Abstract 1577: PF-08046876: A new camptothecin antibody-drug conjugate directed to integrin beta-6 with potent antitumor activity in multiple preclinical solid tumor models

Integrins are a large family of cell surface receptors with diverse roles in cellular adhesion, motility, and cytokinesis. Functional integrins exist as heterodimers consisting of single alpha and beta chains. Within this family, integrin beta-6 (IB6), which dimerizes exclusively with integrin alpha-v, is a target of interest in the clinic for its role in cancer. IB6 expression is low in normal adult epithelial tissues and high in solid tumors. In some cases, high IB6 expression has been demonstrated to be associated with poor prognosis such as in non-small cell lung, colorectal, gastric and cervical carcinomas. PF-08046876 is an investigational antibody-drug conjugate (ADC) composed of an anti-IB6 antibody conjugated to a camptothecin-class topoisomerase I (TOPO1) inhibitor, AMDCPT, using a traceless enzyme-cleavable glucuronide linker. The AMDCPT payload was optimized for potency, reduced susceptibility to MDR efflux pumps and enhanced bystander activity. PF-08046876 leverages the same antibody backbone from Sigvotatug Vedotin (SV) and is specific for IB6 but does not bind other alpha-v family members. In preclinical studies, PF-08046876 has demonstrated activity in vitro and in multiple in vivo models spanning a range of antigen expression levels in several solid tumor carcinomas including non-small cell lung, head and neck squamous cell, urothelial, and pancreatic carcinomas. PF-08046876 demonstrates a tolerability profile in non-human primates that is consistent with camptothecin ADCs. These results suggest that PF-08046876 is promising ADC for the treatment of multiple carcinomas and supports further clinical investigation. A Phase 1, first-in-human study is planned to evaluate the safety and anti-tumor activity of PF-08046876. Citation Format: Rebecca C. Mazahreh, Narayana Yeddula, CB Lim, Gina LoMastro, Nicolas H. Garcia, Vineet Kumar, Christopher Frantz, Lauren Farr, Ryan Lyski, Lori Westendorf, Robert P. Lyon, Vivian H. Trang. PF-08046876: A new camptothecin antibody-drug conjugate directed to integrin beta-6 with potent antitumor activity in multiple preclinical solid tumor models [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 1577.