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Single-chain soluble receptor fusion proteins as versatile cytokine inhibitors

Aurora Holgado Munoz (UGent) , Harald Braun (UGent) , Kenneth Verstraete (UGent) , Domien Vanneste, Nico Callewaert (UGent) , Savvas Savvides (UGent) , Inna Afonina (UGent) and Rudi Beyaert (UGent)
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Abstract
Cytokines are small secreted proteins that among many functions also play key roles in the orchestration of inflammation in host defense and disease. Over the past years, a large number of biologics have been developed to target cytokines in disease, amongst which soluble receptor fusion proteins have shown some promise in pre-clinical studies. We have previously shown proof-of-concept for the therapeutic targeting of interleukin (IL)-33 in airway inflammation using a newly developed biologic, termed IL-33trap, comprising the ectodomains of the cognate receptor ST2 and the co-receptor IL-1RAcP fused into a single-chain recombinant fusion protein. Here we extend the biophysical and biological characterization of IL-33trap variants, and show that IL-33trap is a stable protein with a monomeric profile both at physiological temperatures and during liquid storage at 4 degrees C. Reducing the N-glycan heterogeneity and complexity of IL-33trap via GlycoDelete engineering neither affects its stability nor its inhibitory activity against IL-33. We also report that IL-33trap specifically targets biologically active IL-33 splice variants. Finally, we document the generation and antagonistic activity of a single-chain IL-4/13trap, which inhibits both IL-4 and IL-13 signaling. Collectively, these results illustrate that single-chain soluble receptor fusion proteins against IL-4, IL-13, and IL-33 are novel biologics that might not only be of interest for research purposes and further interrogation of the role of their target cytokines in physiology and disease, but may also complement monoclonal antibodies for the treatment of allergic and other inflammatory diseases.
Keywords
TYPE-2 INFLAMMATION, PERIODIC SYNDROMES, IL-33, RILONACEPT, DUPILUMAB, IL-33, IL-4, IL-13, allergy, inflammation, cytokine, biologics

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MLA
Holgado Munoz, Aurora, et al. “Single-Chain Soluble Receptor Fusion Proteins as Versatile Cytokine Inhibitors.” FRONTIERS IN IMMUNOLOGY, vol. 11, 2020, doi:10.3389/fimmu.2020.01422.
APA
Holgado Munoz, A., Braun, H., Verstraete, K., Vanneste, D., Callewaert, N., Savvides, S., … Beyaert, R. (2020). Single-chain soluble receptor fusion proteins as versatile cytokine inhibitors. FRONTIERS IN IMMUNOLOGY, 11. https://doi.org/10.3389/fimmu.2020.01422
Chicago author-date
Holgado Munoz, Aurora, Harald Braun, Kenneth Verstraete, Domien Vanneste, Nico Callewaert, Savvas Savvides, Inna Afonina, and Rudi Beyaert. 2020. “Single-Chain Soluble Receptor Fusion Proteins as Versatile Cytokine Inhibitors.” FRONTIERS IN IMMUNOLOGY 11. https://doi.org/10.3389/fimmu.2020.01422.
Chicago author-date (all authors)
Holgado Munoz, Aurora, Harald Braun, Kenneth Verstraete, Domien Vanneste, Nico Callewaert, Savvas Savvides, Inna Afonina, and Rudi Beyaert. 2020. “Single-Chain Soluble Receptor Fusion Proteins as Versatile Cytokine Inhibitors.” FRONTIERS IN IMMUNOLOGY 11. doi:10.3389/fimmu.2020.01422.
Vancouver
1.
Holgado Munoz A, Braun H, Verstraete K, Vanneste D, Callewaert N, Savvides S, et al. Single-chain soluble receptor fusion proteins as versatile cytokine inhibitors. FRONTIERS IN IMMUNOLOGY. 2020;11.
IEEE
[1]
A. Holgado Munoz et al., “Single-chain soluble receptor fusion proteins as versatile cytokine inhibitors,” FRONTIERS IN IMMUNOLOGY, vol. 11, 2020.
@article{8672138,
  abstract     = {{Cytokines are small secreted proteins that among many functions also play key roles in the orchestration of inflammation in host defense and disease. Over the past years, a large number of biologics have been developed to target cytokines in disease, amongst which soluble receptor fusion proteins have shown some promise in pre-clinical studies. We have previously shown proof-of-concept for the therapeutic targeting of interleukin (IL)-33 in airway inflammation using a newly developed biologic, termed IL-33trap, comprising the ectodomains of the cognate receptor ST2 and the co-receptor IL-1RAcP fused into a single-chain recombinant fusion protein. Here we extend the biophysical and biological characterization of IL-33trap variants, and show that IL-33trap is a stable protein with a monomeric profile both at physiological temperatures and during liquid storage at 4 degrees C. Reducing the N-glycan heterogeneity and complexity of IL-33trap via GlycoDelete engineering neither affects its stability nor its inhibitory activity against IL-33. We also report that IL-33trap specifically targets biologically active IL-33 splice variants. Finally, we document the generation and antagonistic activity of a single-chain IL-4/13trap, which inhibits both IL-4 and IL-13 signaling. Collectively, these results illustrate that single-chain soluble receptor fusion proteins against IL-4, IL-13, and IL-33 are novel biologics that might not only be of interest for research purposes and further interrogation of the role of their target cytokines in physiology and disease, but may also complement monoclonal antibodies for the treatment of allergic and other inflammatory diseases.}},
  articleno    = {{1422}},
  author       = {{Holgado Munoz, Aurora and Braun, Harald and Verstraete, Kenneth and Vanneste, Domien and Callewaert, Nico and Savvides, Savvas and Afonina, Inna and Beyaert, Rudi}},
  issn         = {{1664-3224}},
  journal      = {{FRONTIERS IN IMMUNOLOGY}},
  keywords     = {{TYPE-2 INFLAMMATION,PERIODIC SYNDROMES,IL-33,RILONACEPT,DUPILUMAB,IL-33,IL-4,IL-13,allergy,inflammation,cytokine,biologics}},
  language     = {{eng}},
  pages        = {{11}},
  title        = {{Single-chain soluble receptor fusion proteins as versatile cytokine inhibitors}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2020.01422}},
  volume       = {{11}},
  year         = {{2020}},
}

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