Cancerous tumours can evade immune-mediated elimination in several ways. One such way is to express immune checkpoints, of which the cell surface protein PD-L1 is a family member. The receptor for PD-L1 (PD-1) is present on activated T cells.
Neutralising antibodies against either PD-1 or PD-L1 are currently approved for use in several cancers. The drugs work by releasing the inhibitory effect of PD-1 activation upon the T cell, therefore prompting an immune response against the existing tumour.
This mode of treatment, while often clinically effective, can cause devastating immune-related adverse effects in patients when the antibodies target healthy tissue, thus triggering an autoimmune reaction.
My project aims to investigate a method of targeting single-domain antibodies (or, nanobodies) against PD-1 and PD-L1 to tumour microenvironments. The strategy involves enclosing the nanobodies into a biologically protective ‘shell’ to render them inactive in healthy tissue. In tumour microenvironments, where high MMP activity is present, the nanobodies are released from the ‘shell’ to execute their site-specific anti-tumour activity.
This would result in a modified immune checkpoint inhibitor which has higher penetrative ability (owed to the smaller dimensions), increased specificity, and fewer side effects than conventional antibodies.
My data shows the process of nanobody development from alpaca immunisation, through phage display, to purification. I also demonstrate the screening process of purified nanobodies in a neutralisation bioassay and investigate the biologically protective nature of the encapsulating ‘shell’ in an in vitro and in vivo setting.