Claudin 18.2 is tight junction protein with a highly selective cell surface expression profile that is limited to the normal gastric mucosa. Importantly, it is often overexpressed in several types of cancers including gastric, pancreatic, esophageal, ovarian, and lung. There are currently no approved targeted therapies for claudin 18.2-expressing cancers. As such, we designed an antibody drug conjugate, EO-3021/SYSA1801 with the potential to selectively target and kill claudin 18.2-expressing cancer cells. EO-3021 is comprised of a novel tumor-targeting monoclonal antibody that selectively binds claudin 18.2 (Kd = 0.6 nM) that is conjugated to monomethyl auristatin E (MMAE). EO-3021 is internalized in claudin 18.2-expressing cells as well as demonstrates cell killing across a range of cancer cell lines with low (IC50 = 228 ng/ml), medium (IC50 = 7 ng/ml), and high levels of claudin 18.2 (IC50 = 28 ng/ml) expression. More specifically, claudin 18.2-expressing cells undergo G2/M cell cycle arrest and apoptosis upon EO-3021 treatment. EO-3021 demonstrates tumor regressions with a single dose across low, medium, and high claudin 18.2-expressing in vivo models derived from pancreatic (9 mg/kg), gastric (2 mg/kg), and lung cancers (8 mg/kg), respectively. In addition, a single dose of EO-3021 outperforms standard of care chemotherapies, such as cisplatin and gemcitabine, across in vivo models. Nonclinical toxicology studies suggested that EO-3021-mediated toxicities were reversible and manageable as well as afford a therapeutic index suitable for testing in humans. EO-3021/SYSA1801 is currently being evaluated in a Phase I dose escalation study (NCT05009966) in patients with claudin 18.2 positive advanced malignant solid tumors. A case study will be presented where a confirmed and durable partial response (66.7% tumor reduction) was observed following EO-3021 treatment.

Citation Format: David Dornan. EO-3021: An antibody drug conjugate targeting CLDN18.2 expressing cancers [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 ND11.