Abstract 6304: Preclinical development of a next generation antibody drug conjugate (ADC) targeting B7-H3 for treatment of solid tumors

Abstract

Abstract B7-H3 (CD276), an immune checkpoint member of the B7/CD28 family, is widely expressed in multiple cancers and is associated with poor prognosis. YL201 is a novel B7-H3-targeting antibody-drug conjugate (ADC) and built on MediLink’s tumor microenvironment activable linker-payload platform (TMALIN platform). This ADC is comprised of an anti-B7-H3 human monoclonal antibody conjugated to a novel topoisomerase 1 inhibitor via a protease-cleavable linker. The novel linker-payload and site-specific conjugation of YL201 results in a homogeneous and more hydrophilic ADC. In addition, the binding specificity, affinity and avidity of antibodies show no impact after conjugation. In vitro, upon binding to B7-H3, the antigen-ADC complexes are internalized to lysosomal vesicles releasing the toxic payload, whose cytotoxic features drive cell cycle arrest, apoptosis, elevation of PARP/caspase 7 expression, as well as cell death and bystander effect. In preclinical studies, YL201 is effective in causing tumor regressions in both cell line- and patient-derived xenograft (CDX and PDX) mouse models at doses that are well tolerated. The in vivo pharmacokinetics in monkeys showed that YL201 is deemed as ‘highly stable’ in circulation. Safety evaluations demonstrated acceptable safety profile and no off-target toxicity in monkeys. These non-clinical data suggest the stability of linker in circulation but efficiently release the payload in tumors, and eventually, expanded the therapeutic window. Taken together, preclinical data suggest that YL201 could be a promising treatment strategy for B7-H3 positive cancer patients. Citation Format: Jian Xu, Qing Zong, Wei Wang, Qigang Liu, Sasha Stann, Jiaqiang Cai. Preclinical development of a next generation antibody drug conjugate (ADC) targeting B7-H3 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 6304.