Title: Development of safer ACTH-based drugs for autoimmune diseases
Funder: Versus Arthritis

Abstract: Autoimmune diseases do not come alone. Chances are that 1 out of 4 patients suffering from an auto-immune disease may develop additional ones over the course of their life. This indicates a genetic component that causes the immune system to attack the body, together with the existence of common causes behind autoimmune diseases. For example, our white cells in the blood may present a group of specific genes (called HLA) that are associated with autoimmune diseases, as variation in these genes are known to increase the risk of rheumatoid arthritis (RA), type-1 diabetes, inflammatory bowel disease, lupus, autoimmune thyroid disease, and more, clearly pointing to common causes behind all or most autoimmune diseases. Understanding these common causes will benefit the development of new therapies and could guide strategies to prevent patients from acquiring multiple autoimmune diseases. The other side of this commonality is that autoimmune diseases could be treated with shared therapies. Indeed, the adrenocorticotropin hormone (ACTH) has been used to treat autoimmune diseases like RA for decades, although its use is currently restricted to specific situations (e.g. acute flares) due to its toxicity. The actions of ACTH are brought about by specific interactions with melanocortin (MC) receptors. For long time, the clinical efficacy of ACTH was associated with stimulation of receptor MC2 on the adrenal glands, releasing the hormone cortisol (mechanism #1). However, the anti-inflammatory actions of ACTH also derive from the activation of the other melanocortin receptors MC1,3,4,5 expressed in immune cells (mechanism #2), a mechanism that we discovered and reported in 2002. The toxicity that ACTH may cause after repeated injections, however only derives from the release of cortisol upon stimulation of MC2 on the adrenal glands. Currently, two ACTH medications are currently approved for clinical use: Acthar® Gel in the US, and Synacthen® depot in Europe. The former is authorised for indications like rheumatoid arthritis, multiple sclerosis and lupus among others, but it is seldom used due to cortisol related side effects. The latter formulation in Europe is mainly restricted as a diagnostic tool to test the functioning of the adrenal glands. With this proposal, we seek to fully characterise the biology of two new forms of ACTH that harness exclusively mechanism #2: i) a modified ACTH peptide (named T39) that does not stimulate the adrenal glands but retain anti-inflammatory and anti-arthritic effects; ii) a fusion protein consisting of the ACTH peptide protected by a shield (named Ab-ACTH), able to release the active drug at inflammation sites. The discovery of the cortisol-independent mechanism of ACTH was the fruit of an Arthritis Research Campaign project (#P0562), while cloning and generation of the novel ACTH drugs described here was made possible by an ARUK Project Grant (#21274). We now seek funding to complete this final stage of development of these novel drugs, with the potential to improve, not only RA patients, but the life of many patients suffering from other auto-immune diseases.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL