Prof. Dr. Jürgen Scheller

Synthetic Cytokine:Receptor Engineering for Immunosignalling 

Interleukin-6 (IL-6) is a key immunomodulatory cytokine that influences the development of various diseases, including autoimmune conditions, chronic inflammatory disorders, and cancer. Classical IL-6 signalling involves the binding of IL-6 to the membrane-bound IL-6 receptor α-subunit (hereafter referred to as 'mIL-6R') and the signal-transducing subunit glycoprotein 130 (gp130). In contrast, IL-6 trans-signalling involves complexes of IL-6 and the soluble form of the IL-6 receptor (sIL-6R), which signal via membrane-bound gp130. A third mode of IL-6 signalling, known as cluster signalling, involves preformed complexes of membrane-bound IL-6 and mIL-6R on one cell activating gp130 subunits on target cells. Antibodies and small molecules that block all three forms of IL-6 signalling have been developed, but IL-6 trans-signalling has emerged as the predominant pathway by which IL-6 promotes disease pathogenesis in the past decade. The first selective inhibitor of IL-6 trans-signalling, sgp130, has demonstrated therapeutic potential in various preclinical disease models, and olamkicept, a sgp130Fc variant, produced promising results in phase II clinical trials for inflammatory bowel disease. Technological developments have led to the creation of next-generation sgp130 variants with increased affinity for and selectivity towards IL-6 trans-signalling in our lab. 

Not only do interleukin-6 (IL-6)-type cytokines have key immunomodulatory functions that affect the pathogenesis of diseases such as autoimmune diseases, chronic inflammatory conditions and cancer, they also fulfil important homeostatic tasks. Although the pro-inflammatory nature of IL-6-type cytokines has hindered the development of therapeutics based on them to date, current synthetic trends may overcome this limitation and lead to immune-inert designer cytokines that could aid in the treatment of type 2 diabetes and brain injuries. These synthetic biology approaches include mutations, fusion proteins and inter-cytokine swapping. They have resulted in IL-6-type cytokines with altered receptor affinities, an extended target cell profile and the ability to target non-natural cytokine receptor complexes. One example is the chimeric cytokine GIL-6 from our lab, which was generated by exchanging the gp130 binding site III of IL-6 with the LIFR binding site III of LIF, resulting in signalling via the non-natural receptor complex consisting of IL-6R, LIFR, and gp130.

Cytokines control immune-related events and play a crucial role in numerous physiological and pathophysiological processes, including autoimmunity and cancer development. Consequently, the modulation of natural cytokine signalling by antibodies and small molecules has enhanced therapeutic regimens. The aim of synthetic biology is to optimise immunotherapeutics, and chimeric antigen receptor (CAR) T cell immunotherapy is the first example to combine synthetic biology with genetic engineering in a therapeutic context. Consequently, synthetic cytokines and cytokine receptors, as well as constitutively active cytokine receptor variants, are emerging as tools to enhance or modify immunotherapeutic strategies. Our lab focuses on developing synthetic cytokine signalling modules and considers potential applications involving physiological immunotherapy targets.

Some review articles from our group:

https://pubmed.ncbi.nlm.nih.gov/30738638/

https://pubmed.ncbi.nlm.nih.gov/37467060/

https://pubmed.ncbi.nlm.nih.gov/37069261/