Targeting the pathogenic Th17 cell axis in autoimmunity:developing a portfolio of novel, rationally designed and innovatively delivered biologics

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Our immune systems have evolved into complex, multi-layered processes that are capable of differentiating between "self" and "non-self" ensuring that we are protected from the external environment, and in particular infections. Each of us contains a sophisticated tool-box that consists of specialised cells, tissues and signalling molecules that act in a co-ordinated fashion to first detect, determine a threat (e.g. pathogen) and then muster an immediate retaliation to an infection; followed by a long-term defence mechanism against future attacks. Under normal circumstances, this system is highly effective, however, like other multi-factorial, complex mechanisms, failures can happen, and undesirable outcomes result where normal tissue is mistaken for foreign and a process of self-destruction is initiated. This auto-immune response (or self-damage) is the underlying issue in many diseases such as Rheumatoid arthritis, Psoriasis, Inflammatory bowel diseases, and affects a significant number of people (approx. 20% of the population) with the currently observed net increase in prevalence and incidence recorded each year predicted to continue, as the global population ages. Antibodies, which are the long-term anti-pathogenic protector molecules within our bodies are now also the leading class of drugs used to treat autoimmune diseases. Antibodies can be screened and selected in the lab and clones isolated that recognise for example cancer or inflammation drug targets. As administered biologic (large molecule) therapies, they target and clear the signalling molecules that cause inflammation, dampening down the response and keeping the disease under control. They have been effective in many patients, however, long-term use results in a decreased response and some people simply do not respond at all. The reasons for this refractory sub-set of patients (up to 80% in some indications) primarily lies in the design and mode of action of "natural" therapeutic antibodies. They are incredibly effective at binding with high affinity and selectivity to target, but they are limited to only one target and given the complexity of auto-immune disease, removal of one component may simply result in another being upregulated, with this compensatory response eventually bypassing the effect of the drug. Furthermore, the large and complex nature of the antibody may mean that the drug itself is "seen" by the patient's immune system as foreign. This results in the rapid removal of the drug from the body, which, in part, may explain why some patients require higher and higher effective dosing over time and eventually stop responding completely. The parenteral route of administration which the biologics are restricted to can causes severe injection site reactions and even infections, thereby complicating and worsening treatment outcomes.This proposal will deliver a new type of antibody-like therapy that overcomes these limitations. Elasmogen, has developed small protein drugs called soloMERs that are simpler than antibodies (1/12 th size) and can be readily formatted to recognise and bind to more than one disease target. In addition, they are inherently non-immunogenic, i.e. they fall below the radar of our immune systems, enabling them to be dosed multiple times without generating anti-soloMER antibodies. As starting material for this research program, an existing "super-potent" candidate anti-inflammatory soloMERs, which targets a key activator of inflammation, will be combined with other disease targeting soloMERs (and/or small molecules) to create simple drugs that act in multiple ways to block the self-destruct pathways in autoimmune diseases. These first-in class drug formats will be capable of simultaneously neutralising targets in the blood, on the cell surface or even inside the cell. We believe that multi-specific drugs have the potential to bring new treatment regimens & hope to those patients with significant medical unmet needs