Investigating how natural (ligand) and non-natural (antibody) affinity and dimersiation states affect the natural (ligand) and non-natural (antibody)

Immunotherapy has revolutionised the treatment of cancer. The 2018 Nobel Prize in medicine to Allison and
Honjo recognised this groundbreaking shift in our approach to cancer treatment whereby instead of
cytotoxic drugs targeting cancer tissue, antibodies are used to remove the "brakes" on the immune system.
This targeting of "immune checkpoints" and not the cancer itself represents a fundamental change in
thinking, recognising that cancer can be targeted by the immune system and therefore manipulating the
immune response can be highly beneficial. Two main checkpoints have been targeted to date (CTLA-4 and
PD-1), whose function is normally to control autoimmune or chronic T cell responses. While blocking these
inhibitory mechanisms for the purpose of cancer therapy is highly effective, remarkably little is known
regarding how these checkpoints actually work.
The aim of the proposed project is therefore to explore how differences in natural ligand interactions in
terms of affinity and dimersiation states affect the fate of CTLA-4 and compare these with interactions driven
by therapeutic antibodies. Indeed, whilst, therapeutic antibodies traditionally have high affinity bivalent
interactions, increasingly bispecific and other designs are increasingly being utilised, allowing us to test the
impact of valence (e.g. bivalent vs. monovalent) and structure/geometry of these antibody interactions on
CTLA-4 biology.