A general approach for the site-selective modification of native proteins, enabling the generation of stable and functional antibody-drug conjugates.
Authors
Omarjee, Soleilmane
Galloway, Warren RJD
Kwan, Terence T-L
Publication Date
2019-01-21Journal Title
Chem Sci
ISSN
2041-6520
Publisher
Royal Society of Chemistry (RSC)
Volume
10
Issue
3
Pages
694-700
Language
eng
Type
Article
This Version
VoR
Physical Medium
Electronic-eCollection
Metadata
Show full item recordCitation
Walsh, S. J., Omarjee, S., Galloway, W. R., Kwan, T. T., Sore, H. F., Parker, J. S., Hyvönen, M., et al. (2019). A general approach for the site-selective modification of native proteins, enabling the generation of stable and functional antibody-drug conjugates.. Chem Sci, 10 (3), 694-700. https://doi.org/10.1039/c8sc04645j
Abstract
Antibody-drug conjugates (ADCs) are a class of targeted therapeutics that utilize the specificity of antibodies to selectively deliver highly potent cytotoxins to target cells. Although recent years have witnessed significant interest in ADCs, problems remain with the standard linkage chemistries used for cytotoxin-antibody bioconjugation. These typically (1) generate unstable constructs, which may lead to premature cytotoxin release, (2) often give a wide variance in drug-antibody ratios (DAR) and (3) have poor control of attachment location on the antibody, resulting in a variable pharmacokinetic profile. Herein, we report a novel divinylpyrimidine (DVP) linker platform for selective bioconjugation via covalent re-bridging of reduced disulfide bonds on native antibodies. Model studies using the non-engineered trastuzumab antibody validate the utility of this linker platform for the generic generation of highly plasma-stable and functional antibody constructs that incorporate variable biologically relevant payloads (including cytotoxins) in an efficient and site-selective manner with precise control over DAR. DVP linkers were also used to efficiently re-bridge both monomeric and dimeric protein systems, demonstrating their potential utility for general protein modification, protein stabilisation or the development of other protein-conjugate therapeutics.
Sponsorship
AstraZeneca, Cambridge Trusts, EPSRC, BBSRC, Royal Society, MRC
Funder references
Engineering and Physical Sciences Research Council (EP/P020291/1)
Royal Society (WM150022)
Engineering and Physical Sciences Research Council (EP/J016012/1)
Cancer Research UK (C14303/A17197)
Identifiers
External DOI: https://doi.org/10.1039/c8sc04645j
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287080
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