The Molecular Mechanisms of Inflammatory Disease

A review article in the July 2015 issue of Nature Medicine examines the therapeutic rationale for targeting interleukin-12 (IL-12) and interleukin-23 (IL-23) pathways. The authors of the review also examine the unintended consequences for host defense, tumor surveillance and potential ways in which these therapies can be applied to other immune disorders.  Pharmaceuticals that have been designed targeting these mechanisms include secukinumab, which was approved for psoriasis earlier this year. Others include ustekinumab, which is used to treat plaque psoriasis and psoriatic arthritis. In addition, guselkumab, briakinumab, tildrakizumab, ixekizumab and brodalumab are in phase III trials for psoriasis or psoriatic arthritis. The FDA has approved secunimumab, which is along IL-17A, for the treatment of moderate to severe plaque psoriasis.

• Ustekinumab has been approved for psoriasis and psoriatic arthritis.
• Secukinumab has been approved for psoriasis. 
• Drugs of this class are in phase 3 trials for rheumatoid arthritis, ankylosisng spondylitis, and Crohn’s disease. 

^{Source:  Nature Medicine}

IL-12 and IL-23 are two protein messengers that bind to two different receptors, on several important inflammatory cascades in autoimmune diseases. Currently, there are approximately 10 therapeutic agents in clinical trials targeting IL-12, IL-23 or IL-17A. They are being tested for more than 17 immune-mediated diseases. “Although the efficacy and safety profiles of IL-12/23p40, IL-23p19 and IL-17A and IL-17RA therapies become clearer with each clinical trial, the decisions to progress these targets were made many years in advance, on the basis of limited data. Animal studies are important for elucidating the cellular and molecular mechanisms, but clinical testing is required to determine whether a specific disease mechanism also operates in humans,” write the authors, who were led by Daniel Cua of the Merck Research Laboratories in Palo Alto. “Immunological research is at an inflection point, where the basic concepts of molecular and cellular immunology are being translated into effective therapies for diseases that were considered intractable only a few years ago. Despite the challenges, efforts to translate basic disease mechanisms to the clinic are finally paying off. Although much work remains to be done, the fundamental question of which immune target will benefit which patient population is now being clarified. We optimistically await the answers that will change the lives of patients with serious immune-mediated conditions,” the authors wrote.  

How IL-12 and IL-23 stimulate the immune system

 The two interleukins share one protein subunit (p40) and its corresponding receptor subunit (IL-12Rβ1). They differ in the other protein subunit, and in their downstream pathways. p40 is the target of ustekinumab. 

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 “Clinical testing of IL-23 and IL-17A inhibitors have confirmed the initial hypotheses that IL-23–TH17 pathways are indispensable in promoting immune-mediated diseases, and agents targeting these pathways work particularly well in specific disease settings. However, it is not clear why IL-17A and IL-17RA antagonists work well for psoriasis but exacerbate Crohn’s disease,” the authors write. The authors discuss the risks of cancer, which are difficult to establish with the small data base and the sometimes-paradoxical mechanisms. IL-17A and IL-17RA antagonists work well for psoriasis, but exacerbate Crohn’s disease.  Interleukin-12 and Interleukin-23 are the targets for at least 10 new monoclonal antibody drugs. Ustekinumab has been approved for psoriasis and psoriatic arthritis. Secukinumab has been approved for psoriasis. Drugs of this class are in phase 3 trials for rheumatoid arthritis, ankylosisng spondylitis, and Crohn’s disease.  

Disclosures:

The authors declare competing financial interests of which details are included in the online version of the paper. 

References:

Teng MWL, Bowman EP, McElwee JJ, et al.

IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases.Nature Medicine.

July 2015 21(7):719–729.