Targeting the binding interface on a shared receptor subunit of a cytokine family enables the inhibition of multiple member-cytokines with selectable target spectrum.

Abstract The common gamma molecule (γc) is a shared signaling receptor subunit used by six γc-cytokines. These cytokines play crucial roles in the differentiation of mature immune system and are involved in many human diseases. Moreover, recent studies suggest that multiple γc-cytokines are pathogenically involved in a single disease, thus making the shared γc-molecule as a logical target for therapeutic intervention. However, the current therapeutic strategies seem to lack options to treat such cases, partly because of the lack of appropriate neutralizing antibodies recognizing the γc, and more importantly because of the inherent and practical limitations in the use of monoclonal antibodies. By targeting the binding interface of the γc and cytokines, we successfully designed peptides that can not only inhibit multiple γc-cytokines but with selectable target spectrum. Notably, the lead-peptide inhibited three γc-cytokines without affecting other three or non- γc cytokines. Biological and mutational analyses of our peptide provide new insights to our current understanding on the structural aspect of the binding of γc-cytokines the γc-molecule. Furthermore, we provide evidence that our peptide, when conjugated to polyethylene glycol to gain stability in vivo, efficiently block the action of one of the target cytokines in animal models. Collectively, our technology can be expandable to target various combinations of γc-cytokines and thereby will provide a novel strategy to the current anti-cytokine therapies against immune, inflammatory and malignant diseases.