Project ID BE-MI2024_08


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Biomedical Engineering & Imaging Sciences, Department of Imaging Chemistry & BiologyWebsite

Co Supervisor 1B Faculty of Natural Mathematical & Engineering Sciences, Department of ChemistryWebsite

Mass spectrometric imaging for understanding receptor-targeted therapies

Scientific background: Receptor-targeted antibody therapies have had huge clinical impact in cancer treatment; new discoveries will result in additional antibody treatments. Imaging antibody biodistribution in cells and in vivo has aided their development.

Mass cytometry, using ICP-MS (inductively coupled plasma mass spectrometry), uses IgG antibodies tagged with metal ions to provide cell-level information on protein expression. LA-ICP-MS (laser ablation ICP-MS) is a relatively new methodology. Laser ablation of a two-dimensional sample, for example a tissue slice, followed by ICP-MS analysis of ablated material, enables highly resolved mapping of elemental distribution. We have recently combined our new chemical technology to tag trastuzumab with metals, and subsequently used metal-tagged trastuzumab with ICP-MS and LA-ICP-MS to map trastuzumab distribution in mice bearing breast cancer tumours (see Figure).

Aims: The overarching objective of this project is to further develop new chemical technology to attach metal tags to antibodies, and using laser-ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS) and inductively-coupled plasma mass spectrometry (ICP-MS), apply this technology to quantify/image:
(i) the biodistribution of antibody-based therapies in vivo in mouse models, and
(ii) quantify the relative distribution of receptor targets in vivo in mouse models.
This will enable high resolution, sensitive and quantitative mapping of both antibody therapies and their target receptors.

Skills: Chemical synthesis, antibody modification and characterisation, tissue culture, in vivo studies in mouse models of cancer, mass spectrometry analysis and imaging, image analysis.

Year 1: Prepare new metal-tagged antibody conjugates targeting receptors of the HER family (EGFR, HER2, HER3 and HER4) implicated in cancer and chemically characterise and test these in vitro.

Year 2: LA-ICP-MS imaging of monolayers of cells treated with new metal-tagged antibody conjugates, and preliminary ICP-MS studies in mouse models of cancer.

Year 3: LA-ICP-MS imaging of tissue from mice administered a combination of new metal-tagged antibody conjugates.

Representative Publications

(1) Versatile Diphosphine Chelators for Radiolabeling Peptides with 99mTc and 64Cu, Hungnes, I. N., Pham, T. T., Rivas, C., Jarvis, J. A., Nuttall, R. E., Cooper, S. M., Young, J. D., Blower, P. J., Pringle, P. G. & Ma, M. T., 2023, Inorganic Chemistry, 10.1021/acs.inorgchem.3c00426.

(2) New Bifunctional Chelators Incorporating Dibromomaleimide Groups for Radiolabeling of Antibodies with Positron Emission Tomography Imaging Radioisotopes, Farleigh, M., Pham, T., Yu, Z., Kim, J., Sunassee, K., Firth, G., Forte, N., Chudasama, V., Baker, J. R., Long, N. J., Rivas, C. & Ma, M., 2021, Bioconjugate Chemistry, 10.1021/acs.bioconjchem.0c00710.

(3) Rapid Kit-based 68Ga-Labelling and PET Imaging with THP-Tyr(3)-Octreotate: A Preliminary Comparison with DOTA-Tyr(3)-octreotate, Ma, M. T., Cullinane, C., Waldeck, K., Roselt, P., Hicks, R. J. & Blower, P. J., 2015, EJNMMI Research, 10.1186/s13550-015-0131-1.

(1) Enhanced selectivity for acidic contaminants in drinking water: From suspect screening to toxicity prediction, Ciccarelli, D., Braddock, D. C., Surman, A. J., Arenas, B. I. V., Salal, T., Marczylo, T., Vineis, P., Barron, L. P., 2023, Journal of Hazardous Materials, 10.1016/j.jhazmat.2023.130906.

(2) Environmental control programs the emergence of distinct functional ensembles from unconstrained chemical reactions, Surman, A. J., Rodriguez-Garcia, M., Abul-Haija, Y. M., Cooper, G. J. T., Gromski, P. S., Turk-MacLeod, R., Mullin, M., Mathis, C., Walker, S. & Cronin, 2019, Proceedings of the National Academy of Sciences, 10.1073/pnas.1813987116.

(3) Sizing and Discovery of Nanosized Polyoxometalate Clusters by Mass Spectrometry, Surman, A. J., Robbins, P. J., Ujma, J., Zheng, Q., Barran, P. E. & Cronin, L., 2016, Journal of the American Chemical Society, 10.1021/jacs.6b00070.