Abstract 563: Preclinical development of YL202, a novel HER3-targeting antibody-drug conjugate (ADC) with novel DNA topoisomerase I inhibitor for treatment of solid tumors

Abstract HER3, a member of the HER family, is over-expressed in cancer cells and further elevated after HER2/EGFR/endocrine targeting treatment. YL202 is a novel HER3-targeting antibody-drug conjugate (ADC) structurally composed of a human anti-HER3 antibody, protease-cleavable linker, and a novel topoisomerase I inhibitor. This ADC was prepared using MediLink’s TMALIN platform, a proprietary tumor microenvironment activable linker-payload platform, which achieved a high drug-to-antibody ratio through homogeneously conjugated and favorable hydrophilic linker-payload. In preclinical studies, YL202 exhibited strong reactivity, highly internalization and potent cytotoxicity toward tumor cells. YL202 also demonstrated significant dose-dependent antitumor activity in cell line- and patient-derived xenograft (CDX and PDX) mouse models representing several cancer types and could induce complete tumor regressions with no observable toxicity. YL202 showed stable PK profile with overlapping ADC and TAb curves in a 28-day cynomolgus monkey study. GLP toxicity studies using cynomolgus monkeys showed that YL202 is well tolerated with calculated therapeutic index (TI, HNSTD/MED) of ~100 for repeat dosing. No lung or platelet toxicity findings were observed at doses up to the maximum tolerated dose (MTD). Based on these preclinical results, it demonstrates that YL202’s advanced ADC design results in an increased therapeutic margin, and YL201 could be further developed in HER3 positive cancer patients. Citation Format: Jian Xu, Qing Zong, Liang Zhu, Qigang Liu, Sasha Stann, Jiaqiang Cai. Preclinical development of YL202, a novel HER3-targeting antibody-drug conjugate (ADC) with novel DNA topoisomerase I inhibitor for treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 563.