Abstract LB157: Discovery and characterization of INCB106385: a novel A2A/A2B adenosine receptor antagonist, as a cancer immunotherapy
Authors: Wang Hui , Alexandra Alexandra , Hansbury Michael , Mason Jennifer , Harris Jennifer , Stevens Christina , Maddage Christopher , Ren Xiaodi , Gao Mingming , Kurzeja-Lipinski Kerri , Yang Gengjie , Conlen Patricia , Stump Kristine , Feldman Patricia , Thekkat Pramod , Lin Luping , Covington Maryanne , Yeleswaram Swamy , Qi Chao , Wang Xiaozhao , Yao Wenqing , Kim Sunkyu , Wee Susan , Chen Yingnan , Koblish Holly 
Published: July 2021

Abstract
In the tumor microenvironment, ATP released by dying cells is converted to adenosine, a well-established potent suppressor of immune cell activity. The immune suppressive function of extracellular adenosine is mediated through two G-protein coupled receptors known as A2A and A2B. Both receptors are expressed on many types of immune cells. While A2B has traditionally been considered of less relevance compared to A2A due to lower affinity to its ligand adenosine, recent evidence suggests a specific role of A2B in immune suppressive myeloid cells in cancer. To determine whether a small molecule inhibitor which blocks both adenosine receptors on immune cells can be used as an immunotherapy to enhance anti-tumor immune responses, we initiated a discovery campaign to identify dual antagonist inhibitors of A2A and A2B. INCB106385 is a potent, selective and orally bioavailable dual antagonist of A2A and A2B receptors. In vitro, INCB106385 potently binds to both A2A and A2B receptors in the single-digit nanomolar range and antagonizes downstream signaling as measured by cAMP production in A2A and A2B expressing cells. In functional studies, INCB106385, in the presence of 50μM AMP, restores effector T cell activity as measured by interferon gamma (IFNγ) production. In vivo, INCB106385 inhibited both the downstream effector pCREB and tumor growth in CT26 and B16-F10 syngeneic tumor models. Furthermore, in in vitro and in vivo combination studies, INCB106385 and anti-PD-1/PD-L1 CPIs demonstrated an increase in T cell function and anti-tumor activity compared to the single agent treatment groups. These data suggests that inhibition of the adenosine pathway is non-redundant to current checkpoint inhibitor therapies and can be an effective combination strategy to enhance anti-tumor immune activities. In summary, the data presented in this study demonstrate that INCB106385 is a potent, selective and orally bioavailable A2A/A2B dual antagonist that can overcome the immune-suppressive effects of high levels of adenosine in the tumor microenvironment. INCB106385 can promote anti-tumor immunity as a monotherapy and in combination with anti-PD-1/PD-L1 treatment.
Citation Format: Hui Wang, Alexandra Alexandra, Michael Hansbury, Jennifer Mason, Jennifer Harris, Christina Stevens, Christopher Maddage, Xiaodi Ren, Mingming Gao, Kerri Kurzeja-Lipinski, Gengjie Yang, Patricia Conlen, Kristine Stump, Patricia Feldman, Pramod Thekkat, Luping Lin, Maryanne Covington, Swamy Yeleswaram, Chao Qi, Xiaozhao Wang, Wenqing Yao, Sunkyu Kim, Susan Wee, Yingnan Chen, Holly Koblish. Discovery and characterization of INCB106385: a novel A2A/A2B adenosine receptor antagonist, as a cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB157.