The development and evaluation of PET imaging agents targeting PD-L1
File(s)
Author(s)
Sharma, Gitanjali
Type
Thesis
Abstract
The Programmed Cell Death Protein-1/ Ligand 1 (PD-1/ PD-L1) axis and its inhibitors have transformed cancer therapy. PD-L1 targeting immune checkpoint inhibitors (ICPIs) contribute to the reinvigoration of exhausted T cells in the cancer immune response. However, efficient methods to monitor real time PD-L1 spatiotemporal changes in cancer-mediated immunosuppression are missing. Currently, the assessment of PD-L1 expression involves biopsy based diagnostic tests, e.g., immunohistochemistry (IHC). Such techniques, although valuable, are characterised by critical limitations. Hence selective, non-invasive imaging tools such as PET, which do not suffer from specific drawbacks, would facilitate the selection of patients who are likely to benefit from ICPIs. Improving patient selection can address the economic impact of immunotherapies and the patients’ exposure to unnecessary and ineffective treatment. Small molecules and small proteins can be used to develop PET probes. Their good tissue penetration and short clearance times allows for same day imaging with short-lived PET radioisotopes, such as fluorine-18 and gallium-68. This PhD project focused on the PET imaging of PD-L1 using two different approaches: 1) with novel fluorine-18 labelled small molecules based on commercially available or published PD-L1 inhibitors and 2) with PD-L1 specific affibody molecule NOTA-ZPD-L1. The small protein conjugate was radiolabelled with fluorine-18 (using the aluminium fluoride ([18F]AlF) technique) and gallium-68. Since high levels of PD-L1 have been associated with greater invasiveness and immune resistance in glioblastoma multiforme (GBM), the radioconjugates were used to measure PD-L1 expression levels in GBM xenograft models using PET/CT. Lastly, the [18F]AlF methodology, commonly used to radiofluorinate peptides, small proteins and small molecules, was applied and optimised on a small scale microreactor. Microscale technology provides benefits of low reagent consumption, short reaction times and potentially high radiochemical yields. Many small molecules have been radiolabelled using this innovative technology but [18F]AlF has never been implemented on a microreactor before.
Version
Open Access
Date Issued
2023-12-08
Date Awarded
2024-03-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Kramer-Marek, Gabriela
Miller, Philip
Smith, Graham
Bhalay, Gurdip
Sponsor
Cancer Research UK
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)