Evaluation of P2X7 as a therapeutic target in autoimmune encephalomyelitis and in tumor immunity

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P2X7, a ligand-gated ion channel, and ARTC2, a toxin-related ecto-enzyme, are immune cell surface proteins that sense ATP and NAD+ released from cells as endogenous danger signals during sterile inflammation. On myeloid cells, P2X7 is a key mediator of inflammation. On T cells, ARTC2 and P2X7 regulate Treg function and survival. We have discovered in a previous collaborative study, that depletion of regulatory T cells by activation the ARTC2/P2X7 axis can be used to promote anti-tumor immune responses. Recently, we have developed P2X7-blocking and P2X7-potentiating nanobodies (Nbs) and Nb based biologics. We found that blocking P2X7 function with these biologics in vivo represents a promising novel therapeutic strategy to ameliorate inflammation. These biologics can be administered either by repeated systemic injections or via continued endogenous synthesis after transduction of cells in vivo with adeno-associated viral (AAV) vectors coding for these Nb. So far, little is known about the in vivo pharmacodynamics of these biologics, and about their capacity to reach and block their targets on immune cells in lymphatic organs, inflamed tissues or tumors. The blood-brain barrier (BBB) in particular poses a natural obstacle for protein-based biologics to reach their targets in the central nervous system (CNS). Moreover, the role of P2X7 in autoimmune inflammatory diseases and in the tumor microenvironment still need to be precisely delineated. The central goal of this study is to evaluate P2X7 as a therapeutic target in models of experimental autoimmune encephalomyelitis (EAE) and in anti-tumor response. A second goal of this study is to optimize the in vivo targeting of P2X7 in the CNS and in the tumor microenvironment using Nb-based biologics. In both models, we will exploit systemic injections as well as AAV-mediated long-term endogenous production of the Nb-based biologics to better understand the role P2X7 and to evaluate the therapeutic benefits associated with its short and long-term functional modulation. Moreover, we will explore the potential of Fc-engineering and of bispecific-targeting to enhance the effector functions of Nb based biologics. We expect the results of this project to provide valuable new insights into the pathophysiological roles of P2X7 in inflammation and immunity and to validate its relevance as a therapeutic target.