Development of a therapeutic antibody for a novel angiogenic target

In several common diseases of the eye, including age-related macular disease and diabetic retinopathy, the network of tiny blood vessels in the light-sensitive part of the eye may undergo major structural changes and grow uncontrollably in a manner severe enough to cause loss of vision. Although some advances have been made in the treatment of these conditions the most effective therapies generally benefit fewer than 50% of patients, and often only delay vision loss. There is therefore an urgent need to develop new therapies, especially of a type that may be useful during the early stages of disease. Our group has discovered a new protein, of previously unknown function, that we have shown to be produced at high levels by abnormal retinal blood vessels and to cause blood vessel cell proliferation. In this project we will generate an antibody that will block the function of this protein, and then create derivatives of the antibody that are safe and effective for use in humans. At the end of the project, if we achieve our objectives, we will be ready to take our new therapy into patients in a Phase I clinical trial.

Neovascularisation and vascular remodelling are key clinical features of several pathologies, including wet age-related macular degeneration (AMD), solid tumours and diabetic retinopathy. Regulation or inhibition of vascular changes in these conditions has been shown to slow or arrest disease, but the number of anti-angiogenic therapeutics available is limited, their efficacy is patchy, and the field is constrained by the paucity of useful molecular targets. We have identified a protein of previously unknown function that we have shown to be a potent regulator of angiogenesis. The protein stimulates endothelial cell tube formation in angiogenesis assays, and its activity can be blocked by specific peptides. The aim of this proposal is to i) develop a function-blocking antibody against the protein, ii) demonstrate the efficacy of the antibody in murine models of retinal vascular disease, and iii) develop a humanised version of the antibody for subsequence evaluation in clinical trials.