Abstract 6299: ZB131 antibody-drug conjugates induce potent antitumor activity

Abstract Antibody-drug conjugates (ADCs) have become increasingly adopted clinically, with 13 drugs FDA-approved and over 100 under clinical development. Despite this momentum and major advances in payload and linker technology, ADCs are limited by off-cancer target-mediated toxicities incurred by currently available targets. In contrast to genomic and proteomic strategies, our unique drug discovery approach accounts for a disease’s native context. This led to the identification of cancer-specific plectin (CSP) as not only overexpressed in malignant tissue compared to healthy, but exclusively present on the surface of cancer cells and absent in normal or pre-malignant tissue. A Phase 0 imaging trial (Biodistribution of Novel Imaging for Resectable Pancreatic Cancer - NCT01962909) evaluating a radiolabeled CSP-targeted peptide has revealed that CSP is bioavailable and abundant, with over a million CSP molecules per cancer cell in pancreatic cancer. Previously, we generated ZB131, a humanized monoclonal antibody that targets CSP. ZB131 demonstrated potent monotherapy efficacy in pancreatic, ovarian, and bile duct preclinical cancer models, indications that have high CSP expression and are being evaluated in a first-in-human Phase 1/2 clinical trial (NCT05074472). Here, we show that CSP is an ideal target for an ADC: it is abundantly and selectively expressed in many indications, bioavailable, and its inhibition is predicted to synergize with FDA-approved payloads. ZB131 binds specifically to CSP, rapidly internalizes, displays linear pharmacokinetics in pre-clinical models, and demonstrates a strong safety profile. We describe the development of two ZB131 ADCs, ZB131-MMAE (monomethyl auristatin E) and ZB131-DXd (Deruxtecan), with drug-to-antibody ratios of 3 – 4 and 7 – 8, respectively. After binding, both ADCs are rapidly and specifically internalized by CSP-positive cells resulting in drug payload release and enhancing cancer cell death compared to ZB131 alone. Moreover, we characterize cytotoxic activity in high and low CSP cell lines to evaluate ADC activity in relation to CSP abundance. In preclinical xenograft models, ZB131-ADC enhanced tumor regression compared to controls at clinically relevant doses. Furthermore, anti-huIgG staining revealed selective target engagement by ZB131-ADC. Taken together, these data show that ZB131-ADCs demonstrate potent antitumor activity and support their evaluation in a Phase 1 clinical trial. Citation Format: Samantha M. Perez, Brian P. Murphy, Danielle B. Heckert, Sarah Hall, Abby L. Colvin, Molly F. Owens, Ben R. Verfurth, Julien Dimastromatteo, Jiang He, Reid B. Adams, Yelena Kovtun, Lindsey T. Brinton, Kimberly A. Kelly. ZB131 antibody-drug conjugates induce potent antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6299.