Abstract 1560: SCR-A0011, a novel bispecific ADC targeting cMET and B7H3, exhibits potent anti-tumor efficacy

Abstract Background: The HGF/cMET signaling pathway plays an important role in the regulation of cell proliferation, differentiation, migration and other normal physiological functions. cMET is expressed in many different normal tissues but is usually expressed at low levels. Abnormal expression and dysfunction of cMET have been found in a variety of tumors. cMET is a well-established target in clinical, but its clinical application is limited, because clinical efficacy was mainly observed in cMET signaling driving tumor or cMET-high expression tumors. To extend the potential therapeutic population and anti-tumor activity, we searching for some new approaches, such as bispecific antibody drug conjugates. Bioinformatics analysis and translational research showed that cMET and B7H3 are co-expressed in multiple types of solid tumors without high expression in normal tissues. Therefore, targeting both B7H3 and cMET could be a new and powerful strategy in pan-tumor therapy. Methods & Results: We developed a novel B7H3xcMET targeted bispecific antibody-drug conjugate (ADC) called SCR-A0011, which is comprised of B7H3/cMET bispecific antibody conjugated with novel topoisomerase 1 inhibitor (CPT116). SCR-A0011 specifically bind B7H3 and cMET with high affinity, and showed enhanced internalization and binding capacity compared to parental monoclonal antibody ADC separately in the B7H3/cMET co-expressing cell line. SCR-A0011 induced tumor cell lysis in various tumor cell types including NSCLC, CRC, OC, HNSCC, etc. SCR-A0011 showed remarkable anti-tumor efficacy in several CDX models in a dose dependent manner. SCR-A0011 exhibits significantly stronger anti-tumor activity than their parental monoclonal-ADC or clinical ADC in B7H3+cMET+ double positive tumor cells. SCR-A0011 also have very good stability and favorable developability. Conclusion: These findings illustrated SCR-A011 could be a potential First-in-Class BsADC to conquer the resistance or non-response of current treatment in broad cancer types and may provide a new therapeutic approach for B7H3 and cMET positive cancer patients in the future. Citation Format: Yayuan Fu, Guangcun Cheng, Hui Zheng, Shuai Wang, Lei Jiang, Chunlei Xia, Huipeng Guo, Xiyuan Wang, Renhong Tang. SCR-A0011, a novel bispecific ADC targeting cMET and B7H3, exhibits potent anti-tumor efficacy [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 1560.