Vladimir Tolmachev – Scaffold protein-based radionuclide tumour targeting

The main goal of our research is to develop a methodology for using radionuclides in the diagnostics and therapy of malignant tumours. Radionuclides can provide information about the molecular composition of the tumour cells and by delivering cytotoxic radionuclides into tumours malignant cells can be eliminated or their growth can be reduced.

Cancer therapy can be improved by identifying specific proteins that are present in the tumour cells but not in normal cells, or that are aberrantly expressed in tumour cells. Already today there are therapies based on the molecular recognition of such proteins by antibodies or kinase inhibitors. However, this kind of targeted therapy is complicated by the varying levels of the aberrantly expressed proteins between patients, or even in a single patient. This warrants the use of methods to identify and image specific proteins in patients. Accomplishment of this goal would make targeted cancer treatment more precise.

Two images in grayscale showing internal organs where the presence of HER is shown as a black spot in one of the images.

Discrimination between malignant breast tumours with high and low HER2 expression using radiolabelled Affibody. Patients with tumours with high HER2 expression will most likely benefit from first-line therapy with trastuzumab. Image from Bragina et al. Theranostics. 2023 Sep 4;13(14):4858-4871. © by authors

Radionuclides for molecular targeting of RTK and pancarcinoma antigens

In our research we develop the use of radionuclides to target and image relevant proteins. Radionuclide imaging is non-invasive and provides important information about proteins in tumours. Specific delivery of cytotoxic radionuclides also has a potential to eradicate malignant cells or, at least, appreciably slow down tumour growth.

We focus on a group of proteins called receptor tyrosine kinases (RTK) as molecular targets for radionuclide targeting. Abnormal expression of RTK:s is part of the malignant feature and a driving force of cancer growth. Tumour treatments based on the molecular recognition of aberrantly expressed RTK:s by antibodies or RTK inhibitors are already in use but with radionuclide targeting of RTK such treatments can be made more personalised.

Another group of targets of interest include so-called pancarcinoma antigens. Such proteins, like e.g. EpCAM, TAG72 or CEACAM5 are often overexpressed in a variety of different malignancies. We utilise our targeting platform, with engineered scaffold proteins, for developing selective delivery of cytotoxic radionuclides, drugs and toxins to malignant tumours that overexpress pancarcinoma antigens. We are co-developing radionuclide-based imaging probes to make such therapy precise.

Preclinical development and clinical translation of scaffold protein-based targeting agents

Our main strategy is to use engineered scaffold protein-based targeting agents. Our group pioneered the use of engineered scaffold proteins (affibody molecules) as probes for radionuclide molecular imaging. We have demonstrated in a series of Phase I/II clinical studies that the use of affibody molecules is safe, well-tolerated and provides excellent imaging just two to four hours after injection.

Currently, we are expanding our “toolbox” by the use of other scaffold proteins, ADAPTs and DARPins. Our Phase I clinical studies have demonstrated that these agents have very promising features to be used as targeting probes.

Our projects also include evaluation of biological aspects of targeting (molecular and cellular biology of a target, radiopharmacology of labelled conjugates) and selection of an optimal radionuclide for a given application. We also work with the selection and development of an optimal labelling chemistry, and preclinical evaluation of the produced radiolabelled conjugates.