학술논문
Aminooxy Click Modification of a Periodate-Oxidized Immunoglobulin G: A General Approach to Antibody–Drug Conjugates with Dye-Mediated Expeditious Stoichiometry Control.
Document Type
Article
Author
Sapozhnikova, Ksenia A.; Gulyak, Evgeny L.; Brylev, Vladimir A.; Misyurin, Vsevolod A.; Oreshkov, Sergey D.; Alexeeva, Anastasiya V.; Ryazantsev, Dmitry Yu.; Simonova, Maria A.; Ryabukhina, Ekaterina V.; Popova, Galina P.; Tikhonova, Nataliya A.; Lyzhko, Natalia A.; Barmashov, Alexander E.; Misyurin, Andrey V.; Ustinov, Alexey V.; Alferova, Vera A.; Korshun, Vladimir A.
Source
Subject
*ANTIBODY-drug conjugates
*STOICHIOMETRY
*CANCER cells
*COPPER
*CELL lines
*CYANINES
*DOXORUBICIN
*GLYCANS
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Language
ISSN
1661-6596
Abstract
A universal approach to the construction of antibody–drug conjugates (ADCs) has been developed. It relies on periodate oxidation of naturally present glycans of immunoglobulin G, followed by oxime ligation and, optionally, copper(I)-catalyzed alkyne-azide cycloaddition for conjugation with a toxic payload. The introduction of highly absorbing cyanine dyes into the linker allows for facile determination of the drug–antibody ratio. We applied this methodology to the synthesis of cytotoxic conjugates of an antibody against the tumor-associated antigen PRAME with doxorubicin and monomethyl auristatin E (MMAE). The resultant conjugates retained their affinity to a large extent, yet their cytotoxicity in vitro varied dramatically: while the doxorubicin-based conjugate did not produce any effect on cells, the MMAE-based one demonstrated specific activity against PRAME-expressing cancer cell lines. Importantly, the latter conjugate constitutes the first reported example of a PRAME-targeting ADC. [ABSTRACT FROM AUTHOR]