Flurry of deal-making surrounds new autoimmunity target

In autoimmune diseases ranging from psoriasis to Crohn's disease, an excess of T helper 17 (T_H17) cells, and the cytokine signaling molecules they produce, is a dominant factor in keeping the immune system in constant overdrive. Clinical approaches to targeting this firehose of immune activation have largely taken one approach: blocking overabundant cytokines. But recent research on a previously underappreciated receptor suggests that there could be a better approach. By modulating the activity of a protein called retinoic acid–related orphan receptor-gamma t (RORγt), scientists have discovered they can prevent the differentiation of T_H17 cells from T cell precursors in the thymus.

The findings have led to a flurry of activity among large drug companies seeking to add RORγt research programs to their portfolios. Most recently, on 31 July, Amgen, the California biotech giant, announced a collaboration with Japan-based Teijin Pharma Limited to discover, develop and commercialize small-molecule drugs that target RORγt.

The beauty of this strategy, says immunologist Dan Littman, whose lab at the New York University Langone Medical Center has been responsible for many of the key findings related to this receptor, is that because RORγt modulators act directly on T_H17 cell development, they would affect all downstream cytokine pathways. In contrast, attempts to block particular cytokines produced by T_H17 cells, such as interleukin-17 (IL-17), still leave production of other cytokines intact. “The cytokine antibodies in development really only hit a part of this pathway, whereas targeting RORγt lets us hit all of it,” Littman says.

The RORγt protein is part of a larger family of receptors within the nucleus that bind response elements in the genome to influence the expression of a multitude of genes. Researchers have known since the 1990s that RORγt is important for T cell differentiation, but it wasn't until more recently, after T_H17 cells were discovered in 2007, that the link to autoimmune disease became apparent. Researchers quickly unraveled the specific effect of this receptor on T_H17 cell development, and, in 2011, a group from the Scripps Research Institute in Jupiter, Florida, showed for the first time that a synthetic ligand that bound RORγt inhibited both the differentiation and function of T_H17 cells and lessened the symptoms of a mouse model of multiple sclerosis (Nature 472, 491–494, 2011).

The effects of blocking RORγt on the immune system, particularly the decrease in T_H17 cells, were immediately clear. But what degree of inhibition is required, and whether such blocking drugs have off-target effects in organs such as the liver, still needs investigation. “The big question remaining is what RORγt, or the lack of it, does in other tissues,” says biochemist Patrick Griffin, who was part of the Scripps team that developed and studied the ligands. Unpublished results out of his lab suggest that complete inhibition of RORγt can lead to opportunistic infections. So, doses of drug that allow low levels of continued RORγt activation may provide the best balance of efficacy and safety, he says.

Jianfei Yang, a principal scientist at Tempero Pharmaceuticals, agrees that more work is needed to understand the broader systematic effects of RORγt inhibitors. At Tempero, a Cambridge, Massachusetts–based subsidiary of GlaxoSmithKline, Yang and his colleagues have focused on identifying compounds that bind RORγt but not other highly similar RORs such as RORα, as the Scripps compound does. He's already found a few drugs that fit the bill. Last October, at the International Conference on Clinical & Cellular Immunology in Chicago, Yang presented results on several compounds that block RORγt activity, and his team has developed additional compounds since.

Off to a rip-RORing start

Tempero isn't the only company on the hunt for such drugs. Since 2010, many big pharma firms, including Bristol-Myers Squibb, Merck and Pfizer, have partnered with smaller companies pursuing RORγt inhibitors (see 'Hear the RORγt'). The companies all remain tight-lipped about when their programs could move from preclinical work to clinical studies. But, as Yang points out, “whoever goes to clinical trials first will not necessarily win this race. What will matter is who gets the best compound.”

Table 1 Hear the RORγt: Drug companies with programs and partnerships aimed at RORγt modulators.

If the ligands live up to their promise in selectively decreasing the prevalence of T_H17 cells without side effects, they could be poised to make a large market impact, says Ling Zhuang, a life sciences analyst at the London office of the research firm GBI Research. The drugs would have to outperform existing blockbuster antibody drugs including Humira (adalimumab) and Remicade (infliximab), both of which target the inflammatory cytokine tumor necrosis factor alpha, as well as IL-17 blockers now in late-stage clinical development (see Nat. Med. 18, 638, 2012). But all those drugs are only available as injectables, and an oral RORγt pill—even one that doesn't outperform in efficacy, as many researchers are hoping—would have a leg up on delivery method preference among patients and doctors.

“Should ROR modulators prove to be effective, safe and with few side effects, they are likely to be used as first-line treatments,” Zhuang says.

The earliest applications of the RORγt modulators will likely be in diseases which have already been validated to be linked to T_H17 cells and IL-17 signaling through cytokine antibody studies, she adds. Such conditions include multiple sclerosis, psoriasis, asthma, rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus.