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Background The inhibition of CD39 contributes to the stabilization of extracellular ATP levels, providing a potent immunostimulatory signal in the tumor microenvironment (TME) and potentially leading to enhanced antitumor immunity. AB598 is a novel, humanized, Fc-silent anti-CD39 antibody that potently binds to CD39 and inhibits its enzymatic activity. ARC-25 ( NCT05891171) is a phase 1/1b trial to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AB598 monotherapy and combination therapy with zimberelimab (anti-PD-1) and standard-of-care chemotherapy. Here we present tumor biomarker data to guide dose selection for an expansion cohort.Methods AB598 was given intravenously once every three weeks (Q3W) in patients with advanced solid tumors. Baseline and on-treatment biopsies were mandatorily collected from patients enrolled in the PD cohorts. Proprietary immunohistochemistry (IHC) assays and enzyme histochemistry (EHC) assays were used to assess tumor CD39 target engagement and enzymatic inhibition. Transcriptomic analysis was also performed on the paired tumor samples collected pre- and post-treatment.Results A total of 15 patients were enrolled in the dose escalation and 16 patients were enrolled in the PD cohorts. As measured by IHC assays, CD39 was highly prevalent and abundantly expressed by various cell types in the tumor microenvironment (TME), including endothelial, fibroblasts, and immune cells across different solid tumors. No changes in total CD39 protein expression levels were observed following AB598 treatment. Receptor occupancy results showed that CD39 was completely occupied by AB598 in 30% (1/3) of subjects at 900 mg and in 100% (7/7) of subjects at ≥1800 mg at the Q3W dosing regimen. As a result, CD39 ATPase activity, measured by EHC assays, showed a dose-dependent enzymatic inhibition pattern. Further exploration showed that serum AB598 concentration, CD39 receptor occupancy, and AB598 mechanisms of action, including CD39 ATPase activity and immunological modulation, are positively correlated.Conclusions AB598 achieved complete CD39 target engagement and inhibition across different tumor types at doses ≥ 1800 mg with Q3W dosing regimen, informing the recommended dose for the expansion cohort. Currently, the ARC-25 expansion cohort in first-line gastric and GEJ cancer is actively enrolling; ARC-25 safety data will be reported in the future.Ethics Approval The study was conducted in compliance with the clinical study protocol, Good Clinical Practice (GCP) as outlined by International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 (R2), and all applicable local and national regulatory requirements. Enrollment at any clinical study site did not begin prior to that site receiving approval from the ethics committee of record for the protocol and all materials provided to potential patients. All participants provided informed consent prior to any clinical research sample collection.