Abstract ND11: Discovery and Preclinical Characterization of a Novel ENPP3-Targeted ADC, JNJ-89862175 to treat Advanced Solid Tumors

Abstract Antibody Drug Conjugates (ADC) are a clinically validated therapeutic modality for solid tumors relying on an antibody that targets a tumor-specific antigen to internalize and deliver cytotoxic agents directly to the tumor. ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase family member 3) is a transmembrane protein that was identified as a tumor selective target based on its apically restricted expression in most normal tissues and elevated depolarized expression in several solid tumors including renal cell carcinoma, endometrioid ovarian cancer, uterine cancers, and lung adenocarcinoma. JNJ-89862175 is an ADC consisting of a fully human ENPP3-targeting antibody conjugated site-specifically to the Dolasynthen linker-payload moiety featuring a proprietary auristatin-based payload with controlled bystander effect. The lead ENPP3 binder demonstrating preferred attributes to progress as an ADC was identified after extensive immunization and screening efforts. When conjugated with Mersana’s Dolasynthen platform, JNJ-89862175 demonstrated ENPP3-specific binding, preferred biophysical properties, rapid internalization and potent tumor cell cytotoxicity (including bystander activity) in vitro. In vivo, potent anti-tumor efficacy with complete tumor regressions was observed in a panel of lung and renal patient tumor derived xenograft models following single dose administration. JNJ-89862175 was well tolerated in preclinical non-human primate studies and demonstrated preferred pharmacokinetics. In summary, these preclinical data support the ongoing first-in-human Phase I trial (NCT07223125) to evaluate safety, tolerability, and preliminary antitumor activity of JNJ-89862175 in patients with ENPP3-expressing advanced solid tumors. Citation Format: Smruthi Vijayaraghavan, Linxiao Chen, Ryan Lenhart, Jennifer Marcy, Nisha Prajapati, Swetha Rao, Onyi Irrechukwu, Suresh Kumar Swaminathan, Kristen Wiley, Eilyn Lacy, Alberto Carpinteiro Soares, Emmanuel Gustin, Heather Deutsch, Gerald Chu, Tammy Bush, Krista Menard, Bethany Mattson Cypert, Shalom Goldberg, Kalli Catcott, Jason Wang, Dorin Toader, Timothy B. Lowinger, Katherine Sacksteder, Jacalyn Clawson, Wan Cheung Cheung, Joshua M. Bauml, Ulrike Philippar. Discovery and Preclinical Characterization of a Novel ENPP3-Targeted ADC, JNJ-89862175 to treat Advanced Solid Tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr ND11.