Oncology Pipeline

The immune system has developed multiple regulatory mechanisms to control for self-tolerance and limit tissue and organ damage during active responses to pathogens. This is partly achieved by a host of inhibitory receptors expressed on cells of the immune system that, upon activation, suppresses the inflammatory responses of immune cells. These pathways are referred to as immune checkpoints.⁶ In the extracellular space, the ecto-nucleotidase CD73 catalyzes the conversation of AMP to adenosine, which acts as an immune-suppressive metabolite.⁷ In the tumor microenvironment, tumor-derived CD73 produces extracellular adenosine that promotes tumor growth by limiting antitumor T-cell immunity via adenosine receptor signaling.⁸ Adenosine signals by binding to four G-protein coupled receptors: A1A, A2A, A2B, and A3.⁹ The most ubiquitously expressed receptor subtype on immune cells is A2A and, upon activation, exerts a suppressive effect of the inflammatory immune response by modulating CD4 and CD8+ T cells and downregulating cytokine expression.⁵

LY3475070 is an oral, selective, noncompetitive inhibitor of CD73. In preclinical xenograft models, LY3475070 demonstrates reduction of adenosine in tumor tissue. In PBMCs, LY3475070 rescues adenosine-mediated suppression of T-cell proliferation and cytokine secretion.