Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis

Scientific Reports

Volumn 6, Issue , 2016, Pages

  Xue, Xiaohua ^a   Soroosh, Pejman ^a   De Leon Tabaldo, Aimee ^a   Luna Roman, Rosa ^a   Sablad, Marciano ^a   Rozenkrants, Natasha ^a   Yu, Jingxue ^a   Castro, Glenda ^a   Banie, Homayon ^a   Fung Leung, Wai Ping ^a   Santamaria Babi, Luis ^b   Schlueter, Thomas ^c   Albers, Michael ^c   Leonard, Kristi ^a   Budelsky, Alison L ^a   Fourie, Anne M ^a  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

^b UNIVERSITY OF BARCELONA   (Spain)

^c PHENEX PHARMACEUTICALS AG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLOPEPTIDE; IL17A PROTEIN, HUMAN; INTERLEUKIN 17; INTERLEUKIN DERIVATIVE; INTERLEUKIN-22; JNJ-54452840; RETINOID RELATED ORPHAN RECEPTOR GAMMA; RORC PROTEIN, HUMAN;

ANIMAL; CELL CULTURE; CELL DIFFERENTIATION; CYTOLOGY; DISEASE MODEL; DOSE RESPONSE; DRUG EFFECT; GENE EXPRESSION REGULATION; GENETIC TRANSCRIPTION; GENETICS; METABOLISM; MOUSE; ORAL DRUG ADMINISTRATION; PSORIASIS; RHEUMATOID ARTHRITIS; TH17 CELL;

ADMINISTRATION, ORAL; ANIMALS; ARTHRITIS, RHEUMATOID; CELL DIFFERENTIATION; CELLS, CULTURED; DISEASE MODELS, ANIMAL; DOSE-RESPONSE RELATIONSHIP, DRUG; GENE EXPRESSION REGULATION; INTERLEUKIN-17; INTERLEUKINS; MICE; NUCLEAR RECEPTOR SUBFAMILY 1, GROUP F, MEMBER 3; PEPTIDES, CYCLIC; PSORIASIS; TH17 CELLS; TRANSCRIPTION, GENETIC;

EID: 85000460301     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep37977     Document Type: Article

References (71)

