Single-photon emission computerized tomography with 99mTC-DARPIN9_29 in diagnostics of breast cancer with Her2/neu overexpression: first clinical experience


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Abstract

Introduction. In recent years, alternative framework proteins are used for the targeted radionuclide imaging. Molecules of DARPin (Design Ankyrin Repeat Protein) are one of the representatives of scaffolds. Despite the continued increase in the number of molecular targets in oncological practice, the epidermal growth receptor Her2/neu is still of great interest, the overexpression of which is most often observed in patients with breast cancer and accounts for 15-20% of cases. However, the methods of the determination of Her2/neu have many significant drawbacks. The aim of the study. Assessment of the 99mTc-DARPin9_29 diagnostic efficacy for the diagnosis of breast cancer (BC) with Her2/neu overexpression. Methods. The study included 8 BC cancer patients (TI4No-M) who were not receiving systemic therapy at the time of the study: in 4 patients, Her2/neu overexpression was noted, in 4 patients - not detected. At the preclinical stage, all patients underwent morphological and immunohistochemical studies of the primary tumor biopsy material. Radiopharmaceutical 99mTc-DARPin9_29 was injected intravenously, WholeBody scintigraphy and SPECT were performed 2 hours after injection. Results. The distribution of radiopharmaceuticals in organs 2 hours after injection revealed the greatest accumulation in the liver and kidneys (26.28 and 6.68% of the administered dose, respectively). In studying tumor/background indices there were revealed values of the studied parameter in patients with overexpression of Her2 receptors to be more than by 2.8 times higher than the values in the subgroup of patients with negative expression of this marker. Conclusion. According to the results obtained at the initial stages of the study, it can be said that the 99mTc-DARPin9_29 preparation can be considered as a promising additional method for the diagnosis of BC with overexpression of the Her2 / neu receptor in the future.

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About the authors

Olga D. Bragina

Tomsk National Research Medical Center, Russian Academy of Sciences; National Research Tomsk Polytechnic University

Email: rungis@mail.ru
Junior Researcher in Nuclear Medicine Department, Cancer Research Institute

Vladimir I. Chernov

Tomsk National Research Medical Center, Russian Academy of Sciences; National Research Tomsk Polytechnic University

Email: chernov@tnimc.ru
Head of the Department of Nuclear Medicine, Cancer Research Institute

Roman V. Zelchan

Tomsk National Research Medical Center, Russian Academy of Sciences; National Research Tomsk Polytechnic University

Email: r.zelchan@yandex.ru
Senior Researcher in Nuclear Medicine Department, Cancer Research Institute

Anna A. Medvedeva

Tomsk National Research Medical Center, Russian Academy of Sciences

Email: medvedeva@tnimc.ru
Senior Researcher in Nuclear Medicine Department, Cancer Research Institute

Evgeniy Yu. Garbukov

Tomsk National Research Medical Center, Russian Academy of Sciences

Email: jrmaximum9@gmail.com
Senior Researcher in General Oncology Department, Cancer Research Institute

Sergey M. Deev

National Research Tomsk Polytechnic University; Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Email: biomem@mail.ru
Head of the Molecular Immunology Laboratory

Vladimir M. Tolmachev

National Research Tomsk Polytechnic University; Uppsala University

Email: vladimir.tolmachev@igp.uu.se
Head of the Department of Immunology, Genetics and Pathology

