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

免疫疗法彻底改变了癌症的治疗。2018年的诺贝尔医学奖授予了艾利森和本庶佑，这是对我们癌症治疗方法的突破性转变的认可，即用抗体来消除免疫系统的“刹车”，而不是用细胞毒性药物靶向癌症组织。这种靶向“免疫检查点”而不是癌症本身的做法代表了思维的根本转变，认识到癌症可以被免疫系统靶向，因此操纵免疫反应是非常有益的。迄今为止，已经针对两个主要检查点（CTLA-4和PD-1），其功能通常是控制自身免疫或慢性T细胞应答。虽然阻断这些抑制机制对癌症治疗非常有效，但关于这些检查点实际上是如何工作的知之甚少。因此，该项目的目的是探索天然配体相互作用的亲和力和二聚化状态的差异如何影响CTLA-4的命运，并将其与治疗性抗体驱动的相互作用进行比较。事实上，虽然治疗性抗体传统上具有高亲和力的二价相互作用，但越来越多的双特异性和其他设计被越来越多地使用，使我们能够测试这些抗体相互作用对CTLA-4生物学的价（例如，二价与单价）和结构/几何形状的影响。

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.