IgG2 disulfide isoform conversion kinetics

被引:20
|
作者
Liu, Yaoqing Diana [1 ]
Wang, Tian [1 ]
Chou, Robert [1 ]
Chen, Louise [1 ]
Kannan, Gunasekaran [2 ]
Stevenson, Riki [1 ]
Goetze, Andrew M. [1 ]
Jiang, Xinzhao Grace [1 ]
Huang, Gang [1 ]
Dillon, Thomas M. [1 ]
Flynn, Gregory C. [1 ]
机构
[1] Amgen Inc, Dept Proc & Prod Dev, Thousand Oaks, CA 91320 USA
[2] Amgen Inc, Dept Biol Optimizat, Thousand Oaks, CA 91320 USA
关键词
Disulfide shuffling; Antibodies; Physiological models; Redox reactions; Blood chemistry; LIGHT-CHAIN; ANTIBODIES; PLASMA;
D O I
10.1016/j.molimm.2012.12.005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Human IgG2 antibodies contain three types of disulfide isoforms, classified by the number of Fab arms having disulfide links to the heavy chain hinge region. In the IgG2-B form, both Fab arms have interchain disulfide bonds to the hinge region, and in IgG2-A, neither Fab arm are disulfide linked to the hinge. The IgG2-A/B is a hybrid between these two forms, with only one Fab arm disulfide linked to the hinge. Changes in the relative levels of these forms over time are observed while IgG2 circulates in humans, suggesting IgG2-A -> IgG2-A/B -> IgG2-B conversion. Using a flow-through dialysis system, we studied the conversion kinetics of these forms in vitro under physiological conditions. For two IgG2 kappa antibodies, in vivo results closely matched the kinetics observed in vitro, indicating that the changes observed in vivo were solely conversions between isoforms, not differential clearance of specific forms. Moreover, the combined results validate the accuracy of the physiological model for the study of blood redox reactions. Further exploration of the conversion kinetics using material enriched in the IgG2-A forms revealed that the IgG2-A -> IgG2-A/B rate was similar between IgG2 kappa and IgG2 lambda antibodies. In IgG2 kappa antibodies, conversion of IgG2-A/B -> IgG2-B was slower than the IgG2-A -> IgG2-A/B reaction. However, in IgG2 lambda antibodies, little IgG2-A/B -> IgG2-B conversion was detected under physiological conditions. Thus, small differences in the C-terminus of the light chain sequences affect the disulfide conversion kinetics and impact the IgG2 disulfide isoforms produced in vivo. (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码:217 / 226
页数:10
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