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J Biol Chem. 2013 Jun 7;288(23):16371-82. doi: 10.1074/jbc.M113.468397. Epub 2013 Apr 25.

IgG1 thioether bond formation in vivo.

Author information

1
Department of Process and Product Development, Amgen Inc., Thousand Oaks, California 91320, USA.

Abstract

During either production or storage, the LC214-HC220 disulfide in therapeutic antibodies can convert to a thioether bond. Here we report that a thioether forms at the same position on antibodies in vivo. An IgG1κ therapeutic antibody dosed in humans formed a thioether at this position at a rate of about 0.1%/day while circulating in blood. Thioether modifications were also found at this position in endogenous antibodies isolated from healthy human subjects, at levels consistent with this conversion rate. For both endogenous antibodies and recombinant antibodies studied in vivo, thioether conversion rates were faster for IgG1 antibodies containing λ light chains than those containing κ light chains. These light chain reaction rate differences were replicated in vitro. Additional mechanistic studies showed that base-catalyzed thioether formation through the light chain dehydrogenation was more preferred on antibodies with λ light chains, which may help explain the observed reaction rate differences.

KEYWORDS:

Antibodies; Disulfide; Drug Development; Light Chain; Mass Spectrometry (MS); Post Translational Modification

PMID:
23625924
PMCID:
PMC3675574
DOI:
10.1074/jbc.M113.468397
[Indexed for MEDLINE]
Free PMC Article
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