Discovery and characterization of a monoclonal antibody targeting a conformational epitope of IL-6/IL-6Rα to inhibit IL-6/ IL-6Rα /gp130 hexameric signaling complex formation

References

• Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–13. doi:10.1038/ni.3153.
   PubMed Web of Science ®Google Scholar
• Schett G. Physiological effects of modulating the interleukin-6 axis. Rheumatology (Oxford). 2018;57:ii43–ii50. doi:10.1093/rheumatology/kex513.
   PubMed Web of Science ®Google Scholar
• Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2012;122:143–59. doi:10.1042/CS20110340.
   PubMed Web of Science ®Google Scholar
• Jones SA. Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol. 2005;175:3463–68. doi:10.4049/jimmunol.175.6.3463.
   PubMed Web of Science ®Google Scholar
• Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620–29. doi:10.1172/JCI137244.
   PubMed Web of Science ®Google Scholar
• Shimabukuro-Vornhagen A, Godel P, Subklewe M, Stemmler HJ, Schlosser HA, Schlaak M, Kochanek M, Böll B, Von Bergwelt-baildon MS. Cytokine release syndrome. J Immunother Cancer. 2018;6:56. doi:10.1186/s40425-018-0343-9.
   PubMed Web of Science ®Google Scholar
• Guaraldi G, Meschiari M, Cozzi-Lepri A, Milic J, Tonelli R, Menozzi M, Franceschini E, Cuomo G, Orlando G, Borghi V, et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol. 2020;2:e474–e84. doi:10.1016/S2665-9913(20)30173-9.
   PubMedGoogle Scholar
• Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509–18. doi:10.1056/NEJMoa1215134.
   PubMed Web of Science ®Google Scholar
• Kaplanski G, Marin V, Montero-Julian F, Mantovani A, Farnarier C. IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol. 2003;24:25–29. doi:10.1016/s1471-4906(02)00013-3.
   PubMed Web of Science ®Google Scholar
• Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, et al. Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med. 2017;377:317–28. doi:10.1056/NEJMoa1613849.
   PubMed Web of Science ®Google Scholar
• De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, Cuttica R, Ravelli A, Schneider R, Woo P, et al. Randomized trial of Tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2385–95. doi:10.1056/NEJMoa1112802.
   PubMed Web of Science ®Google Scholar
• Bijlsma JWJ, Welsing PMJ, Woodworth TG, Middelink LM, Petho-Schramm A, Bernasconi C, Borm MEA, Wortel CH, Ter Borg EJ, Jahangier ZN, et al. Early rheumatoid arthritis treated with Tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016;388:343–55. doi:10.1016/S0140-6736(16)30363-4.
   PubMed Web of Science ®Google Scholar
• Yoshizaki K, Murayama S, Ito H, Koga T. The role of Interleukin-6 in Castleman disease. Hematol Oncol Clin North Am. 2018;32:23–36. doi:10.1016/j.hoc.2017.09.003.
   PubMed Web of Science ®Google Scholar
• van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fossa A, Simpson D, Capra M, Liu T, Hsieh RK, et al. Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014;15:966–74. doi:10.1016/S1470-2045(14)70319-5.
   PubMed Web of Science ®Google Scholar
• Kishimoto T. IL-6: from its discovery to clinical applications. Int Immunol. 2010;22:347–52. doi:10.1093/intimm/dxq030.
   PubMed Web of Science ®Google Scholar
• Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of cytokines and gp130. Blood. 1995;86:1243–54. https://www.ncbi.nlm.nih.gov/pubmed/7632928.
   PubMed Web of Science ®Google Scholar
• Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003;374:1–20. doi:10.1042/BJ20030407.
   PubMed Web of Science ®Google Scholar
• Zegeye MM, Lindkvist M, Falker K, Kumawat AK, Paramel G, Grenegard M, Sirsjö A, Ljungberg LU. Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells. Cell Commun Signal. 2018;16:55. doi:10.1186/s12964-018-0268-4.
   PubMed Web of Science ®Google Scholar
• Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 2012;8:1237–47. doi:10.7150/ijbs.4989.
   PubMed Web of Science ®Google Scholar
• Kallen KJ. The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases. Biochim Biophys Acta. 2002;1592:323–43. doi:10.1016/s0167-4889(02)00325-7.
