ROR gamma: the key to new options for autoimmune disease?

Friday, 15 May 2015

With their pivotal role in driving a range of inflammatory responses, Th17 helper cells are implicated in the development of a number of autoimmune diseases.  Their identification and associated biology have opened a new frontier in immunology.

Small wonder, then, that ROR gamma, a nuclear hormone receptor involved in converting CD4⁺ immune cells into pro-inflammatory Th17 cells and directing production of cytokines that regulate immune responses, is exciting keen interest as a potentially game-changing drug target in autoimmune conditions.

Not only does ROR gamma unlock a completely new biological pathway around IL17 producing cells, it also appears to act on those immune cells alone, leaving the rest of the immune system undisturbed.  As nuclear hormone receptors are a well-know drug target that can be addressed with small molecules rather than larger antibodies, this provides a unique opportunity to modulate specifically an immune response with an oral treatment.

Combining a novel pathway and high specificity for Th17 cells raises the possibility of new therapies for autoimmune diseases with higher efficacy and a cleaner side-effect profile. An oral, small-molecule treatment would also be easier to administer than an injectable antibody.

The identification of Th17 cells is arguably one of the most interesting developments to have occurred in immunology over the last decade. T helper cells confer the potential to differentiate in response to foreign insult, such as pathogens, and will direct the immune response accordingly. Given that they have been studied extensively since their discovery by Miller and Mitchell in 1968, it was quite a surprise to many immunologists when it became clear in 2008 that a novel type of T helper cell existed.

Since then, clinical investigations with Th17 cytokine-neutralising antibodies indicate the potential for unparalleled patient benefit in psoriasis, with many other indications currently under investigation.  (Kollipara et al. 2015 and Gooderham et al. 2015)

Pharmacological inhibition of the ROR gamma receptor can help to reduce the formation of Th17 cells and down-regulate all the pro-inflammatory cytokines produced by already formed Th17 cells.

Experience with using crystal structures of ROR gamma in complex with small molecules suggests that compounds can be designed by combining structural insights, biochemical assays, and studies in primary human Th17 cell assays. This amounts to a compelling platform for the development of potent, selective and safe compounds in a new era of autoimmune-disease therapy.

AstraZeneca is well positioned to explore these possibilities, particularly in light of the recent collaborative agreement with Orca Pharmaceuticals to develop inhibitors of retinoic acid-related nuclear receptor (ROR) gamma will strengthen AstraZeneca’s internal programme in this area with new ROR gamma compounds.

Reciprocal learning and scientific insight should facilitate understanding of how best to use the ROR gamma target pathway in once again expanding the immunology frontier.