGF/EGFR signaling pathway using antagonistic antibodies or ADCs has shown promising results in cancer therapy. However, both approaches can lead to undesirable "on-target/off-tumor" effects. Co-expression of PD-L1 and EGFR is rare in normal tissues but is commonly observed in most PD-L1-expressing tumor cells. In this study, we developed a bispecific antibody, KA-2887, using our common light chain antibody discovery platform to target both EGFR and PD-L1. This bispecific antibody was then used to construct the ADC KA-2887-LD38. KA-2887-LD38 has a conventional IgG1 structure, conjugated with LD-38, an Escugen proprietary ADC platform composed of TopIi payload and highly hydrophilic stable cleavable linker. It binds to EGFR with an affinity of 3.7 nM and to PD-L1 with an affinity of 0.6 nM. KA-2887-LD38 effectively blocks both the interaction between EGF and EGFR, and the interaction between PD-1 and PD-L1.The expression of EGFR on tumor cells enhances the inhibitory effect of KA-2887-LD38 on the PD-1/PD-L1 interaction, and vice versa. Compared to monoclonal antibodies targeting PD-L1, KA-2887-LD38 shows a much faster internalization rate when binding to tumor cells co-expressing EGFR and PD-L1. In vitro, KA-2887-LD38 demonstrates cytotoxicity against tumor cells expressing either EGFR and PD-L1 together or EGFR alone, but has a weaker effect on tumor cells expressing only PD-L1. Tumor cells co-expressing EGFR and PD-L1 are more sensitive to KA-2887-LD38. Additionally, KA-2887-LD38 exhibits strong bystander killing activity. Xenograft mouse tumor models show that KA-2887-LD38 strongly inhibits the growth of various tumor types, including NSCLC, head and neck squamous cell carcinoma, and esophageal squamous cell carcinoma. Toxicity studies on KA-2887-LD38 are ongoing. The results suggest that KA-2887-LD38 holds significant potential for the treatment of a variety of solid tumors. Citation Format: Guojin Wu, Chuanying Xu, Weihong Nian, Zhengcheng Guo, Jiabei Liang, Feng He, Qing Zhou, Jinying Ning. KA-2887-LD38: a novel bispecific antibody-drug conjugate (ADC) targeting both EGFR and PD-L1 [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 2133.