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

Abstract

volume 31 NumBeR 5 mAY 2013 nature biotechnology Ann Arbor, Michigan–based Lycera and Merck entered a second small-molecule discovery deal over undisclosed targets in autoimmune disease, earning the biotech an upfront payment and potentially over $300 million in milestones. The companies report that their first partnership to develop inhibitors of retinoic acid–related orphan receptor gamma t (RORγt) remains on track. Since the two firms began to collaborate (Nat. Biotechnol. 29, 679, 2011), several other big pharma and biotech firms (Table 1) have joined forces in the race to validate inhibitors of this nuclear receptor that plays a key role in the differentiation of naive CD4+ T cells into T-helper 17 (TH17) cells. 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. RORgt 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 Cambridge, Massachusetts, a company formed in 2009 with backing from London-based GlaxoSmithKline, which is focused on suppressing TH17 cells and enhancing regulatory T cells (Treg cells) to treat autoimmune disease. At the International Conference on Clinical & Cellular Immunology on October 22–24, 2012, in Chicago, the company presented results on several small-molecule inverse agonists of RORγt (J. Clin. Cell Immunol. 3, 4, 2012), but it is working on several other undisclosed targets. Kuchroo’s study has identified “another boatload of potential targets,” says Mark Sundrud, of the Scripps Research Institute in Jupiter, Florida, who previously worked at Tempero. But it will take time for the field to sift through these putative targets and link them to actual functions, he says. Sundrud was first author on an earlier study which showed that activation of the amino acid starvation response selectively inhibited TH17 differentiation while boosting Treg cell activation (Science 324, 1334–1338, 2009). Why this effect is limited to TH17 cells is unclear. “One of the thoughts is amino acid deprivation is playing a part in the resolution of inflammation,” Sundrud says. Limited local availability of amino acids could act as a brake on the inflammatory response. “This has nothing to do with dietary restriction,” he observes. In contrast, a study published back to back with the Kuchroo study suggests that dietary salt is a driver of autoimmune disease through TH17 cell activation. Glick plays down its significance, however. “I’d be very cautious about drawing conclusions about cause and effect. Correlations and causality are very different,” he says. Cormac Sheridan Dublin Corrected after print 27 June 2013. Footrace to clinic heats up for T-cell nuclear receptor inhibitors

DOI: 10.1038/nbt0513-370

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@article{Sheridan2013FootraceTC, title={Footrace to clinic heats up for T-cell nuclear receptor inhibitors}, author={Cormac Sheridan}, journal={Nature Biotechnology}, year={2013}, volume={31}, pages={370-370} }