Abstract 1872: A next generation treatment for Nectin-4 positive cancers - Preclinical characterization of LY4052031, an anti-Nectin-4 antibody, conjugated to a novel camptothecin payload

Abstract Nectin-4 is an immunoglobulin-like antigen overexpressed in a variety of cancers including bladder, breast, NSCLC, and gastric. Normal tissues including skin, salivary glands, bladder and esophagus express only low to medium levels of Nectin-4 making the protein an attractive target for cancer therapies. The approval of enfortumab vedotin-ejfv, an anti-Nectin-4 based antibody-drug conjugate (ADC) with a microtubule inhibitor payload, either as a single agent or in combination with pembrolizumab has been a significant advancement in the treatment of metastatic urothelial cancer. We have developed a novel anti-Nectin-4 ADC with a novel topoisomerase I (TOPO 1) inhibitor drug payload. Topoisomerase inhibitor payload-based ADCs offer potential advantages compared to microtubule payload-based ADCs including a different toxicity profile and the differentiated susceptibility to resistance mechanisms, such as P-gp mediated drug efflux. LY4052031 is a fully human monoclonal anti-Nectin-4 antibody conjugated to a novel TOPO 1 inhibitor by a cleavable peptide linker at a homogeneous drug antibody ratio (DAR) of 8: 1. In vitro, both LY4052031 and its unconjugated parental antibody specifically bind to Nectin-4 expressing cell lines and are quickly and efficiently internalized. LY4052031 demonstrated potent cytotoxicity on tumor cells with high and low Nectin-4 expression. Additionally, bystander activity exerted by LY4052031 on antigen negative cells co-cultured with antigen positive cells was greater than that observed with the clinical benchmark enfortumab vedotin-ejfv. In vivo studies in xenografts expressing low to high levels of Nectin-4 showed significant tumor growth inhibition following treatment with LY4052031 as monotherapy. Overall, LY4052031 exhibits specificity, selectivity, potency, and effectiveness as a next generation therapy to treat Nectin-4 positive tumors. An IND submission is planned for 2024. Citation Format: Divya Sagar, Mohan Srinivasan, Kevin Lindquist, Qianxu Guo, Wailin Wong, Maria B. Lebron, Rose Marie Sattler, Jieyu Zhou, Whitney Helms, Jeffrey Boyles, Petra Verdino, Xuan Zhao, Yvonne Mak, Joshua Park, Rikke Holmgaard, Kyla Driscoll, Omar Duramad, Kristin Bedard. A next generation treatment for Nectin-4 positive cancers - Preclinical characterization of LY4052031, an anti-Nectin-4 antibody, conjugated to a novel camptothecin payload abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1872.