   PubMed Web of Science ®Google Scholar
• Wolf J, Rose-John S, Garbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine. 2014;70:11–20. doi:10.1016/j.cyto.2014.05.024.
   PubMed Web of Science ®Google Scholar
• Chalaris A, Garbers C, Rabe B, Rose-John S, Scheller J. The soluble Interleukin 6 receptor: generation and role in inflammation and cancer. Eur J Cell Biol. 2011;90:484–94. doi:10.1016/j.ejcb.2010.10.007.
   PubMed Web of Science ®Google Scholar
• Heink S, Yogev N, Garbers C, Herwerth M, Aly L, Gasperi C, Husterer V, Croxford AL, Möller-Hackbarth K, Bartsch HS, et al. Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nat Immunol. 2017;18:74–85. doi:10.1038/ni.3632.
   PubMed Web of Science ®Google Scholar
• Boulanger MJ, Chow DC, Brevnova EE, Garcia KC. Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science. 2003;300:2101–04. doi:10.1126/science.1083901.
   PubMed Web of Science ®Google Scholar
• Varghese JN, Moritz RL, Lou MZ, Van Donkelaar A, Ji H, Ivancic N, Branson KM, Hall NE, Simpson RJ. Structure of the extracellular domains of the human interleukin-6 receptor alpha -chain. Proc Natl Acad Sci U S A. 2002;99:15959–64. doi:10.1073/pnas.232432399.
   PubMed Web of Science ®Google Scholar
• Simpson RJ, Hammacher A, Smith DK, Matthews JM, Ward LD. Interleukin-6: structure-function relationships. Protein Sci. 1997;6:929–55. doi:10.1002/pro.5560060501.
   PubMed Web of Science ®Google Scholar
• Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting Interleukin-6 Signaling in Clinic. Immunity. 2019;50:1007–23. doi:10.1016/j.immuni.2019.03.026.
   PubMed Web of Science ®Google Scholar
• Garbers C, Heink S, Korn T, Rose-John S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov. 2018;17:395–412. doi:10.1038/nrd.2018.45.
   PubMed Web of Science ®Google Scholar
• Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 2011;121:3375–83. doi:10.1172/JCI57158.
   PubMed Web of Science ®Google Scholar
• Fischer M, Goldschmitt J, Peschel C, Brakenhoff JP, Kallen KJ, Wollmer A, Grötzinger J, Rose-John S. I. . I. A bioactive designer cytokine for human hematopoietic progenitor cell expansion. Nat Biotechnol. 1997;15:142–45. doi:10.1038/nbt0297-142.
   PubMed Web of Science ®Google Scholar
• Peters M, Blinn G, Solem F, Fischer M, Meyer Zum Buschenfelde KH, Rose-John S. In vivo and in vitro activities of the gp130-stimulating designer cytokine Hyper-IL-6. J Immunol. 1998;161:3575–81. https://www.ncbi.nlm.nih.gov/pubmed/9759879.
   PubMed Web of Science ®Google Scholar
• Adams R, Burnley RJ, Valenzano CR, Qureshi O, Doyle C, Lumb S, Del Carmen Lopez M, Griffin R, McMillan D, Taylor RD, et al. Discovery of a junctional epitope antibody that stabilizes IL-6 and gp80 protein:protein interaction and modulates its downstream signaling. Sci Rep. 2017;7:37716. doi:10.1038/srep37716.
   PubMed Web of Science ®Google Scholar
• Wei LH, Kuo ML, Chen CA, Chou CH, Lai KB, Lee CN, Hsieh C-Y. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene. 2003;22:1517–27. doi:10.1038/sj.onc.1206226.
   PubMed Web of Science ®Google Scholar
• Catar R, Witowski J, Zhu N, Lucht C, Derrac Soria A, Uceda Fernandez J, Chen L, Jones SA, Fielding CA, Rudolf A, et al. IL-6 trans-signaling links inflammation with angiogenesis in the peritoneal membrane. J Am Soc Nephrol. 2017;28:1188–99. doi:10.1681/ASN.2015101169.
   PubMed Web of Science ®Google Scholar
• Jones GW, McLoughlin RM, Hammond VJ, Parker CR, Williams JD, Malhotra R, Scheller J, Williams AS, Rose-John S, Topley N, et al. Loss of CD4+ T cell IL-6R expression during inflammation underlines a role for IL-6 trans signaling in the local maintenance of Th17 cells. J Immunol. 2010 Feb 15, 184(4):2130–39. doi:10.4049/jimmunol.0901528.
