Nanobody technology offers promise for stopping cancer spread
A newly discovered nanobody, Nb 3E11, stops a cancer-spreading protein called Fascin-1 from forming cell-surface protrusions.
New research carried out at the University of Leeds, in collaboration with the CRUK Scotland Institute and the University of Cambridge, has led to the discovery of a nanobody that offers a potential new approach for preventing the spread of cancer, known as metastasis.
Cancer cells can use protrusions from their surface to migrate. It’s this that allows cancers to spread and to invade new sites in the body. If we could stop cancer cells forming these protrusions, we could limit tumour metastasis.
A protein called Fascin-1, which is found at high levels in metastatic cancer (stage IV cancer), is instrumental in allowing cancer cells to grow finger-like surface protrusions known as filopodia that they use to move around.
The new nanobody, Nb 3E11, interacts with Fascin-1 and prevents it from carrying out its role in the formation of filopodia.
Nb 3E11 was discovered by Dr Selena Burgess at the University of Leeds, where facilities such as X-ray crystallography and mass spectrometry were used to study its interaction with Fascin-1. It’s effect on filopodia in cancer cells was then studied by scientists at the CRUK Scotland Institute.
These studies confirmed that Nb 3E11 prevents Fascin-1-dependent filopodia formation in three different experimental models of human cancer. Targeting Fascin-1 offers huge promise as an avenue for development of anti-metastatic therapeutics. Further research is needed but finding Nb 3E11 represents an important advance.
Methodology
Scientists made a nanobody library specific to Fascin-1 using using blood from two llamas that had been immunised with Fascin-1 protein. Nanobodies against Fascin-1 were then identified using biochemical screening methods to search the library.
The Fascin-1-binding nanobodies found were classified into 14 families based on their amino acid sequence and a representative nanobody from each group was tested. 13 of the nanobodies did not affect the activity of Fascin-1. But one did - Nb 3E11.
When Nb 3E11 was introduced into cancer cell models, it was shown to significantly reduce the formation of filopodia on the surface of the cells.
The molecular details of the interaction between Fascin-1 and Nb 3E11 were resolved by X-ray crystallography and mass spectrometry.
Nanobody technology
Nanobodies are small antibody fragments derived from heavy-chain only antibodies -a class of antibody that is only produced by the immune systems of certain animals including llamas, camels and sharks.
Nanobodies have caught the attention of scientists as they can bind to targets with similar affinity and specificity as full-sized antibodies but are easier and cheaper to produce. There are nanobodies in clinical trials for the treatment of cancer, rheumatoid arthritis and psoriasis.
Nanobodies are truly versatile molecular tools that we use to label, stabilise, activate or inhibit proteins. They have great potential to form the basis of new biological therapeutics and we’re working with academic and industrial collaborators on several projects in this area.
The paper, “A nanobody inhibitor of Fascin-1 actin bundling activity and filopodia formation”, which is funded by Cancer Research UK, the Biotechnology and Biological Sciences Research Council and Medical Research Council can be read in Open Biology.
