Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells
| Autor: | Daniel V. Kalinovsky, Irina V. Kholodenko, Alexey V. Kibardin, Igor I. Doronin, Elena V. Svirshchevskaya, Dmitriy Y. Ryazantsev, Maria V. Konovalova, Fedor N. Rozov, Sergey S. Larin, Sergey M. Deyev, Roman V. Kholodenko |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
Inorganic Chemistry
Organic Chemistry antibody fragments scFv fragments minibodies antibody-drug conjugates ganglioside GD2 immunotherapy cancer GD2-positive tumors neuroblastoma melanoma General Medicine Physical and Theoretical Chemistry Molecular Biology Spectroscopy Catalysis Computer Science Applications |
| Zdroj: | International Journal of Molecular Sciences; Volume 24; Issue 2; Pages: 1239 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms24021239 |
| Popis: | Ganglioside GD2 is a well-established target expressed on multiple solid tumors, many of which are characterized by low treatment efficiency. Antibody-drug conjugates (ADCs) have demonstrated marked success in a number of solid tumors, and GD2-directed drug conjugates may also hold strong therapeutic potential. In a recent study, we showed that ADCs based on the approved antibody dinutuximab and the drugs monomethyl auristatin E (MMAE) or F (MMAF) manifested potent and selective cytotoxicity in a panel of tumor cell lines and strongly inhibited solid tumor growth in GD2-positive mouse cancer models. Here, we employed two different GD2-binding moieties–minibodies and scFv fragments that carry variable antibody domains identical to those of dinutuximab, and site-directly conjugated them to MMAE or MMAF by thiol-maleimide chemistry with drug-to-antibody ratios (DAR) of 2 and 1, respectively. Specific binding of the antibody fragment-drug conjugates (FDCs) to GD2 was confirmed in direct ELISA, flow cytometry, and confocal microscopy. Selective cytotoxic and cytostatic effects of the conjugates were observed in GD2-positive but not GD2-negative neuroblastoma and melanoma cell lines. Minibody-based FDCs demonstrated more pronounced cytotoxic effects and stronger antigen binding compared to scFv-based FDCs. The developed molecules may offer considerable practical benefit, since antibody fragment-drug conjugates are capable of enhancing therapeutic efficacy of ADCs by improving their pharmacokinetic characteristics and reducing side effects. |
| Databáze: | OpenAIRE |
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