Immunoreceptor Engineering and Synthetic Cytokine Signaling for Therapeutics

Synthetic cytokine biology deconstructs and reassembles cytokines and their receptors to design biological devices as therapeutics. Synthetic cytokines, including neoleukins and synthekines, can activate selective or nonnatural receptor combinations and subsequently induce unique signaling patterns. Cytokines coupled to nanoparticles, peptides, or antibodies and fusokines can allow cell-targeted therapies. Naturally occurring and synthetic constitutively active cytokine receptors have been described for all cytokine receptor classes and might improve immunotherapy approaches. Fully synthetic cytokine signaling systems can allow precisely orchestrated cellular responses. They have been shown to modulate immune responses and presumably, might support immunotherapeutics. Cytokines control immune-related events and are critically involved in a plethora of physiological and pathophysiological processes including autoimmunity and cancer development. Accordingly, modulation of natural cytokine signaling by antibodies and small molecules has improved therapeutic regimens. Synthetic biology sets out to optimize immunotherapeutics, with chimeric antigen receptor (CAR) T cell immmunotherapy being the first example to combine synthetic biology with genetic engineering during therapy. Hence, synthetic cytokines and cytokine receptors, as well as constitutively active cytokine receptor variants, are emerging as tools to improve or modulate immunotherapeutic strategies. This review focuses on recent developments in the growing field of synthetic cytokine signaling, providing an outlook for developing applications that involve physiological targets of immunotherapy. Cytokines control immune-related events and are critically involved in a plethora of physiological and pathophysiological processes including autoimmunity and cancer development. Accordingly, modulation of natural cytokine signaling by antibodies and small molecules has improved therapeutic regimens. Synthetic biology sets out to optimize immunotherapeutics, with chimeric antigen receptor (CAR) T cell immmunotherapy being the first example to combine synthetic biology with genetic engineering during therapy. Hence, synthetic cytokines and cytokine receptors, as well as constitutively active cytokine receptor variants, are emerging as tools to improve or modulate immunotherapeutic strategies. This review focuses on recent developments in the growing field of synthetic cytokine signaling, providing an outlook for developing applications that involve physiological targets of immunotherapy. CD137 (TNF receptor family). Co-stimulatory immune checkpoint protein. a family of metalloendopeptidases which cleave cell surface proteins in a process called shedding. slightly modified version of the human IL-1RA with approval for treating rheumatoid arthritis. cell surface receptor (antigen) of mature B cells. (TNF receptor family; CD137). Co-stimulatory immune checkpoint protein. co-stimulatory immune checkpoint protein. Receptor for CD80 (B7.1) and CD86 (B7.2). T cell engineered to express chimeric antigen receptors that are specific for a certain type of cancer. acts as a competitive cytokine inhibitor because it binds only one receptor chain due to mutation in the other receptor binding site. enzymatic release of cell surface proteins mainly mediated by ADAM proteases. Many cytokines and growth factors undergo shedding for activation. polymer of the amino acid sequence VPGXG with temperature-dependent reversible aggregation (hydrophilicity and hydrophobicity). family of epithelial growth factor receptors (EGFR, HER, and ErbB) stimulating cell growth and differentiation. essential hormone for red blood cell production. EGF-like module-containing mucin-like hormone receptor-like 1 protein expressed on monocytes and macrophages. fusion protein of two cytokines. inducible T cell co-stimulator (CD278): immune checkpoint protein of the CD28 family. cytokines fused to antibodies, scFvs, or VHHs. member of the mFruits family of monomeric red fluorescent proteins (mRFPs) derived from DsRed of Discosoma sea anemones. MESA receptors are composed of a TC and a PC. Both contain an ECD recognizing a ligand of choice; a scaffold region connecting the ligand sensing ECD to the membrane followed by a transmembrane domain; a flexible intracellular linker domain and a sequestered transcription factor on the target chain or a site-specific protease on the adjacent protease chain. monomeric variable single antibody domain from heavy chain antibodies found in camelids. novel class of synthetic cytokines developed by computational design and which recruit natural receptor complexes but have a unrelated topology and amino acid sequence compared with the natural cytokine. signaling pathway promotes developmental processes. Juxtacrine signaling between adjacent cells. CD134 (TNF receptor family). Co-stimulatory immune checkpoint protein. signal transduction pathway promoting cellular survival and growth. surface receptor ligand for PD-1 (group of immune checkpoint inhibitors). PD-L1 can be overexpressed on cancer or stromal cells. Anti-PD-L1 antibodies have been approved to treat certain cancer types. high-affinity single pass transmembrane proteins consisting of extracellular cytokine-binding domain, transmembrane region, and an intracellular domain which is associated with Janus kinases (JAK). : CD4+ T cells that express the transcription factor FoxP3, maintain immune tolerance to self-antigens, prevent autoimmunity, and can also suppress antitumor immune responses. fusion protein of the variable antibody domains of the light and heavy chain. mutations in cytokines that increase binding affinity towards receptors. fusion protein of two dominant negative cytokine variants. any ligand/binding domain or engineered cytokine that activates natural or nonnatural cytokine receptor signaling. Synthetic cytokines might bind to natural cytokine receptors or to engineered cytokine receptors. synNotch in which the extracellular domain is replaced by a nanobody directed against GFP. stimulates production and differentiation of megakaryocytes/platelets. humanized nanobody directed against human IL-6 receptor. group of signaling pathways involved in embryonic development and carcinogenesis. tumor graft taken from a donor of one species (e.g., human) and transplanted into a recipient of another species (e.g., immunodeficient mouse). integral membrane protein that cleaves single pass transmembrane proteins within the trans-membrane domain. Needed for activation of the Notch pathway.