Abstract 1916: Discovery of a novel Nectin4 IPSC-derived cell therapy for the treatment of solid tumors

Abstract Century Therapeutics is developing a Nectin4-targeting IPSC-derived cell therapy for the treatment of Nectin4 expressing solid tumors. The Nectin proteins (Nectin1, Nectin2, Nectin3 and Nectin4) are members of the calcium independent immunoglobulin superfamily of cell adhesion molecules (CAMs) involved in adhesive processes that help in the growth and development of tissues. Nectin 1, 2 and 3 are normally found in adult tissue whereas Nectin4 is mainly found in normal placental and embryonic tissue. Nectin4 is also expressed in different types of cancer including urothelial, ovarian, lung and head/neck cancers. Nectin4 is established as a biomarker for worse prognosis in cancers and is linked with carcinogenesis and disease severity. These features establish Nectin4 as a promising target for anti-tumor drug development. Enfortumab vedotin, an antibody drug conjugate targeting Nectin4 positive tumors, has demonstrated benefit in clinical trials and is FDA approved for treatment of advanced bladder cancer. We have identified novel single-domain antibodies (VHH) that bind to multiple epitopes on Nectin4 extracellular domain. The VHH antibodies were engineered into chimeric antigen receptor (CAR) formats and characterized for expression, cell activation through antigen engagement, and cytotoxicity activity in primary T-cells. Selected binders demonstrated efficacy in multiple CAR formats in primary T-cells in a mouse xenograft model using OVCar-3 tumor cells. The lead CARs engineered into primary T-cells demonstrated tumor inhibition similar to a reference CAR using the ASG-5ME antibody (Enfortumab) as the Nectin4 binder. The CARs were engineered into our IPSC-derived iNK and iT cells and demonstrated cytotoxicity activity against a panel of cell lines with a range of cell surface expression of Nectin4. Based on these studies, Century Therapeutics is advancing the lead Nectin4 binder for development of an IPSC-derived cell therapy to treat Nectin4 positive solid tumors. Citation Format: Jill M. Carton, Chris Dower, Michael Miller, John Wheeler, Sean Heron, Hillary J. Millar, David Walker, Daniel J. Perry, Andriana Lebid, Luis Cocka, Dae Hwan Kim, Barry Morse, Buddha Gurung, Maisha Harris, Annalise Jethon, Michael Naso, Hy Levitsky. Discovery of a novel Nectin4 IPSC-derived cell therapy for the treatment of solid tumors [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(6_Suppl):Abstract nr 1916.