Abstract 5655: YL252: A dual-functional PD-L1/VEGF-targeting ADC integrating immunotherapy, anti-angiogenesis, and cytotoxicity.

Abstract The clinical success of combining immune checkpoint inhibitors with antibody-drug conjugates (ADCs), as well as the well-established synergy among immunotherapy, anti-angiogenic therapy, and chemotherapy, supports the development of multi-mechanistic therapeutic strategies. Based on this rationale, we developed YL252, a dual-functional ADC designed to simultaneously target PD-L1 and VEGF while enabling controlled payload release within the tumor microenvironment. YL252 is derived from Tumor Microenvironment-Activable Linker platform, incorporating a proprietary protease-cleavable tripeptide linker and a novel DNA topoisomerase I inhibitor payload. YL252 binds PD-L1 to modulate immune suppression, while also sequestering soluble VEGF, thereby exerting anti-angiogenic effects. The engineered drug-to-antibody ratio (DAR) is optimized to align with clinically relevant exposures of anti-PD-L1 and anti-VEGF monoclonal antibodies. We conducted a comprehensive nonclinical evaluation of YL252, including assessments of physicochemical properties, antitumor efficacy, pharmacokinetics, and safety. YL252 showed efficient internalization, potent cytotoxicity, and strong bystander effects in PD-L1-expressing tumor cells. In xenograft models, YL252 produced dose-dependent tumor growth inhibition, including complete regressions, without detectable toxicity. Mechanistic studies confirmed that YL252 effectively blocked PD-L1 signaling, consistent with immune activation alongside cytotoxic and antiangiogenic activity. Pharmacokinetic studies in cynomolgus monkeys demonstrated high systemic stability, as shown by overlapping total antibody and conjugated ADC profiles. Repeat-dose toxicology studies established a favorable safety profile, with a therapeutic index of approximately 100 and no drug-related adverse findings in major organs, including lung, liver, and kidney. In summary, YL252 is the first reported ADC that concurrently blocks PD-L1, inhibits VEGF-driven angiogenesis, and releases a cytotoxic payload in the tumor microenvironment, representing a single-agent approach that integrates immunotherapy, anti-angiogenic therapy, and chemotherapy mechanisms. Citation Format: Wei Lian, Xinzhen Shi, Qing Zong, Hanwen Deng, Chun Deng, Tao Wang, Fang Xu, Shuaikun Wang, Tongtong Xue, Jiaqiang Cai. YL252: A dual-functional PD-L1/VEGF-targeting ADC integrating immunotherapy, anti-angiogenesis, and cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5655.