Trends in Immunology
ReviewImmunoreceptor Engineering and Synthetic Cytokine Signaling for Therapeutics
Section snippets
Therapeutic Potential of Synthetic Cytokine Signaling
Cytokines and growth factors, which comprise more than 100 protein mediators can be subdivided into groups including growth, death, and survival factors, interleukins (ILs), interferons (IFNs), and chemokines. Cytokines signal via three different types of transmembrane receptors, receptor tyrosine kinases, receptors with associated kinases (see Glossary), and G-protein-coupled receptors. They are directly secreted as either soluble or membrane-bound proteins, which can be released by ectodomain
Improved Synthetic Cytokines Assemble Novel Receptor Complexes
Recombinant forms of many cytokines are successful drugs, including human growth hormone (hGH), EPO, TPO, G-CSF, IFNs, IL-2, and IL-11 [2]. For all of the previous classes of cytokine, conjugates, fusion proteins, or deletion variants have been generated in order to obtain mimetics with improved biological signaling activity, stability, or novel functions 11, 12, such as mutated inhibitory IL-4 variants, tumor targeting cytokines, and selectively neuroprotective EPO lacking hematopoietic
Synthetic Cytokines for Cell-Targeted Therapies
Cytokines may be promising drugs in cancer therapy, increasing cancer cell apoptosis either directly or indirectly, via immunotherapy. However, cytokines are highly pleiotropic and may exert opposite effects on target cells of different origins; thus, often preventing their systemic administration due to severe side effects 22, 23. It is therefore desirable to design synthetic cytokines for cell-targeted therapies, which are generally considered to be more effective and leading to fewer side
Constitutively Active Cytokine Receptor Variants
A variety of disease-causing gain-of-function receptor mutants have been identified in many structural domains of all cytokine receptors classes (Figure 2, Table S1 in the supplemental information online). Receptor tyrosine kinases are frequently mutated in cancer (https://cancer.sanger.ac.uk/cosmic), among them the human epithelial growth factor receptor (EGFR, HER, and ErbB) family [65]. An EGFR mutant (EGFRvIII) with deletion of 268 amino acids in the extracellular domain is constitutively
Synthetic Cytokine/Cytokine Receptor Systems for Immunotherapies
Aside from the discovery of naturally occurring constitutively active cytokine receptors, significant progress has been made in the generation of switchable synthetic cytokine receptors, including fully synthetic cytokine systems featuring combinations of synthetic ligands and synthetic receptors. As early as 1993 a synthetic receptor/ligand system based on cell permeable dimerized immunophilin ligands was generated [89]. Switchable membrane-bound chimeric cytokine receptors composed of the
Concluding Remarks
Synthetic cytokine biology has become an important research area with novel solutions and ideas for therapeutic approaches, for example, synthekines, fusokines, immunocytokines, neoleukins, MESA receptors, or synthetic Notch or cytokine receptors. In addition to their huge impact on health and disease, the simple and recurrent principle of cytokine–receptor–kinase interaction and activation has laid the molecular basis for their great popularity and some current success stories in modern
Acknowledgments
This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB974 and SFB 1116).
Glossary
- 4-1BB
- CD137 (TNF receptor family). Co-stimulatory immune checkpoint protein.
- A disintegrin and metalloproteinase (ADAM)
- a family of metalloendopeptidases which cleave cell surface proteins in a process called shedding.
- Anakinra
- slightly modified version of the human IL-1RA with approval for treating rheumatoid arthritis.
- CD20
- cell surface receptor (antigen) of mature B cells.
- CD27
- (TNF receptor family; CD137). Co-stimulatory immune checkpoint protein.
- CD28
- co-stimulatory immune checkpoint protein.
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