In the tumor micro-environment (TME), extracellular ATP is sequentially hydrolyzed to adenosine by the ecto-nucleotidases CD39 (ATP→AMP) and CD73 (AMP→adenosine), driving the suppression of immune cell function. A2aR is expressed by a variety of lymphocyte populations, mainly T and NK cells, while myeloid cells express both A2aR & A2bR. A2aR activation results in decreased T cell activation, while binding of adenosine to A2bR on myeloid cells promotes a tolerogenic phenotype. To alleviate immune suppression within the TME, we designed AB928, a potent, first-in-class, dual antagonist of A2aR and A2bR. We will describe our SAR efforts leading to the discovery AB928, which was designed specifically for the oncology setting, with minimal CNS penetration. AB928 inhibits both A2aR and A2bR with similar potencies (KB: 1.4 nM and 2 nM, respectively). Adenosine-mediated suppression of CD8+ T cell activation was reversed by AB928, which restored IFN-gamma and granzyme B production from these cells. AB928 exhibited good selectivity against A1R and A3R, the other two adenosine receptors. AB928 potently inhibited NECA-induced CREB phosphorylation in CD8+ T cells in whole human blood in a dose-dependent manner. AB928 has demonstrated a significant reduction in tumor growth and enhancement of tumor inflammation when tested as monotherapy and in combination with chemotherapy and anti-PD-1 antibody in mice. AB928 has exhibited excellent safety, PK, and PD profiles in a Phase 1 clinical trial in healthy volunteers and is currently being evaluated in cancer patients.

Discovery of AB928, a potent first-in-class dual A2a and A2b receptor antagonist for cancer immunotherapy

2019 Fall National Meeting

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