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Footrace to clinic heats up for T-cell nuclear receptor inhibitors

Nature Biotechnology volume 31, page 370 (2013)Cite this article

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TH17 cells are a pro-inflammatory cell population characterized by the production of interleukin 17 (IL-17). They are involved in host defenses against microbial pathogens, but chronically excessive levels of these cells have been implicated in a wide range of autoimmune conditions. Interest in TH17 cell biology has been spurred by the spectacular clinical results obtained in treating psoriasis with antibodies that target either IL-17 or the p19 subunit of IL-23, a cytokine involved with maintenance of the TH17 phenotype (Nat. Biotechnol. 30, 475–477, 2012). However, TH17 cells may not be the only players in psoriasis, says Gary Glick, who is at the University of Michigan, Ann Arbor, noting that gd T-cells also produce IL-17 and have also been implicated in the disease pathology. The picture in other autoimmune indications is cloudier, although also less mature—psoriasis, as a topical indication, lends itself well to early drug development.

RORγt inhibitors have yet to enter human trials in any indication. “There's a lot of chest beating about who will be first into the clinic,” says Don Nicholson, vice president and head of worldwide discovery, respiratory and immunology, at Merck of Whitehouse Station, New Jersey. “Our strategy is, try to get a molecule as quickly as we can, but a molecule that is likely to make it all the way as a drug.” The target has attracted big pharma interest as it offers a more global way of modulating TH17 biology than hitting targets such as IL-17 or IL-23, whereas its tissue selectivity—it is expressed mainly in the thymus and at certain mucosal surfaces—should ensure potential toxicities are limited, drug developers hope. In the absence of clinical data, it remains an open question for now whether it represents the best entry point for manipulating TH17 biology. “I think it's a compelling target. As we begin to dissect out TH17 cell biology, it could turn out to be the best target; it could be a good target among others; or it could be an inferior target,” says Nicholson.

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Change history

  • 27 June 2013

    In the version of this article initially published, Gary Glick’s affiliation was given incorrectly. He is at the University of Michigan, Ann Arbor, not at the University of Wisconsin, Madison. The error has been corrected in the PDF and HTML versions of this article.

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    Cormac Sheridan

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Sheridan, C. Footrace to clinic heats up for T-cell nuclear receptor inhibitors. Nat Biotechnol 31, 370 (2013). https://doi.org/10.1038/nbt0513-370

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