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LEAD SUPERVISOR: Dr Ricardo A. Fernandes, Nuffield Department of Clinical Medicine

Co-supervisor: Professor Omer Dushek, Sir William Dunn School of Pathology

 

Commercial partner: MiroBio Ltd / Gilead Sciences, Oxford

 

Signalling by inhibitory co-receptors, also termed immune checkpoint receptors, such as PD-1, reduces T cell function and promotes T cell exhaustion, compromising the immune response to pathogens and cancer cells. The development of checkpoint blockade antibodies targeting PD-1 and CTLA-4 revolutionised cancer immunotherapy. However, only a small fraction of patients benefit from this approach. Our understanding of the signalling mechanisms utilised by inhibitory receptors is therefore likely to be incomplete. Recently, we found that PD-1 signals in the absence of ligand engagement, resulting in significant suppression of T cell activation. This observation has now been extended to other inhibitory receptors, and tonic or ligand-independent signalling may thus be a common feature. Notably, ligand-independent signalling escapes antibody blockade. To address this issue, we engineered a bi-specific molecule to recruit CD45, an abundant and promiscuous receptor tyrosine phosphatase, within close proximity of PD-1. In this approach, the phosphatase domain of CD45 acts intracellularly, in cis, on the p-Tyr residues of the PD-1 inhibitory motifs, thus inhibiting sustained signalling. We have shown that Receptor Inhibition by Phosphatase Recruitment (RIPR) potentiates T cell activity beyond that seen with PD-1 antagonist antibodies, both in the presence and absence of PD-1 ligand-binding and reduces tumour growth in various mouse models (Fernandes RA et al., Nature 2020). Currently, we have developed RIPR-based molecules for a number of different target proteins, including SIRPa, CTLA-4, CD28 and PD-1. The RIPR technology thus appears to be sufficiently flexible to be used as an alternative approach to reducing surface receptor signalling for various target receptors. This proposal aims to define critical properties for designing potent RIPR molecules and expand this technology to surface targets that impact the immune response. Determinants of RIPR potency and stability are poorly defined. We will quantify the activity of RIPR molecules using a broad range of anti-CD45 molecules. We reasoned that epitope and binding affinity to CD45 would be essential in determining the efficiency of target receptor dephosphorylation. We will test different anti-CD45 molecules (e.g. scFvs or nanobodies) in the context of RIPR-PD1 to determine how these affect signalling outputs, including PD-1 phosphorylation and T cell activation. Next, we will expand the RIPR technology to target other phosphatases, such as CD148, and target receptors, including checkpoint receptors such as TIM-3, TIGIT, and BTLA. Newly developed RIPR molecules will be extensively tested in vitro using various biophysical and cellular assays. Candidate molecules will be further tested in appropriate tumour models. This work is expected to elucidate critical features of checkpoint receptor signalling in immune cells and contribute to establishing a novel therapeutic strategy to modulate signalling by immune checkpoint receptors. Lastly, this project relies on developing various new molecules, particularly scFvs and nanobodies, which are often challenging to generate. MiroBio has extensive experience in developing and characterising antibodies against various inhibitory receptors and will provide valuable expertise in high-throughput protein production and validation. Moreover, our interest in targeting checkpoint receptors is particularly well aligned with MiroBio’s work in this area. The development of new molecules for immunotherapy is an exciting and competitive area of research, and this collaboration will provide significant benefits to both parties involved.

 

Apply using course: DPhil in Clinical Medicine

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