Abstract 5449: Preclinical development of SCR-A003, a novel topoisomerase I inhibitor-based antibody-drug conjugate (ADC) targeting LIV-1 for solid cancer

Abstract Background: LIV-1, also known as SLC39A6 or ZIP6, a multi- transmembrane protein with putative zinc transporter and metalloproteinase activity. LIV-1 is expressed in a number of cancers with the highest prevalence in breast, prostate, ovary and melanoma, but a limited presence in vital organs. Currently, the clinical-stage ADC drug targeting LIV-1, Ladiratuzumab vedotin (SGN-LIV1A), is undergoing Phase 2 trials and has demonstrated clinical benefits, thus further underscoring LIV-1 as a promising target for advanced solid tumors. Given the broad spectrum of tumor indications addressable by targeting LIV-1, we utilized Simcere Zaiming’ proprietary ADC technology to generate a novel ADC targeted to LIV-1 named SCR-A003. Method: SCR-A003 is comprised of a LIV-1-targeted monoclonal antibody linked to a novel cytotoxic topoisomerase I inhibitor by a protease-cleavable linker. Pharmacokinetic study was conducted in mice in which SCR-A003 administered IV infusion. In vivo efficacy studies were conducted in immunodeficient mice with human tumor cell-lines including NCI-H838 and OVCAR3.The anti-tumor efficacy of SCR-A003 was evaluated in comparison to SGN-LIV1A analogue. Result: SCR-A003 had highly specific binding affinity with human and could cross-bind to cyno LIV-1. Moreover, SCR-A003 exhibited excellent internalization and cell killing ability on multiple tumor cells in-vitro assay. SCR-A003, demonstrated specific, dose-dependent in vivo antitumor activity toward LIV-1-positive tumor xenografts representing lung, ovary and breast cancers. Compared to SGN-LIV1A analogue, SCR-A003 exhibited more robust tumor inhibition capacity at lower doses in OVCAR3 and NCI-H838 xenograft models. Additionally, SCR-A003 also showed prolonged serum half-life and higher drug exposure than SGN-LIV1A analogue in pharmacokinetic study. Conclusions: SCR-A003, exhibited a favorable preclinical profile, with potent in vivo activity toward LIV-1-expressing tumor xenografts representing a range of cancer indications. These data support clinical development of SCR-A003 for the treatment of LIV-1-expressing solid cancers. Citation Format: Yayuan Fu, Changyan Chen, Xiaohua Yan, Zhiyong Yu, Zhuangzhi Zhao, Jingli Liao, Zhenyun Tian, Renhong Tang. Preclinical development of SCR-A003, a novel topoisomerase I inhibitor-based antibody-drug conjugate (ADC) targeting LIV-1 for solid cancer [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 5449.