Journal
CHEMICAL SCIENCE
Volume 13, Issue 30, Pages 8781-8790Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d2sc02198f
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Funding
- AstraZeneca/EPSRC
- AstraZeneca/EPSRC [EP/L015889/1]
- iCASE studentship from GlaxoSmithKline/EPSRC
- CRUK Core award [A20411]
- Engineering and Physical Sciences Research Council [EP/P020291/1]
- UKRI
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This study reports a novel method for generating antibody conjugates with modular cargo loading using a new class of disulfide rebridging linkers. The approach allows all four interchain disulfides in an IgG1 antibody to be bridged with a single linker molecule by reacting with eight cysteine residues. Modulation of cargo loading can be achieved in a quick and selective manner by modifying the antibody with the linker in a 1 : 1 ratio and derivatizing the linker with varying numbers of payload attachment handles.
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.
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