PRECISION-RA: Precision Immunotherapy for Rheumatoid Arthritis

Objective

Rheumatoid arthritis (RA) causes chronic pain and inflammation when the human immune system erroneously attacks healthy joint tissue. In over 70% of cases, B cells secrete anti-citrullinated protein antibodies (ACPAs), which are disease-causing autoreactive antibodies. Current treatments are focussed on dampening the whole immune system. These therapies can suppress or kill all B cells, not only the ACPA-secreting, autoreactive ones, leading to a compromised immune system, increased risk of infection and numerous severe side effects. These treatments are also not curative. We have developed a method to target and kill only the ACPA-specific autoreactive B cells, leaving the rest of the B cell population, and human immune system, intact. This represents an exciting new treatment method for RA. By capitalising on our deep understanding of human complement immunobiology and expertise in synthetic biology, we have developed a C1-activating bispecific (CAB). CAB comprises an engineered antibody fragment that binds to the first complement component, C1, which can induce cell killing when targeted to cell surfaces. We have conjugated CAB to a targeting moiety that directs complement to kill only B cells that secrete the autoreactive antibodies. Our preliminary data demonstrates remarkable cell specificity, as CAB destroys only the ACPA-specific autoreactive B cells in a large population of diverse cell types. Here, we will apply our established protocols and expertise to generate important preclinical data, which includes humanised animal models to exemplify when and how CAB can be used to treat RA. This data will be used to strengthen our IP position, engage with clinical, industrial and patient stakeholders, and develop a robust business case to take CAB forward into clinical trials.