All-in-one disulfide bridging enables the generation of antibody conjugates with modular cargo loading |
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Authors: | Friederike M Dannheim Stephen J Walsh Carolina T Orozco Anders Hjgaard Hansen Jonathan D Bargh Sophie E Jackson Nicholas J Bond Jeremy S Parker Jason S Carroll David R Spring |
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Institution: | Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW UK.; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE UK.; Department of Chemistry, Technical University of Denmark (DTU), 2800 Kgs. Lyngby Denmark ; Analytical Sciences, Biopharmaceutical Development, R&D, AstraZeneca, Granta Park, Cambridge CB21 6GH UK ; Early Chemical Development, Pharmaceutical Development, R&D, AstraZeneca, Macclesfield SK10 2NA UK |
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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.Tetra-divinylpyrimidine (TetraDVP) linkers offer a method for the generation of antibody conjugates with modular cargo loading and excellent stability via all-in-one disulfide bridging. |
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