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Endocytosis features of GD2-specific antibodies of different formats in tumor cells
- Authors: Makarova A.O.1,2, Titov M.M.1,2, Kalinovsky D.V.1, Kholodenko I.V.3, Kibardin A.V.4, Larin S.S.4, Svirshchevskaya E.V.1, Deyev S.M.1,5,6, Kholodenko R.V.1,7
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Affiliations:
- Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
- Lomonosov Moscow State University
- Orekhovich Institute of Biomedical Chemistry
- Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology
- Sechenov First Moscow State Medical University
- National Research Center “Kurchatov Institute”
- LLC “Real Target”
- Issue: Vol 90, No 3 (2025)
- Pages: 471-484
- Section: Articles
- URL: https://journals.rcsi.science/0320-9725/article/view/294708
- DOI: https://doi.org/10.31857/S0320972525030101
- EDN: https://elibrary.ru/BJBRKI
- ID: 294708
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Abstract
Antibody-drug conjugates (ADCs) have emerged as one of the most promising classes of monoclonal antibody-based (mAb) targeted cancer therapies. To date, 15 drugs of this class have been approved for clinical use, while many more are undergoing more than 100 clinical trials. Similarly to unconjugated antibodies, ADCs target various tumor markers including carbohydrate antigens in glycosphingolipids. Among them, ganglioside GD2 is considered the most promising marker, and recent studies have shown significant potential for the use of anti-GD2 ADCs. Receptor internalization after antigen-antibody complex formation and its transport to cell lysosomes are important characteristics of the marker, on which the effectiveness of ADCs largely depends. The ability of GD2-specific antibodies to internalize and the mechanisms of endocytosis of their complexes with GD2 have been poorly studied. The study investigated the mechanisms of internalization of ganglioside GD2 complexes and the most relevant GD2-specific antibodies of various formats, including full-length antibodies, minibodies, and scFv fragments. It was demonstrated that all the antibody variants used are capable of internalizing into GD2-positive tumor cells and entering their lysosomal compartments. Full-length antibodies and minibodies demonstrate high efficiency of endocytosis in GD2-positive cells, which occurs through several pathways, primarily macropinocytosis and caveolae-mediated endocytosis. The obtained data may be of interest for development of more effective targeted drugs for the treatment of GD2-positive tumors.
About the authors
A. O. Makarova
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; Lomonosov Moscow State University
Email: khol@mail.ru
Faculty of Biology
Russian Federation, 1117997 Moscow; 119991 MoscowM. M. Titov
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; Lomonosov Moscow State University
Email: khol@mail.ru
Faculty of Biology
Russian Federation, 1117997 Moscow; 119991 MoscowD. V. Kalinovsky
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
Email: khol@mail.ru
Russian Federation, 1117997 Moscow
I. V. Kholodenko
Orekhovich Institute of Biomedical Chemistry
Email: khol@mail.ru
Russian Federation, 119121 Moscow
A. V. Kibardin
Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology
Email: khol@mail.ru
Russian Federation, 117997 Moscow
S. S. Larin
Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology
Email: khol@mail.ru
Russian Federation, 117997 Moscow
E. V. Svirshchevskaya
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
Email: khol@mail.ru
Russian Federation, 1117997 Moscow
S. M. Deyev
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; Sechenov First Moscow State Medical University; National Research Center “Kurchatov Institute”
Email: khol@mail.ru
Russian Federation, 1117997 Moscow; 119991 Moscow; 123098 Moscow
R. V. Kholodenko
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; LLC “Real Target”
Author for correspondence.
Email: khol@mail.ru
Russian Federation, 1117997 Moscow; 108841 Moscow
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