Insights into Cytokine–Receptor Interactions from Cytokine Engineering

Abstract

Cytokines exert a vast array of immunoregulatory actions critical to human biology and disease. However, the desired immunotherapeutic effects of native cytokines are often mitigated by toxicity or lack of efficacy, either of which results from cytokine receptor pleiotropy and/or undesired activation of off-target cells. As our understanding of the structural principles of cytokine–receptor interactions has advanced, mechanism-based manipulation of cytokine signaling through protein engineering has become an increasingly feasible and powerful approach. Modified cytokines, both agonists and antagonists, have been engineered with narrowed target cell specificities, and they have also yielded important mechanistic insights into cytokine biology and signaling. Here we review the theory and practice of cytokine engineering and rationalize the mechanisms of several engineered cytokines in the context of structure. We discuss specific examples of how structure-based cytokine engineering has opened new opportunities for cytokines as drugs, with a focus on the immunotherapeutic cytokines interferon, interleukin-2, and interleukin-4.

Tuning Cytokine Receptor Signaling by Re-orienting Dimer Geometry with Surrogate Ligands

“…Single-pass Type-I and Type-II transmembrane receptors that contain ligand-binding ECDs constitute a major percentage of all signaling receptors in the mammalian genome, and include cytokine (JAK/STAT) receptors (Spangler et al, 2014), Tyrosine Kinase (RTK) receptors (e.g. EGF-R, Insulin-R, etc) (Lemmon and Schlessinger, 2010), and many others.…”

Immunocytokines: a novel class of products for the treatment of chronic inflammation and autoimmune conditions

“…As reported for the cytokines IFN, IL2, IL4, IL13 and IL15, mutations in key residues within the cytokine can alter the binding affinity to the cognate receptor, modulate cytokine activity and/or promote a selective interaction with different subsets of leukocytes [28].…”

Synthetic biology approaches to engineer T cells

“…It is worth noting the exciting development of synthetic molecules specifically designed to trigger immune cell functions, such as engineered cytokines and their mimics [39] as well as bi-specific antibodies [40]. While most of these molecules are designed to interact with natural immunoreceptors, further engineering could be applied to yield highly specific, orthogonal pairs of synthetic ligands and receptors, which in principle would afford more precise exogenous control over engineered immune cells [41].…”