Puyan Rafii, Patricia Rodrigues Cruz, Julia Ettich, Hendrik Weitz, Christiane Seibel, Doreen Manuela Floss, Kristina Behnke, Jens Moll, Jürgen Scheller

Engineering of synthetic cytokine chimeras (cytokimeras)

Synthetic cytokines like IC7 have proven beneficial in mouse model diseases like type 2 diabetes devoid of significant side effects.  All except one cytokine of the Interleukin (IL-)6 family share gp130 as the common b-receptor chain. Whereas IL-6, IL-11 or ciliary neurotrophic factor (CNTF) require previous attachment to its a-receptor via a binding site I following b-receptor homo- or hetero dimerization, other members of IL-6 family bind b-receptors chains directly via site II and site III. Using IL‑6 or IL-11 as a scaffold, we exchanged the gp130 binding site III of IL-6 or IL-11 with the binding site III of leukemia inhibitory factor (LIF) or oncostatin-M (OSM) in a structure-based approach. The engineered cytokine chimeras (cytokimera) GIL‑6, GIO-6, and GIL-11 are able to efficiently recruit non-natural receptor complexes resulting in signal transduction and proliferation of factor-depending Ba/F3 cells. Human GIL-11 exhibits cross-reactivity to mouse and rescued IL-6R deficient mice following partial hepatectomy, demonstrating gp130:IL11-R:LIFR signaling efficiently induced liver regeneration. The development of these cytokimera has enabled new potential avenues for therapeutic application by assembling novel artificial cytokine receptor complexes.