Discovery of a new anti-γc antibody in clinical development for the treatment of autoimmune diseases.

Abstract

Autoimmune disease refers to a condition when the immune system anomalously attacks its own body and healthy cells. Although the exact causes of autoimmune diseases are unknown, it is recognized that excessive or aberrant cytokine responses contribute significantly to the development of autoimmunity. Among them, the common gamma c chain (γc) cytokines driven signaling cascade plays an indispensable role in driving pathogenic immune responses in patients with autoimmune diseases. Thus, we hypothesize that the development of an antibody targeting γc receptor could serve as a potential approach for treating autoimmune diseases and fulfil the unmet medical needs in this area. Here, we demonstrate that a humanized anti-γc antibody, hC2, could show high binding affinity to the human γc receptor and suppress 6 γc cytokines (interleukin [IL]-2, IL-4, IL-7, IL-9, IL-15 and IL-21)-driven STAT phosphorylation, leading to inhibition of autoimmunity and activation in B, T, and natural killer cell lines. Similar inhibitory effects were observed in the human peripheral blood mononuclear cell culture. Moreover, administration of hC2 could reduce expansion and tissue infiltration of T helper and cytotoxic T cells, leading to attenuation of damages to skin, liver, and kidney in the humanized xenograft mouse model. The current study demonstrates the potential of γc blockades for the treatment of T cell-mediated autoimmune diseases and chronic graft-versus-host disease. Anti-γc antibody hC2 might offer a more efficacious therapy compared with antibodies targeting a single γc cytokine and safer therapy than JAK inhibitors to fulfill the unmet medical needs in the autoimmune diseases in the future.