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(EPSRC DTP) New strategies for immuno-PET radiochemistry to support immunotherapy and facilitate clinical translation of new potential antibody therapies


Project Description

Immuno-PET is an expanding area of nuclear imaging: combining the sensitivity of Positron Emission Tomography (PET) with the high target affinity of antibodies. This is a field of imaging that has seen remarkable growth, driven by the growth of interest in immuno-oncology. The current ‘gold standard’ technique utilises zirconium-89 (89Zr) radiolabelled monoclonal antibodies (mAbs) for immuno-PET[1, 2]. However there are drawbacks associated with using 89Zr-mAbs, namely the need to start with large amounts of mAbs, which are often expensive. Secondly, the slow pharmacokinetics of mAbs necessitates the use of longer lived PET radioisotopes which result in a higher patient radiation dose.

The Wolfson Molecular Imaging Centre has considerable expertise in radiolabelling mAbs with 89Zr, and routinely produces 89Zr-mAbs for preclinical studies. One aim of this project is to further develop 89Zr radiolabelling techniques to enable the use of smaller amounts of starting mAb and to combine radiosynthesis and purification to an automated approach using a microfluidic platform. Scaling down the radiosynthesis and automation of method would permit the development of a large library of available 89Zr-mAbs directed towards a variety of different targets, for preclinical assessment. Moreover, the automated approach would yield a robust 89Zr-mAb production approach with potential for clinical translation.

In collaboration with Shimadzu Analytical/Kratos (Trafford Park), Matrix Assisted Laser Desorption/Ionisation (MALDI) will be used to investigate the effect that labelling (using stable isotope equivalents) has on the structural integrity of the antibody constructs. The method will also be used to image the binding of the antibodies in tissue sections from preclinical models.

Smaller fragments of mAbs and engineered proteins that mimic mAbs are also often used in preclinical immuno-PET[3]. These fragments are engineered to retain the affinity of mAbs, but their smaller size means that they have more favourable pharmacokinetics for PET imaging with short-lived radioisotopes such as fluorine-18. Automated radiosynthesis of smaller antibody fragments with fluorine-18 is challenging due not only to time constraints of the half-life, but also to the more complex radiochemistry.

Anti-IgG affibody molecules bind to human immunoglobulin G (IgG) subclasses. Fluorine-18 radiolabelled anti-IgG affibody may be used to scavenge antibody-based therapies administered as immuno-oncology agents, akin to a secondary antibody in established immunohistochemistry techniques, and could be used as a valuable tool to monitor patient treatment response.

[1] M. J. W. D. Vosjan, L. R. Perk, G. W. M. Visser, M. Budde, P. Jurek, G. E. Kiefer, G. A. M. S. van Dongen, Nature Protocols 2010, 5, 739.
[2] I. Verel, G. W. M. Visser, R. Boellaard, M. Stigter-van Walsum, G. B. Snow, G. A. M. S. van Dongen, Journal of Nuclear Medicine 2003, 44, 1271.
[3] O. Morris, M. Fairclough, J. Grigg, C. Prenant, A. McMahon, Journal of Labelled Compounds and Radiopharmaceuticals 2019, 62, 4.


Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

On the online application form select PhD Biochemistry. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/)

Funding Notes

EPSRC DTP studentship with funding for a duration of 3.5 years to commence in September 2019. The studentship covers UK/EU tuition fees and an annual minimum stipend (£15,009 per annum 2019/20). Due to funding restrictions the studentship is open to UK and EU nationals with 3 years residency in the UK.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Morris, O., M. Fairclough, J. Grigg, C. Prenant and A. McMahon (2019). "A review of approaches to 18F radiolabelling affinity peptides and proteins." Journal of Labelled Compounds and Radiopharmaceuticals 62(1): 4-23.
Morris, O., M. A. Elsawy, M. Fairclough, K. J. Williams, A. McMahon, J. Grigg, D. Forster, A. F. Miller, A. Saiani and C. Prenant (2017). "In vivo characterisation of a therapeutically relevant self-assembling 18F-labelled β-sheet forming peptide and its hydrogel using positron emission tomography." Journal of Labelled Compounds and Radiopharmaceuticals 60(10): 481-488.

Fairclough, M., B. Ellis, H. Boutin, A. K. P. Jones, A. McMahon, S. Alzabin, A. Gennari and C. Prenant (2017). "Development of a method for the preparation of zirconium-89 radiolabelled chitosan nanoparticles as an application for leukocyte trafficking with positron emission tomography." Applied Radiation and Isotopes 130: 7-12.

Fairclough, M., C. Prenant, B. Ellis, H. Boutin, A. McMahon, G. Brown, P. Locatelli and A. K. P. Jones (2016). "A new technique for the radiolabelling of mixed leukocytes with zirconium-89 for inflammation imaging with positron emission tomography." Journal of Labelled Compounds and Radiopharmaceuticals 59(7): 270-276.

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