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Photodisruption of the Structurally Conserved Cys-Cys-Trp Triads Leads to Reduction-Resistant Scrambled Intrachain Disulfides in an IgG1 Monoclonal Antibody.

Abstract：

:Photostability conditions as prescribed by ICH guidelines induced highly reduction-resistant scrambled disulfides that contribute to the population of apparent nonreducible aggregates in an IgG1 mAb. Photoinduced cross-linked species were isolated under reducing conditions using an organic phase size exclusion chromatography (OP-SEC) method, followed by O18-labeling tryptic mapping to identify cross-linked peptides. Disulfide scrambling was observed within the IgG1 structurally conserved-intrachain cysteine-cysteine-tryptophan triads (Cys-Cys-Trp), and correlated with Trp-to-kynurenine (Kyn) photodegradation within these triads. We hypothesize that intrachain disulfides protect the proximal Trp within the Cys-Cys-Trp triads from photodegradation by enabling dissipation of Trp-absorbed UV energy via electron transfer to the disulfide bond. Finally, we propose three distinct mechanisms of photochemical degradation of monoclonal antibodies mediated by Trp residues.

journal_name

Mol Pharm

journal_title

Molecular pharmaceutics

authors

Wecksler AT,Yin J,Lee Tao P,Kabakoff B,Sreedhara A,Deperalta G

doi

10.1021/acs.molpharmaceut.7b01128

subject

Has Abstract

pub_date

2018-04-02 00:00:00

pages

1598-1606

issue

4

eissn

1543-8384

issn

1543-8392

journal_volume

15

pub_type

杂志文章

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