Augurex’s autoimmune portfolio centers on the novelty that, 14-3-3η which is normally inside of cells, is released outside of cells where it perpetuates disease processes.
Extracellular 14-3-3η Perpetuates Disease
Extracellular 14-3-3η protein is a potent ligand and activator of intracellular signalling pathways that lead to the up-regulation of inflammation and joint damage factors involved in RA pathogenesis. The 14-3-3η blood test is clinically available as a diagnostic test whereby a positive result indicates a 5 to 50 times greater likelihood of having RA and informs joint damage prognosis and disease monitoring. 14-3-3η is used in combination with other serological tests and clinical assessment to support RA patient management.
The Body Views Extracellular 14-3-3η as Foreign
14-3-3η is not normally present outside of cells. Therefore, in the disease state, the body views it as foreign and mounts an immune response in an attempt to clear it. This immune response generates 14-3-3η specific auto-antibodies that are measureable in blood and provide complementary disease information to the 14-3-3η protein. In particular, they are highly specific in very early RA and increase the patient identification rate into the 90% range. Early RA diagnosis and treatment improves clinical outcomes and 14-3-3η protein and its auto-antibodies supports that clinical priority.
14-3-3η is Citrullinated in the Presence of Extracellular PAD Enzymes
Citrullination is a highly relevant post-translational modification of proteins that occurs in RA and certain other conditions. In the extracellular space, 14-3-3η becomes citrullinated (cit) in the presence of peptidylarginine deiminases (PAD) enzymes and this extracellular modified form of the protein, cit-14-3-3η, also elicits an auto-immune response that generates cit-14-3-3η specific auto-antibodies. Both the cit-14-3-3η protein and the cit-14-3-3η auto-antibodies are measurable in blood and their clinical utility is a fast-paced area of ongoing clinical research at Augurex.
Extracellular 14-3-3η as a Personalized Medicine Drug Target
In the development of RA and other inflammatory types of arthritis, multiple factors contribute to disease processes to varying degrees in different patients. 14-3-3η is recognized as a new factor within this process and represents a rationale drug target for personalized medicine alongside its 14-3-3η companion biomarker portfolio described above. Augurex preclinical animal studies to date demonstrate that anti-14-3-3η monoclonal antibodies delay the onset of and mitigate the severity of arthritis development. This continued research has the potential to produce the first true personalized medicine in RA, wherein patients with varying levels of 14-3-3η measured by the companion biomarkers, can be optimally dosed with the anti-14-3-3η therapy and monitored for clearance of the protein and maintenance of negative levels along the disease course.