Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical improvement in psoriasis with specific targeting of interleukin-23

Nature volume 521, pages 222–226 (2015)Cite this article

Subjects

This article has been updated

Abstract

Psoriasis is a chronic inflammatory skin disorder that affects approximately 2–3% of the population worldwide and has severe effects on patients’ physical and psychological well-being1,2,3. The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg−1 groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg−1 group and 13 out of 14 subjects in the 10 mg kg−1 group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Tildrakizumab rapidly provides clinical benefit to moderate-to-severe psoriasis patients.
Figure 2: Tildrakizumab resolves altered epithelium in psoriasis patients.
Figure 3: Representative haematoxylin and eosin photomicrographs of sections from lesional and non-lesional skin.
Figure 4: Tildrakizumab diminishes the elevated dermal infiltrate in psoriatic skin.
Figure 5: Identification of IL-23p19-producing cells in psoriatic lesions.
Figure 6: Tildrakizumab inhibits IL-23-associated psoriatic skin gene expression.

Change history

  • 13 May 2015

    A second affiliation was added for author T.K. and affiliations were renumbered accordingly.

References

  1. Schön, M. P. & Boehncke, W. H. Psoriasis. N. Engl. J. Med. 352, 1899–1912 (2005)

    Article  Google Scholar 

  2. Lowes, M. A., Bowcock, A. M. & Krueger, J. G. Pathogenesis and therapy of psoriasis. Nature 445, 866–873 (2007)

    Article  CAS  ADS  Google Scholar 

  3. Krueger, G. et al. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-membership survey. Arch. Dermatol. 137, 280–284 (2001)

    CAS  PubMed  Google Scholar 

  4. 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)

    Article  CAS  Google Scholar 

  5. 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)

    Article  CAS  Google Scholar 

  6. Toichi, E. et al. An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis. J. Immunol. 177, 4917–4926 (2006)

    Article  CAS  Google Scholar 

  7. Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000)

    Article  CAS  Google Scholar 

  8. Lee, E. et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J. Exp. Med. 199, 125–130 (2004)

    Article  CAS  Google Scholar 

  9. Chan, J. R. et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J. Exp. Med. 203, 2577–2587 (2006)

    Article  CAS  Google Scholar 

  10. Lowes, M. A., Suárez-Fariñas, M. & Krueger, J. G. Immunology of psoriasis. Annu. Rev. Immunol. 32, 227–255 (2014)

    Article  CAS  Google Scholar 

  11. Villanova, F. et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis. J. Invest. Dermatol. 134, 984–991 (2014)

    Article  CAS  Google Scholar 

  12. Keijsers, R. R. et al. Balance of Treg vs. T-helper cells in the transition from symptomless to lesional psoriatic skin. Br. J. Dermatol. 168, 1294–1302 (2013)

    Article  CAS  Google Scholar 

  13. Krueger, J. G. et al. IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis. J. Allergy Clin. Immunol. 130, 145–154 (2012)

    Article  CAS  Google Scholar 

  14. Hueber, W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. 2, 52ra72 (2010)

    Article  Google Scholar 

  15. Ngiow, S. F., Teng, M. W. & Smyth, M. J. A balance of interleukin-12 and -23 in cancer. Trends Immunol. 34, 548–555 (2013)

    Article  CAS  Google Scholar 

  16. Bustamante, J., Picard, C., Boisson-Dupuis, S., Abel, L. & Casanova, J. L. Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases. Ann. N. Y. Acad. Sci. 1246, 92–101 (2011)

    Article  CAS  ADS  Google Scholar 

  17. Papp, K. A. et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br. J. Dermatol. 168, 844–854 (2013)

    Article  CAS  Google Scholar 

  18. United States Food and Drug Administration. Guidance for Industry; Assay Development for Immunogenicity Testing of Therapeutic Proteins. Available at http://www.fda.gov/downloads/Drugs/Guidances/UCM192750.pdf (2009)

