IMMUNE NETWORK

  • 제24권1호
  • /
  • Pages.1.1-1.6
  • /
  • 2024
  • /
  • 1598-2629(pISSN)
  • /
  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
권호 표지
DOI QR코드

DOI QR Code

Interleukin-18 Binding Protein (IL-18BP): A Long Journey From Discovery to Clinical Application

  • Soohyun Kim (College of Veterinary Medicine, Konkuk University) ;
  • Hyeon Yu (Laboratory of Cytokine Immunology, Department of Biomedical Science and Technology, Konkuk University) ;
  • Tania Azam (Division of Infectious Disease, Department of Medicine, University of Colorado Anschutz) ;
  • Charles A. Dinarello (Division of Infectious Disease, Department of Medicine, University of Colorado Anschutz)
  • 투고 : 2023.10.30
  • 심사 : 2023.12.17
  • 발행 : 2024.02.29
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

IL-18 binding protein (IL-18BP) was originally discovered in 1999 while attempting to identify an IL-18 receptor ligand binding chain (also known as IL-18Rα) by subjecting concentrated human urine to an IL-18 ligand affinity column. The IL-18 ligand chromatography purified molecule was analyzed by protein microsequencing. The result revealed a novel 40 amino acid polypeptide. To isolate the complete open reading frame (ORF), various human and mouse cDNA libraries were screened using cDNA probe derived from the novel IL-18 affinity column bound molecule. The identified entire ORF gene was thought to be an IL-18Rα gene. However, IL-18BP has been proven to be a unique soluble antagonist that shares homology with a variety of viral proteins that are distinct from the IL-18Rα and IL-18Rβ chains. The IL-18BP cDNA was used to generate recombinant IL-18BP (rIL-18BP), which was indispensable for characterizing the role of IL-18BP in vitro and in vivo. Mammalian cell lines were used to produce rIL-18BP due to its glycosylation-dependent activity of IL-18BP (approximately 20 kDa). Various forms of rIL-18BP, intact, C-terminal his-tag, and Fc fusion proteins were produced for in vitro and in vivo experiments. Data showed potent neutralization of IL-18 activity, which seems promising for clinical application in immune diseases involving IL-18. However, it was a long journey from discovery to clinical use although there have been various clinical trials since IL-18BP was discovered in 1999. This review primarily covers the discovery of IL-18BP along with how basic research influences the clinical development of IL-18BP.

키워드

과제정보

This work was supported by the National Research Foundation of Korea (NRF-2021R1F1A1057397). This research was supported by the Main Research Program (E0210602-02) of the Korea Food Research Institute (KFRI) funded by the Ministry of Science and ICT.

참고문헌

  1. Novick D, Kim SH, Fantuzzi G, Reznikov LL, Dinarello CA, Rubinstein M. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 1999;10:127-136.
  2. Matsudaira P. Sequence from picomole quantities of proteins electroblotted onto polyvinylidene difluoride membranes. J Biol Chem 1987;262:10035-10038.
  3. Novick D, Engelmann H, Wallach D, Rubinstein M. Soluble cytokine receptors are present in normal human urine. J Exp Med 1989;170:1409-1414.
  4. Novick D, Cohen B, Rubinstein M. The human interferon alpha/beta receptor: characterization and molecular cloning. Cell 1994;77:391-400.
  5. Novick D, Rubinstein M, Azam T, Rabinkov A, Dinarello CA, Kim SH. Proteinase 3 is an IL-32 binding protein. Proc Natl Acad Sci U S A 2006;103:3316-3321.
  6. Xiang Y, Moss B. IL-18 binding and inhibition of interferon gamma induction by human poxvirus-encoded proteins. Proc Natl Acad Sci U S A 1999;96:11537-11542.
  7. Hoshino K, Tsutsui H, Kawai T, Takeda K, Nakanishi K, Takeda Y, Akira S. Cutting edge: generation of IL-18 receptor-deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 binding receptor. J Immunol 1999;162:5041-5044.
  8. Kim SH, Eisenstein M, Reznikov L, Fantuzzi G, Novick D, Rubinstein M, Dinarello CA. Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc Natl Acad Sci U S A 2000;97:1190-1195.
  9. Kim M, Choe YH, Lee SI. Lessons from the success and failure of targeted drugs for rheumatoid arthritis: perspectives for effective basic and translational research. Immune Netw 2022;22:e8.
  10. Marks KE, Cho K, Stickling C, Reynolds JM. Toll-like receptor 2 in autoimmune inflammation. Immune Netw 2021;21:e18.
  11. Akkaya I, Oylumlu E, Ozel I, Uzel G, Durmus L, Ciraci C. NLRC4 inflammasome-mediated regulation of eosinophilic functions. Immune Netw 2021;21:e42.
  12. Ham J, Shin JW, Ko BC, Kim HY. Targeting the epithelium-derived innate cytokines: from bench to bedside. Immune Netw 2022;22:e11.
  13. Nowarski R, Jackson R, Gagliani N, de Zoete MR, Palm NW, Bailis W, Low JS, Harman CC, Graham M, Elinav E, et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 2015;163:1444-1456.
  14. Jarret A, Jackson R, Duizer C, Healy ME, Zhao J, Rone JM, Bielecki P, Sefik E, Roulis M, Rice T, et al. Enteric nervous system-derived IL-18 orchestrates mucosal barrier immunity. Cell 2020;180:813-814.
  15. Zhou T, Damsky W, Weizman OE, McGeary MK, Hartmann KP, Rosen CE, Fischer S, Jackson R, Flavell RA, Wang J, et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature 2020;583:609-614.
  16. Gabay C, Fautrel B, Rech J, Spertini F, Feist E, Kotter I, Hachulla E, Morel J, Schaeverbeke T, Hamidou MA, et al. Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease. Ann Rheum Dis 2018;77:840-847.
  17. Canna S, de Jesus AA, Deng Z, Gouni S, Marrero B, Brooks S, Dimattia M, Liu Y, Huang Y, Plass N, et al. A157: Macrophage activation syndrome-like illness due to an activating mutation in NLRC4. Arthritis Rheumatol 2014;66:S203.
  18. Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, DiMattia MA, Zaal KJ, Sanchez GA, Kim H, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet 2014;46:1140-1146.
  19. Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, Overton J, Meffre E, Khokha MK, Huttner AJ, et al. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet 2014;46:1135-1139.
  20. Canna SW, Girard C, Malle L, de Jesus A, Romberg N, Kelsen J, Surrey LF, Russo P, Sleight A, Schiffrin E, et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol 2017;139:1698-1701.