1. Jetten, A. M. Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellularmetabolism. Nuclear receptor signaling 7, e003 (2009).
2. Soroosh, P. et al. Oxysterols are agonist ligands of RORgammat and drive Th17 cell differentiation. Proceedings of the NationalAcademy of Sciences of the United States of America 111, 12163-12168 (2014).
3. Hu, X. et al. Corrigendum: Sterol metabolism controls TH17 differentiation by generating endogenous RORgamma agonists. Naturechemical biology 11, 741 (2015).
4. Santori, F. R. et al. Identification of natural RORgamma ligands that regulate the development of lymphoid cells. Cell metabolism 21,286-297 (2015).
5. Sun, Z. et al. Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science 288, 2369-2373 (2000).
6. Ivanov, I. I. et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helpercells. Cell 126, 1121-1133 (2006).
7. Yen, H. R. et al. Tc17 CD8 T cells: functional plasticity and subset diversity. Journal of immunology 183, 7161-7168 (2009).
8. Sutton, C. E., Mielke, L. A. & Mills, K. H. IL-17-producing gammadelta T cells and innate lymphoid cells. European journal ofimmunology 42, 2221-2231 (2012).
9. Spits, H. & Cupedo, T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annual reviewof immunology 30, 647-675 (2012).
10. Ichiyama, K. et al. Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat.The Journal of biological chemistry 283, 17003-17008 (2008).
11. Zhou, L. et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453,236-240 (2008).
12. Gaffen, S. L., Jain, R., Garg, A. V. & Cua, D. J. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nature reviews.Immunology 14, 585-600 (2014).
13. Kolls, J. K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467-476 (2004).
14. Stamp, L. K., James, M. J. & Cleland, L. G. Interleukin-17: the missing link between T-cell accumulation and effector cell actions inrheumatoid arthritis? Immunology and cell biology 82, 1-9 (2004).
15. McKenzie, B. S., Kastelein, R. A. & Cua, D. J. Understanding the IL-23-IL-17 immune pathway. Trends in immunology 27, 17-23(2006).
16. Dong, C. Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nature reviews. Immunology 6,329-333 (2006).
17. Withers, D. R. et al. Transient inhibition of ROR-gammat therapeutically limits intestinal inflammation by reducing TH17 cells andpreserving group 3 innate lymphoid cells. Nature medicine 22, 319-323 (2016).
18. Leppkes, M. et al. RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17Aand IL-17F. Gastroenterology 136, 257-267 (2009).
19. Bowes, J. & Barton, A. The genetics of psoriatic arthritis: lessons from genome-wide association studies. Discovery medicine 10,177-183 (2010).
20. Gazouli, M. et al. NOD2/CARD15, ATG16L1 and IL23R gene polymorphisms and childhood-onset of Crohn's disease. Worldjournal of gastroenterology: WJG 16, 1753-1758 (2010).
21. Kochi, Y. et al. A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. Nature genetics 42, 515-519(2010).
22. Nunez, C. et al. IL23R: a susceptibility locus for celiac disease and multiple sclerosis? Genes and immunity 9, 289-293 (2008).
23. Safrany, E. & Melegh, B. Functional variants of the interleukin-23 receptor gene in non-gastrointestinal autoimmune diseases.Current medicinal chemistry 16, 3766-3774 (2009).
24. Rahman, P. et al. Association of interleukin-23 receptor variants with ankylosing spondylitis. Arthritis and rheumatism 58,1020-1025 (2008).
25. Papp, K. A. et al. Anti-IL-17 receptor antibody AMG 827 leads to rapid clinical response in subjects with moderate to severepsoriasis: results from a phase I, randomized, placebo-controlled trial. The Journal of investigative dermatology 132, 2466-2469(2012).
26. Papp, K. A. et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. The New England journal of medicine 366,1181-1189 (2012).
27. Papp, K. A. et al. Efficacy and safety of secukinumab in the treatment of moderate to severe plaque psoriasis: a randomised, doubleblind,placebo-controlled phase II dose-ranging study. The British journal of dermatology (2012).
28. Leonardi, C. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. The New England journal ofmedicine 366, 1190-1199 (2012).
29. Papp, K. A. et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis:52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371, 1675-1684 (2008).
30. Leonardi, C. L. et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis:76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371, 1665-1674 (2008).
31. Hueber, W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis.Science translational medicine 2, 52ra72 (2010).
32. Mease, P. J. et al. Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. The New England journal of medicine 370,2295-2306 (2014).
33. Fauber, B. P. & Magnuson, S. Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-gamma (RORgammaor RORc). Journal of medicinal chemistry 57, 5871-5892 (2014).
34. Burris, T. P. et al. Nuclear receptors and their selective pharmacologic modulators. Pharmacological reviews 65, 710-778 (2013).
35. Ferran, M. et al. Streptococcus induces circulating CLA(+) memory T-cell-dependent epidermal cell activation in psoriasis. TheJournal of investigative dermatology 133, 999-1007 (2013).
36. Collingwood, T. N., Urnov, F. D. & Wolffe, A. P. Nuclear receptors: coactivators, corepressors and chromatin remodeling in thecontrol of transcription. Journal of molecular endocrinology 23, 255-275 (1999).
37. Singh, S. P., Zhang, H. H., Foley, J. F., Hedrick, M. N. & Farber, J. M. Human T cells that are able to produce IL-17 express thechemokine receptor CCR6. Journal of immunology 180, 214-221 (2008).
