In addition to the above product candidates, we expect to identify a lead oral CD73 inhibitor in 2018. We have initiated several other programs against promising immuno-oncology targets such as arginase, and we expect to select a development candidate in 2018 and file an IND or foreign regulatory application for the first development candidate from one of these programs by early 2019.
AB928 is a potent and selective dual antagonist of the adenosine receptors known as A2aR and A2bR. Adenosine is a powerful immunosuppressive substance produced inside tumors as a result of rapid cancer cell turnover and, in some cases, in connection with certain anti-tumor interventions, such as chemotherapy and radiation. The A2aR and A2bR receptors are expressed on the surface of immune cells (such as T cells, NK cells, dendritic cells and macrophages) and mediate the immunosuppressive effects of adenosine. AB928, a small-molecule drug that will be administered to patients orally, is the only drug currently in development that is able to block both of these adenosine receptors. AB928 is currently being evaluated in a Phase 1/1b program in combination with our anti-PD-1 antibody (AB122) and with chemotherapy.
AB680 is a potent and selective inhibitor of CD73, the enzyme responsible for the extracellular production of adenosine within the tumor micro-environment. Adenosine is a powerful immunosuppressive substance produced inside tumors as a result of rapid cancer cell turnover and, in some cases, in connection with certain anti-tumor interventions, such as chemotherapy and radiation. Inhibition of adenosine production is an alternative, perhaps complementary, therapeutic strategy to the use of adenosine receptor antagonists such as AB928. AB680 is the only small-molecule CD73 inhibitor currently in development. We anticipate initiating a Phase 1 trial to evaluate AB680 in healthy volunteers in the second half of 2018 and initiating clinical trials in patients in the first half of 2019.
AB122 is a monoclonal antibody (mAb) that potently and selectively blocks a protein called PD-1. This immune checkpoint is expressed by tumor-infiltrating T cells that recognize tumor antigens but have become exhausted by chronic exposure to those antigens in the tumor’s tolerogenic environment. By producing proteins (PD-L1 and PD-L2) that bind to PD-1, cancer cells and even immune cells in the tumor micro-environment can interfere with the ability of T cells to mount an effective anti-tumor response. Like other agents in this class that have already received regulatory approval, AB122 potently and selectively blocks this interaction between PD-1 and its ligands, which we expect will result in a powerful anti-tumor effect. AB122 is currently in a Phase 1 trial in cancer patients and is also being evaluated in our Phase 1/1b program in combination with AB928.
AB154 is a monoclonal antibody (mAb) that potently and selectively blocks a novel immune checkpoint called TIGIT. Like some of the first-generation immune checkpoints (e.g., PD-1 and CTLA-4), TIGIT is expressed on exhausted T cells, which may reside inside tumors but are unable to mount an effective attack against the cancer cells. It is also expressed on a wide range of other tumor-infiltrating immune cells, such as NK cells and regulatory T cells. By producing proteins that bind to TIGIT, cancer and other cells can interfere with the ability of tumor-infiltrating immune cells to mount an effective anti-tumor response. AB154 will block this interaction, which we expect will result in a powerful anti-tumor effect. We anticipate submitting our first regulatory application for AB154 in the middle of 2018.