Abstract C076: Clinical pharmacokinetic/pharmacodynamic relationship for AB598, a large molecule inhibitor of CD39

Abstract Background: AB598 is a novel, humanized, Fc-silent anti-CD39 monoclonal antibody that potently binds to CD39 and inhibits its enzymatic activity with subnanomolar potency. AB598 is under investigation in a first-in-human, multicenter, non-randomized, open-label phase 1 study in patients with advanced solid tumors (NCT05891171). Objective: To characterize the pharmacokinetics (PK) of AB598 in cancer patients To describe the relationship between AB598 PK and tumor pharmacodynamic (PD) markers (receptor occupancy and enzymatic inhibition) to inform the selection of an appropriate dose for future clinical trials. Methods: The study consists of two phases: a monotherapy AB598 dose escalation phase (300 mg, 900 mg, 1800 mg and 3000 mg IV Q3W) that is complete, and an ongoing combination dose expansion phase (AB598 + FOLFOX + zimberelimab). Safety, PK, and PD data from dose escalation phase were used to determine the recommended dose for expansion. PK samples were collected to characterize AB598 PK profile in cycle 1; thereafter, sparse samples were collected. Paired PK/PD samples were collected at baseline and at cycle 2 day 8 from select patients enrolled in the dose escalation phase at 900 mg, 1800 mg and 3000 mg IV Q3W. PK parameters were estimated using noncompartmental analysis (Phoenix WinNonlin v8.4). A target mediated drug disposition (TMDD) PK model with non-linear clearance and a maximum drug effect (Emax) PK/PD model were developed to describe AB598 PK and AB598 PK/PD relationship, respectively. Results: A total of 33 patients were included in the PK analysis set. AB598 was well tolerated; no dose limiting toxicities were observed, and the maximum tolerated dose was not reached. AB598 PK was approximately dose proportional over 900 mg – 3000 mg dose range. Limited accumulation (1.2 - 1.5-fold) was observed based on the maximum concentration (Cmax) following multiple doses. AB598 half-life ranged 6 – 8 days after a single dose and was consistent across 900 mg – 3000 mg dose range. The TMDD model adequately described AB598 PK, and an Emax model described the relationship between AB598 serum concentrations with tumor receptor occupancy and enzymatic inhibition. AB598 concentrations of 107 ug/mL and 176 ug/mL are sufficient to achieve 90% tumor receptor occupancy and 90% enzymatic inhibition, respectively. Based on modeling and simulation, 2000 mg IV Q2W yielded similar steady state exposure to 3000 mg IV Q3W, therefore, 2000 mg IV Q2W was selected as the expansion dose. Modeling indicates that the expansion dose of 2000 mg IV Q2W achieves 90% receptor occupancy and 90% enzymatic inhibition. PK data confirmed this prediction. Conclusion: AB598 exhibited linear, time-invariant PK across 900 mg – 3000 mg dose range. AB598 half-life is consistent with other anti-CD39 antibodies. 2000 mg IV Q2W observed concentrations adequately achieve the target effective concentrations. Citation Format: Lilian W. Adeojo, Angelo Kaplan, Haben Ghermazien, Ramon Jones, Haiying Zhou, Balaji Agoram. Clinical pharmacokinetic/pharmacodynamic relationship for AB598, a large molecule inhibitor of CD39 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C076.