T-cells are a key component of our immune systems, patrolling the body, interacting with proteins on the surface of cells which display small fragments from the cell interior. Usually, these fragments are ‘self’ – small parts of our own proteins. Where infection occurs, the cell displays fragments of the infectious agent, alerting T-cells to the presence of a pathogen. This activates the immune system, and allows the body to act against the invader and destroy the infected cell without spreading infection.
T-cells receptors (TCRs), the proteins on the surface of the T-cell which detect the fragments displayed on our cells, are being investigated as a possible cancer therapy – binding to specific tumours and encouraging the body’s own immune system to destroy the cancer cell. However, natural TCRs bind quite weakly to their target, a feature important in the body to avoid auto-immunity. To use a TCR as a drug therapy, the binding, or affinity, for the target would need to be much stronger. This can be achieved by replacing key amino acids within the binding site.
A group from Cardiff, led by Dr David Cole, has built on this work to increase the affinity of the TCR to its target. They investigated a new high affinity TCR, generated by their industrial collaborators (Immunocore), which targeted a melanoma specific antigen. The new TCR bound with an affinity 30,000 times greater than natural TCRs.
Figure 1. shows the high affinity TCR reagent (blue and cyan) binding to the fragment from the melanoma skin cancer cell (yellow and red balls and grey).
Figure 2. shows the high affinity TCR reagent (red, green, blue, cyan, magenta, orange) binding to the fragment from the melanoma skin cancer cell (grey).
Figure 3. shows the atomic interactions between the high affinity TCR reagent (cyan) binding to the fragment from the melanoma skin cancer cell (yellow) that allow it to specifically target skin cancer cells.
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