Improving chemical and immunological assessment to drive safer development of the new breed of drugs: PROTACS

Description

Proteolysis-targeting chimeras (PROTACs) are a new class of drugs with immense potential across multiple therapeutic areas in drug development. These drugs act by enhancing the degradation of disease-related proteins of interest (POIs). This is achieved by bringing the POI into the proximity of E3 ligases, this facilitates ubiquitination and subsequent degradation of target proteins, leading to complete inhibition of POI and the downstream signalling cascades.

One underexplored aspect of the PROTAC mechanism is what effects the degradation protein of interest or off-target proteins might have on adaptive immunity. Human leukocyte antigen (HLA) is responsible for presenting antigenic peptides to T-cells and one of the major sources of these peptides is degradation of endogenous proteins. Some drugs and chemicals can perturb antigen processing and presentation, leading to neo-antigen formation and subsequent activation of T-cells, which can result in life threatening hypersensitivity reactions. It is therefore important to understand how PROTACs affect such pathways, and whether it is possible to evaluate immunotoxicological risks applicable to PROTACs.

This multidisciplinary project aims to develop analytical platforms to map the cellular protein targets of PROTACs, examine the potential landscape of antigens presented by HLA class I alleles in the presence of PROTACs, and assess the impact of PROTACs on T-cell immunity. We will generate PROTACs using synthetic methods developed in Dr Nixon’s lab at Chemistry department, Liverpool University. The selectivity of PROTACs degradation activity will be assessed using quantitative proteomics analysis. The neoantigens presented by specific HLA alleles in the presence of PROTACs will be eluted from antigen presenting cells (cell lines expressing a single HLA allele, B cells, and dendritic cells) and characterised using state-of-art Mass spectrometry methods. Furthermore, the potential of PROTACs to activate T cells will be assessed using an HLA genotyped cell bank containing PBMCs from healthy donors. Emerging as a new modality in precision medicine, PROTAC technology is still in its embryonic form. The data generated in this study will help our understanding of the unique mode of action and guide the development of the PROTAC technology.

This project will utilise our world-class facilities including proteomics and cell culturing of human primary cells. The student will be based in the immunopharmacology group led by Prof Naisbitt (X: @ImmunoPharm) and Dr Meng (X: @xl_meng) at the Pharmacology department, University of Liverpool. The student will receive training in a wide variety of techniques including chemical synthesis, proteomics, and advanced primary cell culturing. They will get the chance to study and apply their skills at crossroads of four scientific disciplines: chemistry, pharmacology, immunology and toxicology, on a real-world emerging question in drug development, with the guidance and support of a team leading experts. An industrial placement at Apconix will also provide the student with opportunity to gain hands-on experience in relevant immunotoxicity assessment within real-world drug development.

For informal enquiries about the project, please contact Dr Meng (xlmeng@Liverpool.ac.uk).