Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 58, Issue 25, Pages 8489-8493Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201903494
Keywords
antibody-drug conjugate; Diels-Alder reaction; diene; non-canonical amino acid; proximity-driven reaction
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Funding
- AstraZeneca
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- National Institutes of Health [1S10OD012077-01A1]
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Here, we describe a diene-containing noncanonical amino acid (ncAA) capable of undergoing fast and selective normal electron-demand Diels-Alder (DA) reactions following its incorporation into antibodies. A cyclopentadiene derivative of lysine (CpHK) served as the reactive handle for DA transformations and the substrate for genetic incorporation. CpHK incorporated into antibodies with high efficiency and was available for maleimide conjugation or self-reaction depending on position in the amino acid sequence. CpHK at position K274 reacted with the maleimide drug-linker AZ1508 at a rate of approximate to 79m(-1)s(-1) to produce functional antibody-drug conjugates (ADCs) in a one-step process. Incorporation of CpHK at position S239 resulted in dimerization, which covalently linked antibody heavy chains together. The diene ncAA described here is capable of producing therapeutic protein conjugates with clinically validated and widely available maleimide compounds, while also enabling proximity-based stapling through a DA dimerization reaction.
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