Acid-cleavable thiomaleamic acid linker for homogeneous antibody-drug conjugation

In this communication we describe a novel acid-cleavable linker strategy for antibody-drug conjugation. Functional disulfide bridging of the single interchain disulfide bond of a trastuzumab Fab fragment yields a homogeneous antibody-drug conjugate bearing a thiomaleamic acid linker. This linker is...

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Bibliographic Details
Published in:Chemical communications (Cambridge, England) England), 2013-01, Vol.49 (74), p.8187-8189
Main Authors: Castañeda, Lourdes, Maruani, Antoine, Schumacher, Felix F, Miranda, Enrique, Chudasama, Vijay, Chester, Kerry A, Baker, James R, Smith, Mark E B, Caddick, Stephen
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal, Humanized - chemistry
Bearing
Chemical bonds
Conjugates
Conjugation
Disulfides
Disulfides - chemistry
Hydrogen-Ion Concentration
Maleates - chemistry
Molecular Structure
Payloads
Pharmaceutical Preparations - chemistry
Strategy
Temperature
Trastuzumab
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Summary:In this communication we describe a novel acid-cleavable linker strategy for antibody-drug conjugation. Functional disulfide bridging of the single interchain disulfide bond of a trastuzumab Fab fragment yields a homogeneous antibody-drug conjugate bearing a thiomaleamic acid linker. This linker is stable at physiological pH and temperature, but quantitatively cleaves at lysosomal pH to release the drug payload.
ISSN:1359-7345
1364-548X
DOI:10.1039/c3cc45220d