Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 11, Pages 2831-2834Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201712370
Keywords
antibody-drug conjugates; bioorthogonal reactions; cyclopropene; drug delivery; protein engineering
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Funding
- Medical Research Council, UK [MC_U105181009, MC_UP_A024_1008]
- EMBO fellowship [ATLF 158-2016]
- MRC [MC_U105181009] Funding Source: UKRI
- Medical Research Council [MC_UP_A024_1008, MC_U105181009] Funding Source: researchfish
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Homogeneous antibody-drug conjugates (ADCs), generated by site-specific toxin linkage, show improved therapeutic indices with respect to traditional ADCs. However, current methods to produce site-specific conjugates suffer from low protein expression, slow reaction kinetics, and low yields, or are limited to particular conjugation sites. Here we describe high yielding expression systems that efficiently incorporate a cyclopropene derivative of lysine (CypK) into antibodies through genetic-code expansion. We express trastuzumab bearing CypK and conjugate tetrazine derivatives to the antibody. We show that the dihydropyridazine linkage resulting from the conjugation reaction is stable in serum, and generate an ADC bearing monomethyl auristatinE that selectively kills cells expressing a high level of HER2. Our results demonstrate that CypK is a minimal bioorthogonal handle for the rapid production of stable therapeutic protein conjugates.
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