EOS100850, an insurmountable and non-brain penetrant A2A receptor antagonist, inhibits adenosine-mediated T cell suppression and exhibits anti-tumor activity.
Houthuys E., Marillier R., Deregnaucourt T., Brouwer M., Pirson R., Marchante J., Basilico P., Prasad S., Hermant A., Nyawouame F., Preillon, J., Frederix K., Michaux A-C., Moulin C., Lambolez F., Swiercz J., Driessens G., Wald N., Martinoli C., Bodo V., Detheux M., Crosignani S. and Leroy X. iTeosTherapeutics
High levels of extracellular adenosine in the tumor microenvironment promote tumor immune evasion by suppressing Th1 cytokine production and cytolytic activity of T and NK cells. We defined the expression of the four adenosine receptors in primary human immune cells by nanostring. A2A was the main adenosine receptor expressed by T lymphocytes and monocytes, and the only one in mature monocyte-derived dendritic cells and NK cells. We further demonstrated that selective A2A agonists suppressed cytokine production by human activated T lymphocytes and monocytes, highlighting that A2A is the main receptor mediating adenosine signaling in these cells. We demonstrated that A2A antagonists initially designed for Parkinson's disease but repurposed for immuno-oncology dramatically lost potency in a high adenosine environment. We therefore developed EOS100850, a novel non-brain penetrant inhibitor of A2A with sub-nanomolar Ki and selectivity versus A1, A2B, and A3 receptors. EOS100850 potently inhibited A2A signaling in human T lymphocytes independently of adenosine concentrations, and rescued cytokine production in the presence of high concentrations of A2A agonists. iTeos A2A antagonist EOS100850 potently rescued Th1 cytokine production in human whole blood treated by A2A agonists, and increased CD8+ T cell cytotoxicity in a co-culture assay of effector CD8+ T cells and target cancer cells. ITeos EOS100850 insurmountable A2A receptor antagonist, uniquely designed to address the challenge of counteracting elevated adenosine concentrations in tumors, was tested in mouse A20 lymphoma model. Combined with anti-PD-L1, iTeos A2a antagonist showed significant enhancement of antitumor activities compared with anti-PD-L1 alone. In addition, 5/10 complete tumor regressions and 3/10 tumor free survivals were observed in this combination group. in order to restore antitumor immunity. ESO200850 represents a novel, potent, and best-in-class A2A blocker that has been specifically optimized for immuno-oncology indications.