   PubMed Web of Science ®Google Scholar
• Castell JV, Gomez-Lechon MJ, David M, Andus T, Geiger T, Trullenque R, Fabra R, Heinrich PC. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett. 1989;242:237–39. doi:10.1016/0014-5793(89)80476-4.
   PubMed Web of Science ®Google Scholar
• Paonessa G, Graziani R, De Serio A, Savino R, Ciapponi L, Lahm A, Salvati AL, Toniatti C, Ciliberto G. Two distinct and independent sites on IL-6 trigger gp 130 dimer formation and signalling. EMBO J. 1995;14:1942–51. https://www.ncbi.nlm.nih.gov/pubmed/7744001.
   PubMed Web of Science ®Google Scholar
• Barton VA, Hudson KR, Heath JK. Identification of three distinct receptor binding sites of murine interleukin-11. J Biol Chem. 1999;274:5755–61. doi:10.1074/jbc.274.9.5755.
   PubMed Web of Science ®Google Scholar
• Mihara M, Kasutani K, Okazaki M, Nakamura A, Kawai S, Sugimoto M, Matsumoto Y, Ohsugi Y. Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol. 2005;5:1731–40. doi:10.1016/j.intimp.2005.05.010.
   PubMed Web of Science ®Google Scholar
• Schuster B, Kovaleva M, Sun Y, Regenhard P, Matthews V, Grotzinger J, Rose-John S, Kallen K-J. Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF. J Biol Chem. 2003;278:9528–35. doi:10.1074/jbc.m210044200.
   PubMed Web of Science ®Google Scholar
• Garbers C, Spudy B, Aparicio-Siegmund S, Waetzig GH, Sommer J, Holscher C, Rose-John S, Grötzinger J, Lorenzen I, Scheller J, et al. An interleukin-6 receptor-dependent molecular switch mediates signal transduction of the IL-27 cytokine subunit p28 (IL-30) via a gp130 protein receptor homodimer. J Biol Chem. 2013;288:4346–54. doi:10.1074/jbc.M112.432955.
   PubMed Web of Science ®Google Scholar
• Lokau J, Nitz R, Agthe M, Monhasery N, Aparicio-Siegmund S, Schumacher N, Wolf J, Möller-Hackbarth K, Waetzig GH, Grötzinger J, et al. Proteolytic Cleavage Governs Interleukin-11 Trans-signaling. Cell Rep. 2016;14:1761–73. doi:10.1016/j.celrep.2016.01.053.
   PubMed Web of Science ®Google Scholar
• Lamertz L, Rummel F, Polz R, Baran P, Hansen S, Waetzig GH, Moll JM, Floss DM, Scheller J. et al. Soluble gp130 prevents interleukin-6 and interleukin-11 cluster signaling but not intracellular autocrine responses. Sci Signal. 2018;11. doi:10.1126/scisignal.aar7388.
   Web of Science ®Google Scholar
• Okazaki M, Yamada Y, Nishimoto N, Yoshizaki K, Mihara M. Characterization of anti-mouse interleukin-6 receptor antibody. Immunol Lett. 2002;84:231–40. doi:10.1016/s0165-2478(02)00202-x.
   PubMed Web of Science ®Google Scholar
• Schett G, Elewaut D, McInnes IB, Dayer JM, Neurath MF. How cytokine networks fuel inflammation: toward a cytokine-based disease taxonomy. Nat Med. 2013;19:822–24. doi:10.1038/nm.3260.
   PubMed Web of Science ®Google Scholar
• Choy EH, De Benedetti F, Takeuchi T, Hashizume M, John MR, Kishimoto T. Translating IL-6 biology into effective treatments. Nat Rev Rheumatol. 2020;16:335–45. doi:10.1038/s41584-020-0419-z.
   PubMed Web of Science ®Google Scholar
• Shaw S, Bourne T, Meier C, Carrington B, Gelinas R, Henry A, Popplewell A, Adams R, Baker T, Rapecki S, et al. Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling. MAbs. 2014;6:774–82. doi:10.4161/mabs.28612.
   PubMed Web of Science ®Google Scholar
• Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495–97. doi:10.1038/256495a0.
   PubMed Web of Science ®Google Scholar