Adenosine is generated through the hydrolysis of extracellular adenosine mono phosphate (AMP) by the ectonucleotidase CD73. It is an important mechanism for immunosuppression in cancer development. A2aR and A2bR drive primarily Adenosine’s suppressive effects on immune cells. High expression of CD73 correlates with poor outcomes in tumor types such as triple-negative breast cancer and non-small-cell lung cancer. Extracellular adenosine triggers signaling pathways through 4 distinct G-protein-coupled adenosine receptors: A1, A2a, A2b, and A3. Of these receptor subtypes, A2aR has the relation with the immunosuppressive effects. A2aR stimulation impairs T cell activation, leading to reduced proliferation and cytokine release. In this study, AB928 is an orally bioavailable, selective dual adenosine receptor (A2aR/A2bR) antagonist. AB928 relieves adenosine-mediated immune suppression. AB928 also has immunomodulatory and antitumor activities.
In human in vitro cell cultures, moDC differentiated in the presence of adenosine showed a decreased ability to stimulate IFN-γ secretion from allogenic CD4+ T-cells in an MLR. This suppression is significantly reversed by the addition of AB928. Multiplexed gene expression profiling using NanoString identified a cassette of 39 genes. Adenosine regulates these genes during moDC differentiation. AB928 shows rescue of these gene expression changes. Concurrent treatment with AB928 and chemotherapy results in significantly reduced tumor volume in vivo using AT3-OVA tumors. AB928 is also capable of suppressing the growth of B16-F10 tumors both as a single agent or in combination with α-PD-1 therapy. It also increases the antitumor immune response leading to suppressed tumor growth and increased immune cell infiltration in mouse syngeneic tumors.
In summary, AB928 is a dual antagonist of the A2aR and A2bR adenosine receptors. In addition, it relieves adenosine-mediated immune suppression.
Seitz L, et al. Invest New Drugs. 2019;37(4):711-721. ; Daniel DiRenzo, et al. Cancer Immunol Res 2019;7(2 Suppl): Abstract nr A162.