Abstract LB122: JNJ-87890387, a novel ENPP3 bispecific T-cell redirector (ENPP3xCD3) with tumor selectivity through targeting apical surface antigens

Abstract Clinical success of T-cell redirection therapy for solid tumors has been limited potentially due to a lack of target specificity against cancer, leading to on-target off-tumor toxicity at sub-efficacious doses. ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase family member 3) is a transmembrane protein that was identified with the help of an artificial intelligence machine learning algorithm. ENPP3 is characterized by apically restricted expression in most normal tissues and elevated, depolarized expression in several solid tumors, thus potentially providing tumor selectivity. ENPP3 expression exhibits a high prevalence in several solid tumors including renal cell carcinoma (RCC) - clear cell (93%) and papillary (78%), lung adenocarcinoma (50%), endometrioid uterine (53%) and ovarian (47%) cancers, colorectal carcinoma (51%), and hepatocellular carcinoma (HCC, 47%). JNJ-87890387 is a fully human bispecific antibody with high affinity and specific binding to ENPP3 on tumor cells and lower affinity binding to cluster of differentiation (CD)3 on T-cells. In vitro, JNJ-87890387 demonstrated potent (pM) T-cell activation and cytotoxicity against tumor cell lines with different levels of endogenous ENPP3 membrane expression, and absence of killing against cells lacking ENPP3 expression, confirming JNJ-87890387 specificity. In vivo, JNJ-87890387 demonstrated ENPP3-expression-dependent potent anti-tumor activity in multiple cell line-derived and patient tumor-derived RCC and HCC xenograft models with complete tumor regressions, and evidence of dose-dependent CD4+ and CD8+ T cell infiltration into the tumors. Preclinical safety assessment in the cynomolgus monkey with a tool molecule using the therapeutic ENPP3 binding arm but with a cynomolgus CD3 cross-reactive arm only identified toxicities consistent with the modality. In summary, these data support JNJ-87890387’s clinical development with an ongoing first-in-human Phase I study to evaluate the safety and preliminary anti-tumor activity in advanced-stage solid tumors with a high prevalence of ENPP3 expression. Citation Format: Smruthi Vijayaraghavan, Pankaj Seth, Annmarie Winkis, Kristen Chevalier, Alexa Marthaler, Katrin Sproesser, Vince Torti, Nirav Shah, Eilyn Lacy, Anna-Lena Frisk, Heather Deutsch, Gerald Chu, Michael Sharp, Jonathan Pabalan, Cholpon Tilegenova, Katherine Thorton, Josh Lauring, Bethany Mattson, Ken Tian, Jacqueline Kinyamu-Akunda, Laurie Lenox, Wan Cheung Cheung, Sheri Moores, Sylvie Laquerre. JNJ-87890387, a novel ENPP3 bispecific T-cell redirector (ENPP3xCD3) with tumor selectivity through targeting apical surface antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB122.