  19. Torzicky, M. et al. Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) and CD99 are critical in lymphatic transmigration of human dendritic cells. J. Invest. Dermatol. 132, 1149–1157 (2012)

    Article  CAS  Google Scholar 

  20. Trozak, D. J. Histologic grading system for psoriasis vulgaris. Int. J. Dermatol. 33, 380–381 (1994)

    Article  CAS  Google Scholar 

  21. Wolk, K. et al. The Th17 cytokine IL-22 induces IL-20 production in keratinocytes: a novel immunological cascade with potential relevance in psoriasis. Eur. J. Immunol. 39, 3570–3581 (2009)

    Article  CAS  Google Scholar 

  22. Sa, S. M. et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J. Immunol. 178, 2229–2240 (2007)

    Article  CAS  Google Scholar 

  23. Guttman-Yassky, E. et al. Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis. J. Immunol. 181, 7420–7427 (2008)

    Article  CAS  Google Scholar 

  24. Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006)

    Article  CAS  Google Scholar 

  25. Homey, B. et al. Up-regulation of macrophage inflammatory protein-3 α/CCL20 and CC chemokine receptor 6 in psoriasis. J. Immunol. 164, 6621–6632 (2000)

    Article  CAS  Google Scholar 

  26. Lew, W., Lee, E. & Krueger, J. G. Psoriasis genomics: analysis of proinflammatory (type 1) gene expression in large plaque (Western) and small plaque (Asian) psoriasis vulgaris. Br. J. Dermatol. 150, 668–676 (2004)

    Article  CAS  Google Scholar 

  27. Fredriksson, T. & Pettersson, U. Severe psoriasiseoral therapy with a new retinoid. Dermatologica 157, 238–244 (1978)

    Article  CAS  Google Scholar 

  28. Langley, R. G. Effective and sustainable biologic treatment of psoriasis: what can we learn from new clinical data? J. Eur. Acad. Dermatol. Venereol. 26 (suppl. 2). 21–29 (2012)

    Article  Google Scholar 

  29. Stary, G., Bangert, C., Stingl, G. & Kopp, T. Dendritic cells in atopic dermatitis: expression of FcepsilonRI on two distinct inflammation-associated subsets. Int. Arch. Allergy Immunol. 138, 278–290 (2005)

    Article  CAS  Google Scholar 

  30. Ackerman, A. B., Boer, A., Bennin, B. & Gottlieb, G. J. Histologic Diagnosis of Inflammatory Skin Diseases: an Algorithmic Method Based on Pattern Analysis 3rd edn (Ardor Scribendi, 2005)

    Google Scholar 

  31. Bangert, C., Friedl, J., Stary, G., Stingl, G. & Kopp, T. Immunopathologic features of allergic contact dermatitis in humans: participation of plasmacytoid dendritic cells in the pathogenesis of the disease? J. Invest. Dermatol. 121, 1409–1418 (2003)

    Article  CAS  Google Scholar 

  32. Bangert, C. et al. Clinical and cytological effects of pimecrolimus cream 1% after resolution of active atopic dermatitis lesions by topical corticosteroids: a randomized controlled trial. Dermatology 222, 36–48 (2011)

    Article  CAS  Google Scholar 

  33. Skvara, H. et al. The PKC inhibitor AEB071 may be a therapeutic option for psoriasis. J. Clin. Invest. 118, 3151–3159 (2008)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank E. Marcantonio (Merck & Co., Inc.) for his supervision of research and review of this manuscript and J. Pawlowski (Merck & Co., Inc) for editorial and administrative assistance with this manuscript. This study was funded by Merck & Co., Inc.

