Extracellular adenosine (ADO) is present in high concentrations in the tumor microenvironment (TME) and exerts profound immunosuppressive effects on a variety of tumor-infiltrating leukocytes. Intra-tumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP→AMP) and CD73 (AMP→ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. We will describe the evolution of a concise series of potent and selective CD73 inhibitors optimized via interrogation of structure activity relationships (SAR) and structure-based drug design. From this series, AB680 was identified as a highly potent, reversible and selective inhibitor of both soluble and cell-bound CD73 (IC50 &lt; 0.01 nM on human CD8+ T cells). X-ray crystallography of hCD73-AB680 co-crystals confirms that AB680 binds to the closed form of the enzyme at its active site and identifies specific inter-molecular interactions responsible for the approximately 1,000,000-fold greater affinity of AB680 relative to the enzyme’s substrate, AMP. AB680 potently reverses AMP and ADO-mediated suppression of human immune cell function in vitro and has demonstrated antitumor activity in xenograft mouse models. The high potency of AB680 is complemented by excellent pharmacokinetic properties. AB680 has demonstrated very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in Phase 1 clinical trials.

Discovery of AB680: A potent and selective CD73 inhibitor for cancer immunotherapy

2019 Spring National Meeting

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