References

  1. Брагина О.Д., Чернов В.И., Зельчан Р.В., Синилкин И.Г., Медведева А.А., Ларькина М.С. Альтернативные каркасные белки в радионуклидной диагностике злокачественных образований. Бюллетень сибирской медицины. 2019; 18 (3): 125-33
  2. Чернов В.И., Брагина О.Д., Зельчан Р.В., Медведева А.А., Синилкин И.Г., Ларькина М.С., Стасюк Е.С., Нестеров Е.А., Скуридин В.С. Меченые аналоги соматостатина в тераностике нейроэндокринных опухолей. Медицинская радиология и радиационная безопасность. 2017; 62 (3): 42-9
  3. Pluckthun A. Designed ankyrin repeat proteins (DARPins): binding proteins for research, diagnostics, and therapy. Annu Rev Pharmacol Toxicol. 2015; 55: 489-511.
  4. Garousi J., Honarvar H., Andersson K.G., Mitran B., Orlova A., Buijs J., Lofblom J., Frejd F.Y., Tolmachev V Comparative Evaluation of Affibody Molecules for Radionuclide Imaging of in Vivo Expression of Carbonic Anhydrase IX. Mol Pharm. 2016; 13 (11): 3676-87.
  5. Lindbo S., Garousi J., Mitran B., Altai M., Buijs J., Orlova A., Hober S., Tolmachev V Radionuclide Tumor Targeting Using ADAPT Scaffold Proteins: Aspects of Label Positioning and Residualizing Properties of the Label. J. Nucl Med. 2018; 59 (1): 93-9.
  6. Tolmachev V, Orlova A., Andersson K. Methods for radiolabelling of monoclonal antibodies. Methods Mol Biol. 2014; 1060: 309-30.
  7. Nicholes N., Date A., Beaujean P., Hauk P, Kanwar M, Ostermeier M. Modular protein switches derived from antibody mimetic proteins. Protein Engineering, Design and Selection. 2016; 29: 77-85.
  8. Stumpp M.T., Binz H.K., Amstutz P. DARPins: A new generation of protein therapeutics. Drug Discovery Today. 2008; 13 (15): 695-701.
  9. Tamaskovic R., Simon M., Stefan N., Schwill M., Pluckthun A. Designed ankyrin repeat proteins (DARPins) from research to therapy. Methods Enzymol. 2012; 503: 101-34.
  10. Boersma Y.L., Pluckthun A. DARPins and other repeat protein scaffolds: advances in engineering and applications. Curr. Opin. Biotechnol. 2011; 22: 849-57.
  11. Binz H.K., Stumpp M.T., Forrer P., Amstutz P., Pluckthun A. Designing repeat proteins: well-expressed, soluble and stable proteins from combinatorial libraries of consensus ankyrin repeat proteins. J. Mol. Biol. 2003; 332:489-503.
  12. Goldstein R., Sosabowski J., Livanos M., Leyton J., Vigor K., Bhavsar G., Nagy-Davidescu G., Rashid M., Miranda E., Yeung J., Tolner B., Pluckthun A., Mather S., Meyer T, Chester K. Development of the designed ankyrin repeat protein (DARPin) G3 for HER2 molecular imaging. Eur J Nucl Med Mol Imaging. 2015; 42 (2): 288-301.
  13. Hausammann S., Vogel M., Kremer J.A. Designed Ankyrin Repeat Proteins: A New Approach to Mimic Complex Antigens for Diagnostic Purposes? PLoS One. 2013; 8: 1-9.
  14. Moody P., Chudasama V, Nathani R. I., Maruani A., Martin S., Smith M.B., Caddick S. A rapid, site-selective and efficient route to the dual modification of DARPins. Chem Commun (Camb). 2014: 50 (38): 4898-900.
  15. Kramer L., Renko M., Zavrsnik J., Turk D., Seeger M.A., Vasiljeva O., Grutter M.G., Turk V, Turk B.Non-invasive in vivo imaging of tumour-associated cathepsin B by a highly selective inhibitory DARPin. Theranostics. 2017; 8: 2806-21.
  16. Houlihan G., Gatti-Lafranconi P., Lowe D., Hollfelder F. Directed evolution of anti-HER2 DARPins by SNAP display reveals stability/ function trade-offs in the selection process. Protein Eng Des Sel. 2015; 28 (9): 269-79.
  17. Hanenberg M., McAfoose J., Kulic L. Amyloid-p peptide-specific DARPins as a novel class of potential therapeutics for Alzheimer disease. J. Biol. Chem. 2014; 26: 27080-9.
  18. Romond E.H., Perez E.A., Bryant J., Suman V.J., Geyer C.E. Jr., Davidson N.E., Tan-Chiu E., Martino S., Paik S., Kaufman P.A., Swain S.M., Pisansky T.M., Fehrenbacher L., Kutteh L.A., Vogel V.G., Visscher D.W., Yothers G., Jenkins R.B., Brown A.M., Dakhil S.R., Mamounas E.P., Lingle W.L., Klein P.M., Ingle J.N., Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 2005; 353: 1673-84.
  19. Zahid M., Khan S., Khan R. Detection of Her2/neu gene amplification by fluoro-scence in situ hybridization technique. Pathology 2016; 48 (1): 163-70.
  20. Orlando L., Viale G., Bria E. Lutrino E.S., Sperduti I., Carbognin L., Schiavone P., Quaranta A., Fedele P., Caliolo C., Calvani N., Criscuolo M., Cinieri S. Discordance in pathology report after central pathology review: Implications for breast cancer adjuvant treatment. Breast. 2016; 30: 151-5.
  21. Telugu R.B., Chowhan A.K., Rukmangadha N., Patnayak R., Phaneendra B.V, Prasad B.C., Reddy M.K. Human epidermal growth factor receptor 2/neu protein expression in meningiomas: An immunohistochemical study J. Neurosci Rural Pract. 2016; 7 (4): 526-31.
  22. Брагина О.Д., Ларькина М.С., Стасюк Е.С., Чернов В.И., Юсубов М.С., Скуридин В.С., Деев С.М., Зельчан Р.В., Булдаков М.А., Подрезова Е.В., Белоусов М.В. Разработка высокоспецифичного радиохимического соединения на основе меченых 99mTc рекомбинантных адресных молекул для визуализации клеток с гиперэкспрессией Her2/neu. Бюллетень сибирской медицины. 2017; 16 (3): 25-33
  23. Vorobyeva A., Garousi J., Tolmachev V, Schulga A., Konovalova E., Deyev S.M., Guler R., Lofblom J., Sandstrom M., Chernov V, Bragina O., Orlova A. Optimal composition and position of histidine-containing tags improves biodistribution of 99mTc-labeled DARPinG3. Scientific Reports. 2019: 9 (1); 9405
  24. Vorobyeva A., Bragina O., Altai M., Mitran B., Orlova A., Shulga A., Proshkina G., Chernov V, Tolmachev V, S. Deyev Comparative Evaluation of Radioiodine and Technetium-Labeled DARPin 9_29 for Radionuclide Molecular Imaging of HER2 Expression in Malignant Tumors. Contrast Media & Molecular Imaging. 2018; 6930425
  25. Брагина О.Д., Воробьева А.Г., Толмачев B.М., Орлова А.М., Чернов В.М., Деев C.М., Прошкина Г.М., Шульга А.А., Ларькина М.С., Зельчан Р.В., Синилкин И.Г., Медведева А.А. Доклинические исследования меченных 125I таргетных молекул DARPin9_29 для радионуклидной диагностики злокачественных опухолей с гиперэкспрессией Her2/neu. Молекулярная медицина. 2018; 16 (6): 41-5

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