Anzhelika Vorobyeva – Targeted drug delivery using scaffold proteins for cancer therapy

One of the biggest challenges in cancer treatment is developing effective therapies for metastatic cancer, where the disease has spread throughout the body. Standard treatment of cancer, such as chemotherapy, kills cancer cells but also damages healthy cells, leading to severe side effects. Our research group is developing new approaches to make cancer treatment more precise and less harmful.

We use small scaffold engineered proteins, such as affibody molecules, ADAPTs, and DARPins, that can be designed to recognize and bind specifically to receptors found on cancer cells. By attaching cytotoxic drugs to these proteins, we aim to deliver the treatment directly to tumours while sparing healthy tissues.

This modular protein design allows us to tailor properties such as binding strength and cytotoxicity, and to attach drugs in a controlled and uniform way. To evaluate how well these drug conjugates work, we use advanced radiolabelling and imaging methods to study how they distribute in the body and how effectively they reach tumours.

Our long-term goal is to identify the most promising candidates for further clinical development. By advancing our understanding about these targeted drug conjugates, we aim to open the way for new cancer therapies that are more selective, safer, and effective. As the targeted receptors are present across a wide range of cancers, this treatment could be applied to different cancer types, potentially improving both quality of life and survival for patients.

Development of affibody-drug conjugates

In collaboration with Professors Torbjörn Gräslund, John Löfblom, and Stefan Ståhl at the Royal Institute of Technology (KTH), Stockholm - world-leading experts in biotechnology and protein engineering - we are investigating approaches for optimization of the molecular design of affibody-drug conjugates. This includes fine-tuning of parameters such as the number of protein domains, the type of linkers, and the type and number of attached drugs.

Our joint efforts have resulted in affibody-drug conjugates that specifically target the HER2 receptor, a protein often overexpressed in aggressive breast and gastric cancers. Our drug conjugates have shown strong anti-tumour activity with no apparent toxic effects on healthy tissues in preclinical models.

A graph showing improved survival of mice experimentally treated with affibody-drug conjugates, the chemical structures of the drugs used and symbols showing that the drugs have an anti-tumour effect.

In vivo experimental therapy with affibody-drug conjugates, and the chemical structures of the drugs used. The graph shows the survival of mice bearing ovarian cancer xenografts after five treatment cycles with equimolar doses of the two drug conjugates (ZHER2-ABD-DM1 and ZHER2-ABD-MMAF), compared to a non-targeting control group (Ztaq-ABD-DM1, dashed, grey line) and a vehicle control group (PBS, pink line). Asterisks indicate statistically significant differences in median survival between groups.

Translation research: preclinical to clinical development of radiopharmaceuticals

Our research focuses on advancing translational studies of a novel class of targeting agents, engineered scaffold proteins, from conceptualization through preclinical development to clinical application. Assoc. Prof. Anzhelika Vorobyeva contributed to the preclinical development and Phase I clinical translation of DARPin G3 and ADAPT6 proteins for molecular imaging of HER2 expression in breast cancer, as well as DARPin Ec1 for imaging EpCAM expression in lung cancer in collaboration with Prof. Vladimir Tolmachev and Prof. Anna Orlova (Uppsala University), Prof. Sophia Hober (KTH Royal Institute of Technology), and Prof. Sergey Deyev, Prof. Vladimir Chernov, and Dr. Olga Bragina from the Tomsk Cancer Research Institute.

Images visualising tumours and metastases in different colours in different organs

A. Visualization of primary HER2-expressing breast tumour (red arrow) and its metastasis (yellow arrow) using [99mTc]Tc-ADAPT6. Courtesy of Dr. Olga Bragina. B. SPECT/CT images using [99mTc]Tc-Ec1 in lung cancer and lymph nodes metastases (red arrows). From Zelchan, R. et al. Phase I Clinical Evaluation of Designed Ankyrin Repeat Protein [99mTc]Tc(CO)3-(HE)3-Ec1 for Visualization of EpCAM-Expressing Lung Cancer. Cancers 2024, 16, 2815. © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.

Selected publications and other research output