Unlocking the Potential of AB680: A Breakthrough CD73 Inhibitor in Cancer Immunotherapy

Extracellular adenosine (ADO) is known to inhibit immune function by suppressing T cell and NK cell activation, and it is prevalent in the tumor microenvironment (TME). The production of ADO within the TME is facilitated by the sequential action of two enzymes, CD39 and CD73, which convert ATP to AMP and then to ADO, respectively. Targeting CD73 to halt ADO production presents a strategy to counteract immune suppression mediated by ADO. AB680 is a newly developed, potent, and selective small molecule inhibitor of CD73 that is currently in preclinical development for potential use as an anti-tumor agent.

The potency of AB680 was evaluated using a malachite green assay to measure AMP hydrolysis by CHO-CD73 cells, as well as in human T-cells and soluble recombinant CD73. The compound showed high selectivity against related ecto-nucleotidases and a large panel of other enzymes, receptors, and ion channels. Notably, AB680 did not significantly inhibit major CYP450 isoforms or the hERG potassium channel. It effectively reversed AMP and ADO-mediated immune suppression in vitro, restoring CD25 expression, IFN-γ production, and proliferation in human CD4+ and CD8+ T-cells.

Pharmacokinetic assessments of AB680 in preclinical species indicated low clearance and long half-lives, suggesting a human dosing schedule compatible with typical monoclonal antibody dosing cycles. The compound was well-tolerated in high-dose infusions in these species.

In conclusion, AB680 is a highly potent and selective CD73 inhibitor capable of blocking adenosine production in the TME, thereby mitigating tumor-induced immune suppression. With its favorable projected human pharmacokinetic profile, AB680 is poised for clinical development as a potential new immunotherapy agent for cancer treatment.