Abstract 3139: The novel peptide drug conjugate AVA6103 is a FAP-enabled pre|CISION® medicine which targets exatecan, a topoisomerase I inhibitor, to the tumor microenvironment following FAP cleavage

Abstract AVA6103 is a novel peptide drug conjugate (PDC) based on proprietary pre|CISION® technology which incorporates a dipeptide that is specifically cleaved by Fibroblast Activation Protein α (FAP). FAP is a post-proline protease that is overexpressed on the surface of cancer associated fibroblasts (CAFs) in many solid tumors, and facilitates delivery of pre|CISION® medicines specifically to the tumor microenvironment (TME). AVA6103 consists of exatecan, a potent Topoisomerase I warhead, covalently linked to a dipeptide containing a cleaving sequence (D-Ala-L-Pro), which is susceptible to hydrolysis by FAP but is resistant to hydrolysis by other mammalian proteases. Exatecan has been investigated both as a single agent and as a warhead in ADC therapeutics in the clinic. However, clinical utility of this family of warheads is limited by dose-limiting toxicities, including severe neutropenia. The exquisite selectivity of the pre|CISION® substrate to FAP results in release of exatecan warhead in the TME, greatly increasing the therapeutic window and hence reducing systemic exposure and associated toxicities. AVA6103 is a pre|CISION-enabled exatecan programme, with a candidate in IND-enabling studies. A series of compounds have been engineered with modifications in the capping-group and linker portions. Using structure-based drug design, clear structure-activity relationships have been established for affinity to, and susceptibility of linker cleavage by FAP and subsequent warhead release. Concentric partitioning algorithms show differential FAP expression in stromal regions closest to cancer cells vs. those more distal to cancer cells, in multiple indications. Multiplex-immunofluorescence (mIF) data also shows the spatial organization of blood vessels, FAP-positive CAFs, and adjacent FAP-negative cancer cells provide an ideal architecture for the delivery, cleavage, and warhead uptake of a FAP-enabled PDC. In a cancer cell line/fibroblast cell co-culture, AVA6103 demonstrates FAP-dependent release of exatecan and bystander cancer cell kill. In vivo studies demonstrate targeting and accumulation of warhead in the TME, resulting in tumor growth inhibition and complete tumor regressions. Tolerability profiles of AVA6103, allied with tumor growth inhibition efficacy, shows a greatly increased therapeutic window compared to conventional exatecan, with pharmacodynamic biomarkers demonstrating on-target activity of the warhead. The enhanced therapeutic index and efficacy data shown here supports the rationale to progress AVA6103 towards clinical development and supports wider utility of the pre|CISION® platform to target warheads to the tumor while reducing systemic dose-limiting toxicities. Citation Format: Curtis Rink, Tom Clough, Ellen Watts, Folake Orafidiya, Marine Houee, Cindy Tong, Victoria Juskaite, Michelle Morrow, David Jones, Francis Wilson. The novel peptide drug conjugate AVA6103 is a FAP-enabled pre|CISION® medicine which targets exatecan, a topoisomerase I inhibitor, to the tumor microenvironment following FAP cleavage [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 3139.