Abstract 324: PF-08052666 (SGN-MesoC2; HBM9033), a first-in-class topoisomerase 1 inhibitor-based ADC targeting MSLN, demonstrates potent antitumor activity in preclinical models of ovarian, lung, and colorectal cancers

Abstract Mesothelin (MSLN) is a cell surface molecule that is expressed in its mature form as a 40 kDa protein anchored to the cell membrane through a glycosylphosphatidylinositol linkage. While its expression is limited in normal tissues, MSLN is overexpressed in numerous solid tumors, including ovarian, pancreatic, endometrial, lung and colorectal cancers. Since its discovery, MSLN has been a target of interest for the development of anti-tumor therapeutics across a variety of modalities, including antibodies, CAR-T, and multiple antibody-drug conjugates (ADCs). To-date, anti-MSLN ADCs have focused on the delivery of anti-tubulin payloads, including DM4, MMAE, and tubulysin. While these ADCs have had manageable safety profiles in the clinic, efficacy has been modest. Here we present the nonclinical characterization of PF-08052666 (SGN-MesoC2; HBM9033), a first-in-class topoisomerase 1 inhibitor (TOP1i)-based ADC targeting MSLN. PF-08052666 has been designed to overcome the shortcomings of the previous generation of anti-MSLN ADCs through a novel antibody, differentiated payload, and a higher drug-to-antibody ratio (DAR). PF-08052666 consists of a human IgG1 monoclonal antibody conjugated to a potent camptothecin-based TOP1i payload with a protease cleavable linker at an average DAR of 8. In vitro, PF-08052666 drives direct cytotoxicity through delivery of payload to MSLN-positive cells, bystander killing activity on co-cultured MSLN-negative cells, and retains cytotoxicity in the presence of physiologically relevant concentrations of soluble MSLN. In vivo, PF-08052666 outperformed a DM4-based anti-MSLN benchmark ADC in cell-line and patient-derived xenograft models across various tumor types, including ovarian, lung, and colorectal cancers. PF-08052666 also outperformed the DM4-based anti-MSLN benchmark ADC in heterogenous xenograft models consisting of ad-mixed MSLN-positive and MSLN-negative cells, demonstrating the increased bystander activity of the TOP1i-based payload of PF-08052666. These data support the ongoing first-in-human phase 1 clinical trial of PF-08052666 in patients with advanced solid tumors, which is currently enrolling (NCT06466187). Note: All procedures performed on animals were in accordance with regulations and established guidelines and were reviewed and approved by an Institutional Animal Care and Use Committee or through an ethical review process. Citation Format: Garrett L. Cornelison, Meihong Zhang, Cui Nie, Guangbei Zhu. PF-08052666 (SGN-MesoC2; HBM9033), a first-in-class topoisomerase 1 inhibitor-based ADC targeting MSLN, demonstrates potent antitumor activity in preclinical models of ovarian, lung, and colorectal cancers [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 324.