Aims of the Project:
- Develop a panel of new bioconjugates that incorporate metal complexes into receptor-targeted antibodies.
- Study the biodistribution of this library of new chelator-antibody conjugates tagged with non-radioactive metals in tumour-bearing mice, using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and inductively coupled plasma mass spectrometry (ICP-MS).
Receptor-targeted antibody therapies have had huge clinical impact in the treatment of cancer, and new discoveries will result in further antibody treatment options. Imaging the biodistribution of antibodies in cells and in vivo has aided their development. However, state-of-the-art quantitative radionuclide in vivo tracking methods (e.g. positron emission technology, PET, or single photon emission computed tomography, SPECT) have relatively low spatial resolution (approximately 1 mm). On the other hand, fluorescence imaging methods, which can pinpoint sub-cellular localisation of antibodies, are not quantitative.
Mass cytometry uses IgG antibodies tagged with transition and lanthanide metal ions (referred to here as “heavy” metals) to provide information at the single cell level on protein expression and cell processes. Typically, these are single isotopes of non-endogenous metals – metal ions that are not used by organisms for normal physiological processes. Cells are first exposed to a panel of antibodies, with each antibody tagged with a single stable isotope of a heavy metal. Individual cells or populations of cells are then analysed by mass spectrometry (typically with inductively coupled plasma mass spectrometry, ICP-MS) to measure the metal content of cells, with metal content providing a measure of antibody accumulation. As mass spectrometry can quantitatively measure many heavy metals in a single sample (approximately 20), a cocktail of antibodies, each with a unique metal tag, can provide a vast array of information on single cell processes.
LA-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.
The overarching objective of this project is to develop new chemical technology to attach heavy 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 the relative distribution of target receptors, thus giving insight into therapeutic efficacy of these treatments.
This project would suit a student with a background in synthetic chemistry, inorganic chemistry, pharmaceutical sciences, biochemistry, protein chemistry or medicinal chemistry.