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Catalytic Cleavage of Disulfide Bonds in Small Molecules and Linkers of Antibody-Drug Conjugates.
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2019 Oct; Vol. 47 (10), pp. 1156-1163. Date of Electronic Publication: 2019 May 13. - Publication Year :
- 2019
-
Abstract
- In cells, catalytic disulfide cleavage is an essential mechanism in protein folding and synthesis. However, detailed enzymatic catalytic mechanism relating cleavage of disulfide bonds in xenobiotics is not well understood. This study reports an enzymatic mechanism of cleavage of disulfide bonds in xenobiotic small molecules and antibody conjugate (ADC) linkers. The chemically stable disulfide bonds in substituted disulfide-containing pyrrolobenzodiazepine (PBD, pyrrolo[2,1-c][1,4]benzodiazepine) monomer prodrugs in presence of glutathione or cysteine were found to be unstable in incubations in whole blood of humans and rats. It was shown the enzymes involved were thioredoxin (TRX) and glutaredoxin (GRX). For a diverse set of drug-linker conjugates, we determined that TRX in the presence of TRX-reductase and NADPH generated the cleaved products that are consistent with catalytic disulfide cleavage and linker immolation. GRX was less rigorously studied; in the set of compounds studied, its role in the catalytic cleavage was also confirmed. Collectively, these in vitro experiments demonstrate that TRX as well as GRX can catalyze the cleavage of disulfide bonds in both small molecules and linkers of ADCs.<br /> (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)
- Subjects :
- Animals
Benzodiazepines chemistry
Benzodiazepines metabolism
Disulfides chemistry
Disulfides metabolism
Female
Humans
Immunoconjugates chemistry
Male
Pyrroles chemistry
Pyrroles metabolism
Rats
Recombinant Proteins metabolism
Thioredoxin-Disulfide Reductase metabolism
Glutaredoxins metabolism
Immunoconjugates pharmacokinetics
Thioredoxins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-009X
- Volume :
- 47
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 31085544
- Full Text :
- https://doi.org/10.1124/dmd.118.086132