38. Voo, K. S. et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proceedings of the National Academy ofSciences of the United States of America 106, 4793-4798 (2009).
39. Roark, C. L. et al. Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing gamma delta T cells. Journal ofimmunology 179, 5576-5583 (2007).
40. Sutton, C. E. et al. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses andautoimmunity. Immunity 31, 331-341 (2009).
41. Webster, K. E. et al. IL-17-producing NKT cells depend exclusively on IL-7 for homeostasis and survival. Mucosal immunology 7,1058-1067 (2014).
42. Caccamo, N. et al. Differentiation, phenotype, and function of interleukin-17-producing human Vgamma9Vdelta2 T cells. Blood118, 129-138 (2011).
43. Rachitskaya, A. V. et al. Cutting edge: NKT cells constitutively express IL-23 receptor and RORgammat and rapidly produce IL-17upon receptor ligation in an IL-6-independent fashion. Journal of immunology 180, 5167-5171 (2008).
44. Moreira-Teixeira, L. et al. Proinflammatory environment dictates the IL-17-producing capacity of human invariant NKT cells.Journal of immunology 186, 5758-5765 (2011).
45. Chan, J. R. et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications forpsoriasis pathogenesis. The Journal of experimental medicine 203, 2577-2587 (2006).
46. Suarez-Farinas, M. et al. Suppression of molecular inflammatory pathways by Toll-like receptor 7, 8, and 9 antagonists in a model ofIL-23-induced skin inflammation. PloS one 8, e84634 (2013).
47. Mease, P. J. Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis andpsoriasis. Current opinion in rheumatology 27, 127-133 (2015).
48. Xu, T. et al. Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgamma tprotein. The Journal of biological chemistry 286, 22707-22710 (2011).
49. Chang, M. R., Lyda, B., Kamenecka, T. M. & Griffin, P. R. Pharmacologic repression of retinoic acid receptor-related orphan nuclearreceptor gamma is therapeutic in the collagen-induced arthritis experimental model. Arthritis & rheumatology 66, 579-588 (2014).
50. Skepner, J. et al. Pharmacologic inhibition of RORgammat regulates Th17 signature gene expression and suppresses cutaneousinflammation in vivo. Journal of immunology 192, 2564-2575 (2014).
51. Xiao, S. et al. Small-molecule RORgammat antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms.Immunity 40, 477-489 (2014).
52. Huh, J. R. et al. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity. Nature 472,486-490 (2011).
53. Solt, L. A. et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472, 491-494 (2011).
54. Ciofani, M. et al. A validated regulatory network for Th17 cell specification. Cell 151, 289-303 (2012).
55. Cai, Y. et al. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity 35, 596-610 (2011).
56. Peternel, S. & Kastelan, M. Immunopathogenesis of psoriasis: focus on natural killer T cells. Journal of the European Academy ofDermatology and Venereology: JEADV 23, 1123-1127 (2009).
57. Chabaud, M. et al. Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium.Arthritis and rheumatism 42, 963-970 (1999).
58. Kotake, S. et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. TheJournal of clinical investigation 103, 1345-1352 (1999).
59. Raza K1, F. F., Curnow, S. J., Ross, E. J., Lee, C. Y., Akbar, A. N., Lord, J. M., Gordon, C., Buckley, C. D. & Salmon, M. Earlyrheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin.Arthritis Res Ther (2005).
60. van Hamburg JP, A. P., Davelaar, N., Mus, A. M., Colin, E. M., Hazes, J. M., Dolhain, R. J. & Lubberts, E. Th17 cells, but not Th1 cells,from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines uponsynovial fibroblast interaction, including autocrine interleukin-17A production. (2011).
61. Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+ CD4-CD8-entheseal resident T cells.Nature medicine 18, 1069-1076 (2012).
62. Martin, D. A. et al. A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response ofbrodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis. Arthritis Res Ther 15, R164 (2013).
63. Pavelka, K. et al. A study to evaluate the safety, tolerability, and efficacy of brodalumab in subjects with rheumatoid arthritis and aninadequate response to methotrexate. The Journal of rheumatology 42, 912-919 (2015).
64. Genovese, M. C. et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, doubleblind,randomised, placebo controlled study. Annals of the rheumatic diseases 72, 863-869 (2013).
65. Genovese, M. C. et al. A phase II randomized study of subcutaneous ixekizumab, an anti-interleukin-17 monoclonal antibody, inrheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis factor inhibitors.Arthritis & rheumatology 66, 1693-1704 (2014).
66. McInnes, I. B. et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 386, 1137-1146 (2015).
67. McInnes, I. B. et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3,multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet 382, 780-789 (2013).
68. Ritchlin, C. et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriaticarthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of thephase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Annals of the rheumatic diseases 73, 990-999(2014).
69. Rizzo, H. L. et al. IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A. Journal of immunology 186,1495-1502 (2011).
70. Sofen, H. et al. Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-toseverepsoriasis. The Journal of allergy and clinical immunology 133, 1032-1040 (2014).
71. Canavan, T. N., Elmets, C. A., Cantrell, W. L., Evans, J. M. & Elewski, B. E. Anti-IL-17 Medications Used in the Treatment of PlaquePsoriasis and Psoriatic Arthritis: A Comprehensive Review. American journal of clinical dermatology 17, 33-47 (2016).