MICA: Developing novel human antibodies targeting the OPG/TRAIL axis for the treatment of pulmonary arterial hypertension (PAH)

Pulmonary Arterial Hypertension (PAH) describes a group of rapidly progressive conditions that share a common diagnosis of increased blood pressure in the lungs that over time the increased pressure causes heart failure. The raised blood pressure is caused by a progressive narrowing and in some cases blockage of the blood vessels carrying the blood throughout the lung. This process occurs due to a combination of sustained constriction or tightening and an inward growth of cells within the walls of the blood vessels. As a consequence PAH carries a high level of suffering and carries a median expected survival of 5-6 years from diagnosis. Current drug treatments carry an annual cost per patient of between £5,000 - £300,000, and target only the sustained constriction of the blood vessel constriction and do nothing to slow or halt the cell growth. Subsequently these current drugs do not cure this condition. We have identified that two proteins, OPG and TRAIL are found at increased levels within the diseased blood vessels of both patients with PAH, and animal models of the disease.

We have subsequently demonstrated that levels of both OPG and TRAIL proteins are controlled by several other genes and proteins well recognised to play important roles in PAH. We have also shown that both OPG and TRAIL cause the main cells from blood vessel walls to grow suggesting that they may have an active role in disease. Studies performed in rodent disease models have demonstrated that both TRAIL & OPG are required to develop experimental PAH. Critically, we have also shown that targeting OPG or TRAIL with antibodies in these rodents' disease models can not only stop the disease from progressing but actually cure this condition. These studies are the first to demonstrate the critical importance of both OPG and TRAIL in PAH, and highlight their potential as novel and rational targets for which to develop new drugs against to generate a new treatment for PAH. New data obtained since our preliminary application has established that OPG arising from the bone marrow is critical to cause disease in these experimental models. Furthermore, we have shown that OPG actually causes the levels of TRAIL to increase within the cells of the blood vessel wall, and that TRAIL within these cell is critical to disease progression. The aim of this proposal is therefore to develop and screen novel therapeutic human anti-OPG antibodies for their ability block the growth of these cells, firstly in a cell culture models and then subsequently animal modesl of disease. These experiments will identify a lead antibody for further translational towards clinical trials.

Pulmonary Arterial Hypertension (PAH) describes a group of rapidly progressive conditions sharing a common haemodynamic diagnosis that results in right heart failure. The disease is driven by progressive pulmonary vascular remodelling that comprises a combination of sustained vasoconstriction and the obliteration of small pulmonary arteries through a process of cellular proliferation, intimal fibrosis and the formation of angio-proliferative (plexiform) lesions. Current treatments carry an annual cost per patient of between £5000-£300000, and target vasoconstriction via the prostacyclin, endothelin or nitric oxide pathways. These drugs do little to address the underlying proliferative vascular disease and there remains no curative pharmacological treatment for PAH. We have identified that increased expression of OPG and TRAIL are found within remodelled tissue from patients with PAH, and animal models. We have subsequently demonstrated that both are regulated by multiple pathways important in PAH pathogenesis (e.g. BMP/5-HT/Inflammation). Both OPG and TRAIL stimulate PA-SMC proliferation and migration in vitro suggesting an active role in disease. Studies in pre-clinical rodent models have demonstrated that both proteins are required for disease, and critically, that targeting OPG or TRAIL with antibodies reverses established disease in rodents. These studies are the first to demonstrate the critical importance of both OPG and TRAIL, and highlight their potential as therapeutic targets. New data demonstrates that bone marrow-derived OPG is predominant in driving disease, and that OPG stimulates TRAIL expression in PA-SMCs. We have previously reported that tissue TRAIL is critical to disease progression. Since OPG is upstream of TRAIL, the aim of this proposal is therefore to develop and screen novel therapeutic human anti-OPG antibodies for efficacy utilising both in vitro and in vivo disease models to identify a lead antibody for further translational studies.

The impact of this research will cross disciplines throughout medical research and impact both academics and non-academics as well as the healthcare profession and patients who suffer from this disease.

- Training of research staff for the future - on the job training will provide a broad range of professional skills and techniques for the biomedical and biotech / pharmaceutical industry.
- Sheffield, the city - producing high quality data that results in high impact publications will be highlighted internally to all staff (including professional services) and to local and national press through press releases. These press releases (Dept Twitter account) can generate significant interest from a diverse audience including the general public, health agencies and government.
- Medical Experts/Doctors - this research will develop novel therapies that will help doctors to treat this condition.
- Pharmaceutical industry - this research will generate a potential new therapeutic reagent that will have impact on the current pharmaceutical industry.
- Training of collaborators in techniques relating to animal models of pulmonary hypertension particularly in relation to telemetry measurements of pulmonary artery pressure.
- "UK plc" - I have already secured initial IP on this programme of work. With the development of a therapeutic agent that will require access to this background IP we will generate income and local investment, possibly through a spin-out company creating further jobs.
- Patients - ultimately, I hope that the main impact will be felt by the patients with pulmonary arterial hypertension (and their doctors), who currently have no curative treatment available other than transplantation.