Abstract B033: A novel IL-2 and IL-15 antagonist shifting the immune balance towards tolerance: Potential therapeutic applications

Interleukin-15 and interleukin-2 are two hematopoietic cytokines belonging to γ c family and both share the IL2/15Rβ chain and the common γ chain. The IL-15Rα and IL-2Rα chains confer specific binding and signalling for IL-15 and IL-2 respectively. IL-15 and IL-2 induce T-cell proliferation, effector T-cell differentiation and memory T-cell survival. Unlike IL-15, IL-2 plays a crucial role, in development and activation of regulatory T cells, which constitutively express specific IL-2Rα chain. In order to inhibit IL-2 and IL-15 dependent effector functions, we developed an original antagonist called BinhG which target the shared IL-2/15Rβγ receptor. To characterize BinhG9s mechanism and therapeutic potential, we first studied its effect in vitro on IL-15 and IL-2-induced proliferation on cell lines and peripheral blood mononuclear cells. We found that BinhG was able to inhibit IL-15 and IL-2-dependent proliferation of effector NK and CD8 T cells expressing the IL-2/15Rβγ dimeric receptor, whereas it was unable to inhibit IL-2 induced-T-reg cells due to ILtheirs IL-2Rα expression. These results were confirmed in vivo , by inhibition of IL-2 or IL-15 induced activation in mice. Moreover, after PolyIC stimulation in vivo , BinhG was able to reduce IFNγ secretion by NK cells and activation marker CD69 surface expression by CD4 T and CD8 T lymphocytes, but has no effect on T-reg cells. In the light of these observations, BinhG was evaluated in order to induce tolerance. Thus, we set up a murine model of skin graft rejection, and we observed that BinhG prolonged the skin graft survival. The use of the BinhG antagonist appears to have much promise, as it is able to shift immune response towards the tolerance side of the balance. However, further studies are needed to maximize the therapeutic outcome, by improving BinhG in vivo half-life. Moreover, it would be of interest to evaluate BinhG9s effect in autoimmune contexts. Citation Format: Meghnem Dihia, Sebastien Morisseau, Kilian Trillet, Marie Frutoso, Isabelle Barbieux, Agnes Quemener, Yannick Jacques, Erwan Mortier. A novel IL-2 and IL-15 antagonist shifting the immune balance towards tolerance: Potential therapeutic applications [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B033.