Abstract 3591: First in class drug ZB131 shows efficacy in cholangiocarcinoma models

Abstract

Abstract Cholangiocarcinoma (CCA) is a lethal cancer with a high unmet need. The survival rate is low (5-year survival <20%), most non-palliative patients relapse within two years, and treatments in the advanced setting are limited. While FGFR2 and IDH1 inhibitors are effective in patients with select genomic alterations, they address only a small fraction (<20%) of biliary tract cancers. We now present the discovery and characterization of ZB131, a first in class humanized monoclonal antibody targeted to cancer specific plectin (CSP). CSP is a pro-tumorigenic protein exclusively expressed on the cancer cell surface. Previously, we demonstrated remarkable tumor regressions in preclinical murine models of pancreatic and ovarian cancer using a tool anti-CSP murine antibody. Here, we show that intra- and extra-hepatic CCA are 92% and 86% positive for membranous plectin staining by IHC, respectively, suggesting that anti-CSP therapy could be broadly effective against CCA. Indeed, in CCA cell lines in vitro, ZB131 (0.4nM binding affinity) arrests cell cycle, inhibits cell migration, and triggers intracellular ROS accumulation. In addition, both ZB131 and its murine version significantly suppressed tumor growth in 83% of the mice in a xenograft model and caused complete regression in the remaining 17%. Previous data from our group and others suggesting that CSP plays a role in chemoresistance led us to evaluate the efficacy of ZB131 in combination with gemcitabine. In vitro, we treated CSP-positive WITT cells with combinations of 0-500nM gemcitabine plus 0-1000nM ZB131 and found pockets of synergy or additivity. In a CCA xenograft model, the combination of 1mg/kg ZB131 and 100mg/kg gemcitabine showed 91% suppression in tumor growth compared with 74% in gemcitabine alone and 77% in huIgG plus gemcitabine at day 32. Collectively, our results suggest that ZB131 renders CCA tumors more chemosensitive and enhances the antitumor effects of gemcitabine. In contrast to the standard-of-care CCA treatment regimen, ZB131 showed remarkably low toxicity, likely because the antibody bypasses any non-malignant cells where plectin remains strictly cytoplasmic. Fc effector functional studies revealed a lack of antibody-dependent cell-mediated and complement-dependent cytotoxicity. Hemolysis and cytokine release studies suggested that ZB131 is compatible with human blood and unlikely to cause adverse cytokine release. Furthermore, in GLP toxicology studies, no signs of toxicity were observed at the highest dose evaluated of 100mg/kg/week, providing a >30-fold safety margin from the estimated human efficacious dose of 3mg/kg/week. In summary, ZB131 is an exciting new avenue for the treatment of CCA and other CSP-positive cancers with an excellent safety profile and strong antitumor activity in vitro and in murine models. Phase I clinical trials of ZB131 have been initiated. Citation Format: Samantha M. Perez, Randall Burton, Denise Krawitz, Christopher Sheth, Pina Cardarelli, Molly Owens, Brian Murphy, Matthew J. Reilley, Lindsey T. Brinton, Kimberly A. Kelly. First in class drug ZB131 shows efficacy in cholangiocarcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3591.