Author information

Author notes

  1. Tamara Kopp, Elisabeth Riedl and Christine Bangert: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, University of Vienna Medical School, Vienna, 1090, Austria

    Tamara Kopp, Christine Bangert & Elli Greisenegger

  2. Juvenis Medical Center, Vienna, 1010, Austria

    Tamara Kopp

  3. Department of Dermatology, Division of General Dermatology, University of Vienna Medical School, Vienna, 1090, Austria

    Elisabeth Riedl & Harald Kittler

  4. Merck & Co., Inc., Whitehouse Station, 08889, New Jersey, USA

    Edward P. Bowman, Ann Horowitz, Wendy M. Blumenschein, Terrill K. McClanahan, Danlin Xu, Xiaoli Shirley Hou, Anish Mehta, Anthe S. Zandvliet, Diana Montgomery, Frank van Aarle & Sauzanne Khalilieh

  5. Orlando Clinical Research Center, Orlando, 32809, Florida, USA

    Thomas Marbury

  6. Department of Dermato-allergology, Gentofte Hospital, University of Copenhagen, Kildegaardsvej 28, DK-2900 Hellerup, Denmark,

    Claus Zachariae

Authors
  1. Tamara Kopp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisabeth Riedl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christine Bangert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edward P. Bowman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elli Greisenegger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ann Horowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Harald Kittler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wendy M. Blumenschein
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Terrill K. McClanahan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thomas Marbury
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Claus Zachariae
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Danlin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xiaoli Shirley Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Anish Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Anthe S. Zandvliet
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Diana Montgomery
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Frank van Aarle
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Sauzanne Khalilieh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors provided substantive suggestions and critically reviewed the manuscript. T.K., E.R., C.B., A.M., E.P.B. and S.K. wrote sections of the initial draft. T.K., E.R., C.B., E.P.B., H.K., T.K.M., A.S.Z., W.M.B., X.S.H., D.M. and S.K. collected/assembled data and/or performed or supervised analyses. T.K., A.H., D.X. and X.S.H. were involved in the design and planning of the study.

Corresponding author

Correspondence to Sauzanne Khalilieh.

Ethics declarations

Competing interests

T.K. and H.K. and E.R. received research support from Merck & Co., Inc. E.R. received travel support from Merck & Co., Inc., and speaker’s fees, travel support, or served on advisory boards for AbbVie, Novartis, Pfizer, Janssen and Amgen. C.B. received travel support from Merck. C.Z. has served as a scientific consultant for Abbvie, Pfizer, Janssen-Cilag, Merck & Co., Inc., Eli Lilly, Takeda and Novartis and clinical study investigator for AbbVie, Amgen, Eli Lilly, Merck & Co., Inc., Takeda and Novartis. T.M. is an employee of Orlando Clinical Research Center, which was contracted by Merck to conduct the trial. E.P.B., A.H., W.M.B., T.K.M., D.X., X.S.H., A.M., A.S.Z., D.M., F.V.A. and S.K. are current or former employees of Merck & Co., Inc, and may own Merck stock. C.B. and E.G. have no competing interests.

Extended data figures and tables

Extended Data Figure 1 Tildrakizumab binds to IL-23, but not IL-12.

a, b, Biacore sensorgrams showing the 37 °C binding kinetics of human IL-23 (a) and human IL-12 (b) to immobilized tildrakizumab as a threefold dilution series from 0.091 to 22.2 nM. The association phase was measured for 220 s followed by a dissociation phase measurement for 1,800 s. The affinity of tildrakizumab for IL-23 is ∼300 pM.

Extended Data Figure 2 Study flow chart.

Extended Data Table 1 Baseline patient demographics
Full size table
Extended Data Table 2 Subjects on tildrakizumab who achieved PASI75 and PASI90 on day 112
Full size table
Extended Data Table 3 Summary of adverse events occurring in 2 or more subjects within a treatment group
Full size table
Extended Data Table 4 Summary of serious adverse events
Full size table
Extended Data Table 5 The histopathologic psoriasis severity score
Full size table
Extended Data Table 6 Antibodies used for immunohistochemistry and immunofluorescence
Full size table

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kopp, T., Riedl, E., Bangert, C. et al. Clinical improvement in psoriasis with specific targeting of interleukin-23. Nature 521, 222–226 (2015). https://doi.org/10.1038/nature14175

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature14175

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing