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

点击翻译按钮获取中文摘要

Immunotherapy has revolutionised the treatment of cancer. The 2018 Nobel Prize in medicine to Allison andHonjo recognised this groundbreaking shift in our approach to cancer treatment whereby instead ofcytotoxic 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 inthinking, recognising that cancer can be targeted by the immune system and therefore manipulating theimmune response can be highly beneficial. Two main checkpoints have been targeted to date (CTLA-4 andPD-1), whose function is normally to control autoimmune or chronic T cell responses. While blocking theseinhibitory mechanisms for the purpose of cancer therapy is highly effective, remarkably little is knownregarding how these checkpoints actually work.The aim of the proposed project is therefore to explore how differences in natural ligand interactions interms of affinity and dimersiation states affect the fate of CTLA-4 and compare these with interactions drivenby therapeutic antibodies. Indeed, whilst, therapeutic antibodies traditionally have high affinity bivalentinteractions, increasingly bispecific and other designs are increasingly being utilised, allowing us to test theimpact of valence (e.g. bivalent vs. monovalent) and structure/geometry of these antibody interactions onCTLA-4 biology.