Abstract 6026: A novel lutetium-177 radioligand therapy targeting FAP has potent antitumor activity in xenograft cancer model

Abstract Fibroblast Activation Protein (FAP) is an attractive target for cancer therapy due to its overexpression in most solid tumors, predominantly localized on cancer associated fibroblasts. Unfortunately, trials with first generation FAP-targeted radioligand therapies (RLTs) have produced only modest clinical responses, indicating the need for improvements. We developed a library of over 40 fully synthetic, novel FAP-targeted RLTs comprising a FAP inhibitor with a stable linker to an albumin binding domain and a DOTA-lutetium-177 payload. Screening this library for binding, biodistribution and pharmacology properties identified a 177Lu-FAP RLT lead molecule. The novel 177Lu-FAP RLT demonstrates high selectivity and binds to FAP with a sub-nanomolar binding affinity. Biodistribution of the 177Lu-FAP RLT was evaluated in mice bearing U87MG tumors, demonstrating delivery and retention of a high tumor absorbed dose. In vivo efficacy of the 177Lu-FAP RLT at 150 µCi or 500 µCi was evaluated in mice bearing U87MG tumors. The 177Lu-FAP RLT elicits potent and dose-dependent antitumor activity with 80% reduction in tumor volume of 8/10 mice following a single 500 µCi dose. The treatment was well-tolerated, with no significant weight loss or deaths. The outstanding antitumor activity and high selectivity for FAP support further evaluation of this investigational RLT in patients with solid tumors. Citation Format: Spencer Lindeman, Jack Higgins. A novel lutetium-177 radioligand therapy targeting FAP has potent antitumor activity in xenograft cancer model 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 6026.