CGEN-15001: a Novel B7-like regulator of immune homeostasis and inducer of Ag-specific tolerance

B7 proteins play critical immunomodulatory roles and provide attractive targets for development of novel therapies for cancer and autoimmunity, both of which involve improper immune tolerance. A major medical need in autoimmunity is restoration of immune tolerance to self-antigens. CGEN-15001, an Fc fusion protein of a novel B7-like protein that we identified, regulates immune homeostasis by inhibiting Th1/Th17 responses while enhancing Th2 and anti-inflammatory cytokines such as IL-10, and promoting iTreg differentiation. This was observed in vitro using murine cells and in PBMCs of healthy donors and MS patients, as well as in vivo in R-EAE model and in HY transplantation model. Short-term administration of CGEN-15001 in R-EAE model of MS and in NOD model of T1D resulted in durable therapeutic effects which lasted long after cessation of treatment, suggestive of restoration of immune tolerance. Treg blockade with anti-IL-10 or anti-TGFβ, and transient Treg neutralization with anti-CD25 abolished these therapeutic effects. Importantly, transferring CD4+ T cells from CGEN-15001-treated mice to naive recipients protected them from R-EAE induction in Ag-specific manner, demonstrating induction of Ag-specific tolerance. In contrast, tolerance transfer was not achieved following CTLA4-Ig treatment in spite of the remission it induced in the donor mice. In summary, CGEN-15001 has a unique mode of action, combining immunomodulation and regulation of immune homeostasis, as well as re-establishment of Ag-specific tolerance via enhancing Treg differentiation, leading to durable disease amelioration. These findings support the potential of CGEN-15001 to provide a promising therapeutic approach across autoimmune diseases.