Abstract 3140: Preclinical development of YL242, a non-internalized antibody-drug conjugate (ADC) targeting soluble VEGF for treatment of solid tumors

Traditional ADC technologies require overexpressed targets, high internalization and efficient intracellular processing. To this end, a non-internalized antibody-drug conjugate (ADC) targeting soluble VEGF was developed using MediLink’s TMALIN® platform. VEGF is overexpressed in virtually all human tumors and contributes to key aspects of tumorigenesis and angiogenesis. YL242 incorporates an anti-VEGF antibody, protease-cleavable tripeptide linker and novel DNA topoisomerase I inhibitor. It introduces a novel cleavage mechanism that occurs in the tumor microenvironment while stable during systemic circulation. YL242 is designed to leverage anticancer activity through both anti-angiogenesis by the VEGF antibody and the cytotoxicity of the extracellularly released payload. The linker of YL242 can be enzymatically cleaved by enzymes in TME (tumor microenvironment) to release payload C24, subsequently inducing cytotoxic effects to kill cancer cells. Significant dose-dependent antitumor effects, including complete tumor regressions were observed in tumor xenograft mouse models. The stability of YL242 has been demonstrated by incubation with various plasmas under physiological conditions. This high stability was further evidenced by the pharmacokinetic profiles in non-human primate (NHP) studies, where both the ADC and TAb curves are overlapped. YL242 demonstrated promising safety profiles in pivotal non-human primate (NHP) toxicity studies with no drug-related adverse effects observed. In summary, VEGF-targeted ADC YL242 synergistically combines both antitumor activity of cytotoxic payload and anti-angiogenesis effect of antibody and demonstrated both antitumor efficacy and safety. Consequently, YL242 holds promise for further development in the treatment of cancer patients. Citation Format: Tongtong Xue, Wei Lian, Qing Zong, Chun Deng, Qigang Liu, Peng Zou, Jiaqiang Cai. Preclinical development of YL242, a non-internalized antibody-drug conjugate (ADC) targeting soluble VEGF for treatment of solid tumors [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 3140.