Shark antibodies as therapeutic agents of disease

Shark antibodies (IgNARs) are a subset of antibodies found in sharks, rays and other cartilaginous fish. Some IgNARs have been shown to possess an elongated CDR3 loop, that is significantly larger those of human and murine antibodies. The IgNAR extended CDR3 loop is considered to be ideal for targeting cleft-type epitopes such as enzyme active sites and surface receptors, which are otherwise inaccessible to conventional antibodies. Using Plasmodium falciparum as a model system we have identified peptides and shark antibodies that block invasion of malaria parasites into host erythrocytes. The structure of the complex of this IgNAR and its target revealed that the IgNARs penetrate a hydro- phobic trough on the malarial protein.

We have created a humanized version of these antibodies and have identified antibodies from this library that bind to the chemokine receptor CXCR4. This molecule is up-regulated in many cancer cells and is an important target in fibrosis. We are therefore exploring the use of these antibodies in both cancer and fibrosis. These antibodies can bind to and block the growth of cancer cells as well as block inflammatory cells from migrating towards the site of inflammation. Moreover these antibodies can prevent the development of fibrosis in an animal model.

This project will examine the mechanism of action of these antibodies in both cancer and fibrosis with a view to developing improved molecules to progress towards human clinical trials. By examining the single domain antibodies in different model systems we hope to determine whether blocking CXCR4 has a role in different diseases where there is an inflammatory component and a fibrotic component.