Aminooxy Click Modification of a Periodate-Oxidized Immunoglobulin G: A General Approach to Antibody-Drug Conjugates with Dye-Mediated Expeditious Stoichiometry Control

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 p...

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Published in:International journal of molecular sciences 2023-03, Vol.24 (6), p.5134
Main Authors: 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
Format: Article
Language:English
Subjects:
Alkynes
Amino acids
Analog to digital converters
Antibodies
Antigen (tumor-associated)
Antigens
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Apoptosis
Biopharmaceutics
Cell division
Cell Line, Tumor
Conjugates
Conjugation
Copper
Cyanine dyes
Cycloaddition
Cytotoxicity
Doxorubicin
Dyes
Genetic engineering
IgG antibody
Immunoconjugates - pharmacology
Immunoglobulin G
Immunoglobulins
Leukemia
Melanoma
Methods
Oxidation
Polysaccharides
Proteins
Reagents
Stoichiometry
Tumor cell lines
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms24065134