Cytokine Couture: Designer IL2 Molecules for the Treatment of Disease

Amy Dashwood,1,2 Arman Ali Ghodsinia,1 James Dooley,1 Adrian Liston1 1Department of Pathology, University of Cambridge, Cambridge, UK; 2Immunology Programme, Babraham Institute, Cambridge, UKCorrespondence: Amy Dashwood; Email [email protected] Adrian Liston, Email [email protected]: Interleukin 2 (IL2) is a dual-acting cytokine, playing important roles in both immune activation and regulation. The role IL2 plays as a potent activator of CD8 T cells saw IL2 become one of the earliest immunotherapies, used for the treatment of cancer. In more recent years refined understanding of IL2, and the potent capacity it has for Treg stimulation, has seen low-dose IL2 therapy trialled for the treatment of auto-immune and inflammatory conditions. However, despite clinical successes, IL2 therapy is not without its caveats. The complicated receptor biology of IL2 gives rise to a narrow therapeutic window, made problematic by its short half-life. Armed with a better understanding of the structure of IL2 in complex with its receptors, many attempts have been made to create designer IL2 molecules which overcome these problems. A wide range of approaches have been used, resulting in > 100 designer IL2 molecules. These include antibody complexes, fusion proteins, mutant IL2 molecules and PEGylation, each uniquely modifying the biological activity in an effort to enhance its therapeutic potential. Collectively, designer IL2 molecules form a blueprint outlining modification pathways available to other immunotherapeutics, paving the way for the next generation of immunotherapy.Keywords: cytokine, protein engineering, T cell, treg, interleukin 2