Influence of disulfide bond isoforms on drug conjugation sites in cysteine-linked IgG2 antibody-drug conjugates

Lily Liu-Shin, Adam Fung, Arun Malhotra, Gayathri Ratnaswamy

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Cysteine-linked antibody-drug conjugates (ADCs) produced from IgG2 monoclonal antibodies (mAbs) are more heterogeneous than ADCs generated from IgG1 mAbs, as IgG2 ADCs are composed of a wider distribution of molecules, typically containing 0–12 drug-linkers per antibody. The three disulfide isoforms (A, A/B, and B) of IgG2 antibodies confer differences in solvent accessibilities of the interchain disulfides and contribute to the structural heterogeneity of cysteine-linked ADCs. ADCs derived from either IgG2-A or IgG2-B mAbs were compared to better understand the role of disulfide isoforms on attachment sites and distribution of conjugated species. Our characterization of these ADCs demonstrated that the disulfide configuration affects the kinetics of disulfide bond reduction, but has minimal effect on the primary sites of reduction. The IgG2-A mAbs yielded ADCs with higher drug-to-antibody ratios (DARs) due to the easier reduction of its interchain disulfides. However, hinge-region cysteines were the primary conjugation sites for both IgG2-A and IgG2-B mAbs.

Original languageEnglish (US)
Pages (from-to)583-595
Number of pages13
JournalmAbs
Volume10
Issue number4
DOIs
StatePublished - May 19 2018

Keywords

  • ADC
  • DAR
  • IgG2
  • antibody-drug conjugate
  • conjugation positions
  • disulfide isoforms
  • drug loading
  • drug-to-antibody ratio

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Influence of disulfide bond isoforms on drug conjugation sites in cysteine-linked IgG2 antibody-drug conjugates'. Together they form a unique fingerprint.

  • Cite this