La Trobe University > LIMS > Research > Infection and Immunity > Members > Foley - Single domain antibodies in human disease

Foley - Single domain antibodies in human disease

Our group is using single domain antibodies that have been developed from sharks to identify novel therapeutics against a number of chronic diseases.

Monoclonal antibodies are a growing class of drugs to many human diseases, however they have some limitations. Shark antibodies and their human equivalents are small and extremely stable with long loops that are able to penetrate into important regions of proteins. Thus, in certain situations, they may offer advantages over traditional antibodies.

Our group uses a library of shark antibodies and a library of the human version of these antibodies to identify molecules that will bind to proteins that have been shown to be involved in human diseases. We have obtained high affinity, single domain antibodies to a variety of targets including ion channels as well as G-protein coupled receptors (GPCRs) such as CXCR4, which are two important classes of molecules that many of the popular medicines target. Our single domain antibody against CXCR4 was found to block HIV invasion as well as being able to reduce inflammation and stop the development of fibrosis in mouse models of lung fibrosis and eye fibrosis.

Through the company AdAlta, our group is continuing to progress this CXCR4 binder towards human clinical trials in pulmonary fibrosis, a devastating disease for which there is limited treatment. In addition we are collaborating with various groups to identify other single domains from our libraries against other targets of interest including Amyloid protein, which is involved in Alzheimer's disease.

Research areas

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.

Meet the team

Group members

PhD students

Rodrigo Lizarraga Ruelas
Xilun Wang
Callum Cairns

Patents

CXCR4 Binding Molecules: WO 2016/109872 A1

Novel Amyloid beta oligomer specific binding molecule WO 2018/084712 A1

Ama-1 epitopes, antibodies, compositions, and methods of making and using the same: WO 2015/070207 A3