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Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells

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 therapeuti...

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Autores principales: Kalinovsky, Daniel V., Kholodenko, Irina V., Kibardin, Alexey V., Doronin, Igor I., Svirshchevskaya, Elena V., Ryazantsev, Dmitriy Y., Konovalova, Maria V., Rozov, Fedor N., Larin, Sergey S., Deyev, Sergey M., Kholodenko, Roman V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9860947/
https://www.ncbi.nlm.nih.gov/pubmed/36674755
http://dx.doi.org/10.3390/ijms24021239
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author Kalinovsky, Daniel V.
Kholodenko, Irina V.
Kibardin, Alexey V.
Doronin, Igor I.
Svirshchevskaya, Elena V.
Ryazantsev, Dmitriy Y.
Konovalova, Maria V.
Rozov, Fedor N.
Larin, Sergey S.
Deyev, Sergey M.
Kholodenko, Roman V.
author_facet Kalinovsky, Daniel V.
Kholodenko, Irina V.
Kibardin, Alexey V.
Doronin, Igor I.
Svirshchevskaya, Elena V.
Ryazantsev, Dmitriy Y.
Konovalova, Maria V.
Rozov, Fedor N.
Larin, Sergey S.
Deyev, Sergey M.
Kholodenko, Roman V.
author_sort Kalinovsky, Daniel V.
collection PubMed
description 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.
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spelling pubmed-98609472023-01-22 Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells Kalinovsky, Daniel V. Kholodenko, Irina V. Kibardin, Alexey V. Doronin, Igor I. Svirshchevskaya, Elena V. Ryazantsev, Dmitriy Y. Konovalova, Maria V. Rozov, Fedor N. Larin, Sergey S. Deyev, Sergey M. Kholodenko, Roman V. Int J Mol Sci Article 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. MDPI 2023-01-08 /pmc/articles/PMC9860947/ /pubmed/36674755 http://dx.doi.org/10.3390/ijms24021239 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kalinovsky, Daniel V.
Kholodenko, Irina V.
Kibardin, Alexey V.
Doronin, Igor I.
Svirshchevskaya, Elena V.
Ryazantsev, Dmitriy Y.
Konovalova, Maria V.
Rozov, Fedor N.
Larin, Sergey S.
Deyev, Sergey M.
Kholodenko, Roman V.
Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells
title Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells
title_full Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells
title_fullStr Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells
title_full_unstemmed Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells
title_short Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells
title_sort minibody-based and scfv-based antibody fragment-drug conjugates selectively eliminate gd2-positive tumor cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9860947/
https://www.ncbi.nlm.nih.gov/pubmed/36674755
http://dx.doi.org/10.3390/ijms24021239
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