Drug design for specific inhibition of the Membrane Attack Complex (MAC) in common inflammatory diseases

End of project summary

Main messages

Overview:

his project was set up to develop novel drug candidates to target the complement system, specifically the protein complex called MAC, a driver of inflammation in common diseases such as rheumatoid arthritis (RA), ischemia reperfusion injury (IRI) multiple sclerosis (MS) and Alzheimer’s Disease (AD). For many of these diseases treatment options are limited; drugs that specifically block inflammation (anti-inflammatory) are widely used and of some benefit, but neither cure the disease nor, in many conditions, prevent progression. There is a need for better ways of stopping inflammation in these diseases. Turning down or switching off complement is therefore a potential way in which disease-causing inflammation could be suppressed. There is already one MAC-blocking drug in the clinic called Eculizumab which has proved very effective for a few extremely rare diseases; however, its eye- watering cost (£420,000 per patient per year) means that it cannot be considered for therapy of common diseases without bankrupting the health system. Significant results:

• I have studied precisely MAC formation and identified novel targets for better ways of blocking MAC that might enable treatment of common inflammatory diseases.
• I have generated immune molecules called monoclonal antibodies (mAb) that bind to and block the MAC. The mAb work at least as well as Eculizumab in tests of MAC inhibition, offering better, safer, cheaper MAC-blocking drugs for treatment of common inflammatory diseases.
• The best mAb were tested in collaboration in rodent disease models (IRI and AD) providing proof of concept of their use for treatment of common inflammatory diseases.
• Since the beginning of the pandemic I have re-focussed my work to address relevant issues; I supported a compassionate use study of anti-complement therapy in severe Covid-19. This work provided the first evidence of potential therapeutic value of anti-complement drugs in severe Covid-19. Also I have developed a sensitive and specific assay for antibodies against the RBD domain of the SARS-Cov2 virus. I supported research by testing patients and staff samples in this assay which generated several publications.