{
  "abstract": "Background CD39 is a cell surface enzyme that degrades extracellular ATP, a potent immunostimulatory signal in the tumor microenvironment (TME). AB598 is a novel, humanized, Fc-silent anti-CD39 antibody that potently binds to CD39 and inhibits its enzymatic activity, which may potentiate enhanced antitumor immunity. ARC-25 ( NCT05891171) is an ongoing phase 1/1b first-in-human trial to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of both AB598 monotherapy and AB598 in combination with zimberelimab (anti-PD1) and mFOLFOX chemotherapy in patients with advanced solid tumors.Methods Here we present peripheral PD data from AB598 monotherapy dose escalation cohorts (31 subjects dosed at 300, 900, 1800, or 3000 mg Q3W). Flow cytometry, ELISA, and qRT-PCR were utilized to assess CD39 cellular expression, plasma concentrations, and transcriptional dynamics in peripheral blood. Target engagement by AB598 was determined by CD39 receptor occupancy (RO) and enzymatic inhibition on peripheral immune cells.Results CD39 is abundantly expressed in peripheral immune cell types, including B cells, regulatory T cells (T reg), monocytes, dendritic cells, and neutrophils. AB598 treatment led to significant reduction in total CD39 protein, with the largest loss observed in B cells. Loss of cellular CD39 correlated with increases in soluble CD39 (sCD39). CD39 mRNA remained unchanged throughout treatment, suggesting that AB598-mediated CD39 release does not alter basal CD39 transcription in peripheral immune cells. Complete and sustained peripheral coverage was achieved in all patients dosed with AB598 at 900 mg Q3W or higher. Loss of complete RO and enzymatic inhibition at the lowest dose administered corresponded with reversal of cellular CD39 loss and a decrease in sCD39. The mechanism of AB598-mediated CD39 release is unknown. However, we have demonstrated that AB598 is able to fully bind sCD39 in plasma from AB598-dosed patients, indicating that complete target engagement is achieved and maintained across all peripheral compartments.Conclusions Peripheral PD data presented here as well as other tumor PD data (baseline and on-treatment biopsies collected in the PD cohorts) and safety assessments were considered in selecting the recommended dose for expansion. Lower doses of AB598 achieved complete target engagement in the periphery (900 mg Q3W) than were required to achieve complete target binding and inhibition within the TME (1800 mg Q3W). A dose expansion cohort in first-line gastric and GEJ cancer is actively enrolling with safety data to be reported in the future.Acknowledgements The authors wish to acknowledge the patients and physicians who contributed to this research.Ethics Approval The study was conducted in compliance with this 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.",
  "authors": [
    {
      "affiliations": [
        "Arcus Biosciences, Inc., Hayward, CA, USA"
      ],
      "name": "Jacob AVan Winkle"
    },
    {
      "affiliations": [
        "Arcus Biosciences, Inc., Hayward, CA, USA"
      ],
      "name": "Urvi Vani"
    },
    {
      "affiliations": [
        "Arcus Biosciences, Inc., Hayward, CA, USA"
      ],
      "name": "Omar Kabbarah"
    },
    {
      "affiliations": [
        "Arcus Biosciences, Inc., Hayward, CA, USA"
      ],
      "name": "Haiying Zhou"
    },
    {
      "affiliations": [
        "Arcus Biosciences, Inc., Hayward, CA, USA"
      ],
      "name": "Lisa Seitz"
    },
    {
      "affiliations": [
        "Arcus Biosciences, Inc., Hayward, CA, USA"
      ],
      "name": "Amy E Anderson"
    }
  ],
  "title": "170 Peripheral pharmacodynamic analysis of anti-CD39 monoclonal antibody AB598 in a first-in-human phase I trial in patients with advanced solid tumors",
  "uid": "61b87812-e138-52b6-81f6-2bd342652d08"
}