Abstract 5840: PF-08046037, a PD-L1 targeted TLR7 agonist ISAC, drives innate immune activation and anti-tumor efficacy in preclinical in vitro and in vivo models

Abstract PF-08046037 (formerly known as SGN-PDL1iT) is an immune-stimulating antibody conjugate (ISAC) designed to induce an immune response against cancer cells by delivering a potent Toll-like receptor 7 (TLR7) agonist to tumor associated antigen-presenting cells (APCs) expressing PD-L1. The ISAC consists of an anti-PD-L1 antibody linked to an imidazoquinoline-based TLR7 agonist using a mannosidase-cleavable maleimidopropionyl-mannose linker (mp-mann). Upon binding to PD-L1 on APCs, PF-08046037 internalizes and releases the payload into TLR7-containing endosomes. To minimize off-target immune activation, PF-08046037 incorporates Fc mutations in the antibody to reduce FcγR binding, and the agonist payload is designed to have low membrane permeability. Through targeting PD-L1-expressing immunosuppressive macrophages and dendritic cells within the tumor and associated immune compartments, PF-08046037 aims to repolarize the suppressive tumor microenvironment, enhance antigen presentation, and establish robust anti-tumor immunity. Here, we present preclinical data demonstrating the potency, targeted delivery, and anti-tumor efficacy of PF-08046037 in both in vitro and in vivo models. In vitro, PF-08046037 induces potent and selective activation of TLR7 reporter cells and PD-L1-expressing human macrophages and dendritic cells. In syngeneic hPD-L-1 .CT26 and hPD-L-1 .MC38 tumor models using human PD-L1-expressing mice, PF-08046037 shows single-agent efficacy and provides anamnestic protection against tumor rechallenge. The in vivo pharmacodynamic effects of PF-08046037 align with its intended mechanism of action, including acute tumor inflammation, loss of CD206+ suppressive macrophages, upregulation of activation and costimulatory molecules on APCs in tumors and tumor-draining lymph nodes (tdLN), and increased activity of cytotoxic cells. Collectively, these data highlight the therapeutic potential of targeted TLR7 agonist delivery to PD-L1-expressing APCs in cancer and support the clinical investigation of PF-08046037 in advanced malignancies. Citation Format: Giacomo Tampella, Catalina Sakai, Weiping Zeng, Eleanor Hendrickson, Sasha Lucas, Kung-Pern Wang, Aly Smith, Ryan A. Heiser. PF-08046037, a PD-L1 targeted TLR7 agonist ISAC, drives innate immune activation and anti-tumor efficacy in preclinical in vitro and in vivo 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 5840.