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 payload, 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 in the clinic, however, its utility is limited by dose-limiting toxicities. The exquisite selectivity of the pre|CISION® substrate for FAP results in release of exatecan payload selectively in the TME, greatly increasing the therapeutic window and hence reducing systemic exposure and associated toxicities. AVA6103 is a pre|CISION-enabled PDC that demonstrates FAP-dependent release of exatecan and kills cancer cells via a bystander mechanism. In multiple in vivo efficacy studies utilizing diverse cell and patient-derived models, AVA6103 achieved complete regressions and sustained, durable responses which remained until study termination. Biomarker assessment indicated on-target activity of the exatecan payload. The PK profile of AVA6103 and released-exatecan were assessed in tumor-bearing mice, showing that released-exatecan levels in the plasma were undetectable after 4 hours, whereas in the tumor, released-exatecan persisted throughout the 5-day observation period of the study, indicating the potential for AVA6103 to deliver sustained exatecan to the tumor whilst minimizing systemic exposure of exatecan below clinically toxic levels. To gain a greater understanding of patient populations that may be sensitive to AVA6103, co-expression of FAP and SLFN11, a gene linked to sensitivity to topoisomerase inhibitors, were evaluated using Tempus AI’s LENS database. A positive correlation was observed between FAP and SLFN11 across multiple tumor types, further supporting the rationale for clinical development. Additional mechanistic studies demonstrated on-target activity and supported utility of AVA6103 in specific cancer indications to exploit genetic vulnerabilities. This preclinical data package highlights the potential for AVA6103 to selectively target exatecan to the tumor microenvironment in a wide range of cancers. A Phase 1 dose escalation study designed to evaluate the safety, pharmacokinetics, and preliminary anti-tumor activity of AVA6103 in gastric, pancreatic, cervical and small cell lung cancers is anticipated to start in 1H 2026. Citation Format: Curtis Rink, Tom Clough, Ellen Watts, Folake Orafidiya, Marine Houée, Sophie Brown, Victoria Juskaite, Gezim Lahu, Ruairidh Edwards, Karen Campbell, Dave Liebowitz, David Jones, Francis Wilson, Michelle Morrow. AVA6103 is a FAP-enabled pre|CISION®peptide-drug conjugate delivering sustained release of exatecan in the tumor microenvironment with potent antitumor activity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5846.
Rink et al. (Fri,) studied this question.