Adenosine receptor antagonists and inhibitors of adenosine production are expected to be highly synergistic with other immuno-oncology mechanisms, as well as with chemotherapy. Because of the promise of the adenosine pathway, several adenosine receptor antagonists discovered years ago and initially developed for other indications have been repurposed for oncology. Arcus Biosciences has generated novel small- molecule dual antagonists of the key adenosine receptors A2aR and A2bR, and is also developing a monoclonal antibody to target TIGIT (T cell immunoreceptor with Ig and ITIM domains) and other novel entities.
Adenosine is a powerful immunosuppressive agent 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 in preclinical development, is able to block both of these adenosine receptors.
Like some 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 cells and other cell types can interfere with the ability of tumor-infiltrating immune cells to mount an effective anti-tumor response. AB154 is a monoclonal antibody under development which is expected to result in an anti-tumor effect by potently and selectively blocking this interaction.
The research and development of these small molecule and antibody based drug candidates will be discussed, along with the challenges met as they approach clinical testing.
Tim has been involved in multiple aspects of drug discovery and development in pharmaceutical and biotechnology companies in the U.S. for more than 15 years, leading discovery and pharmacology teams in a variety of therapeutic areas (e.g., oncology, autoimmune, inflammatory, metabolic and CNS diseases) as well as being involved in groups focused on the external identification of novel technologies and assets suitable for in-licensing and/or acquisition. Prior to joining Arcus, Tim was a Senior Director in the External R&D Innovation (ERDI) group at Pfizer where he focused on identifying new Immuno-Oncology opportunities across all therapeutic modalities, as well as managing the global alliances with Servier and Cellectis focused on the discovery and development of allogeneic CAR-T cell products. Before Pfizer, Tim was a Director in the New Frontier Science group at Takeda, where he primarily focused on identifying and funding very early-stage technologies being developed in academic settings to determine utility in accelerating drug discovery and development.
Prior to Takeda, Tim held various scientific management roles, first at Tularik/Amgen and then as Director of Biology at ChemoCentryx. Tim holds a B.A. degree from the University of Notre Dame and a Ph.D. degree in Cellular and Molecular Biology from the University of California, Berkeley where he trained in the laboratory of Dr. James Allison.