Issue 30, 2022

All-in-one disulfide bridging enables the generation of antibody conjugates with modular cargo loading

Abstract

Antibody–drug conjugates (ADCs) are valuable therapeutic entities which leverage the specificity of antibodies to selectively deliver cytotoxins to antigen-expressing targets such as cancer cells. However, current methods for their construction still suffer from a number of shortcomings. For instance, using a single modification technology to modulate the drug-to-antibody ratio (DAR) in integer increments while maintaining homogeneity and stability remains exceptionally challenging. Herein, we report a novel method for the generation of antibody conjugates with modular cargo loading from native antibodies. Our approach relies on a new class of disulfide rebridging linkers, which can react with eight cysteine residues, thereby effecting all-in-one bridging of all four interchain disulfides in an IgG1 antibody with a single linker molecule. Modification of the antibody with the linker in a 1 : 1 ratio enabled the modulation of cargo loading in a quick and selective manner through derivatization of the linker with varying numbers of payload attachment handles to allow for attachment of either 1, 2, 3 or 4 payloads (fluorescent dyes or cytotoxins). Assessment of the biological activity of these conjugates demonstrated their exceptional stability in human plasma and utility for cell-selective cytotoxin delivery or imaging/diagnostic applications.

Graphical abstract: All-in-one disulfide bridging enables the generation of antibody conjugates with modular cargo loading

Supplementary files

Article information

Article type
Edge Article
Submitted
18 Apr. 2022
Accepted
10 Jūl. 2022
First published
20 Jūl. 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2022,13, 8781-8790

All-in-one disulfide bridging enables the generation of antibody conjugates with modular cargo loading

F. M. Dannheim, S. J. Walsh, C. T. Orozco, A. H. Hansen, J. D. Bargh, S. E. Jackson, N. J. Bond, J. S. Parker, J. S. Carroll and D. R. Spring, Chem. Sci., 2022, 13, 8781 DOI: 10.1039/D2SC02198F

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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