Aminooxy Click Modification of a Periodate-Oxidized Immunoglobulin G: A General Approach to Antibody–Drug Conjugates with Dye-Mediated Expeditious Stoichiometry Control
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Published:2023-03-07
Issue:6
Volume:24
Page:5134
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Sapozhnikova Ksenia A.1ORCID, Gulyak Evgeny L.1, Brylev Vladimir A.12, Misyurin Vsevolod A.3, Oreshkov Sergey D.14, Alexeeva Anastasiya V.5, Ryazantsev Dmitry Yu.1ORCID, Simonova Maria A.1, Ryabukhina Ekaterina V.1, Popova Galina P.1, Tikhonova Nataliya A.5, Lyzhko Natalia A.5, Barmashov Alexander E.3, Misyurin Andrey V.5, Ustinov Alexey V.12, Alferova Vera A.1ORCID, Korshun Vladimir A.1ORCID
Affiliation:
1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia 2. Lumiprobe RUS Ltd., Kotsyubinskogo 4, 121351 Moscow, Russia 3. N.N. Blokhin National Medical Cancer Research Center, Ministry of Health of Russia, Kashirskoye sh. 24, 115478 Moscow, Russia 4. Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia 5. GeneTechnology LLC, Profsoyuznaya 104, 117485 Moscow, Russia
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.
Funder
Russian Science Foundation
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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