当前位置： SCI文献检索 > JOURNAL OF PHARMACEUTICAL SCIENCES期刊下所有文献 > Understanding the Increased Aggregation Propensity of a Light-Exposed IgG1 Monoclonal Antibody Using Hydrogen Exchange Mass Spectrometry, Biophysical Characterization, and Structural Analysis.

Understanding the Increased Aggregation Propensity of a Light-Exposed IgG1 Monoclonal Antibody Using Hydrogen Exchange Mass Spectrometry, Biophysical Characterization, and Structural Analysis.

Abstract：

:This work compares the conformational stability, backbone flexibility, and aggregation propensity of monomer and dimer fractions of an IgG1 monoclonal antibody (mAb) generated on UVA light exposure for up to 72 h collected by preparative size-exclusion chromatography, compared with unstressed control. UVA light exposure induced covalent aggregation, and fragmentation as measured by size-exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis, and extensive oxidation of specific methionine residues (Met 257, Met 433, and Met 109) in both size fractions identified by reverse phase chromatography coupled to mass spectrometry. Compared with unstressed mAb, both the monomer and dimer fractionated from 72 h UVA light-exposed mAb had decreased thermal melting temperatures (Tm1) by 1.4°C as measured by differential scanning calorimetry, minor changes in tertiary structure as measured by near-UV CD, increased monomer loss, and aggregation on accelerated storage at 35°C. Hydrogen/deuterium exchange mass spectrometry identified local segments with increased flexibility in CH2 and CH3 domains of both size fractions, and decreased flexibility in few segments of Fab and CH1 domains in the dimer fraction. Segment 247-256 in heavy chain, an established aggregation hotspot in IgG1 mAbs had large increase in flexibility in both size fractions compared with unstressed mAb.

journal_name

J Pharm Sci

journal_title

Journal of pharmaceutical sciences

authors

Bommana R,Chai Q,Schöneich C,Weiss WF 4th,Majumdar R

doi

10.1016/j.xphs.2018.01.017

subject

Has Abstract

pub_date

2018-06-01 00:00:00

pages

1498-1511

issue

6

eissn

0022-3549

issn

1520-6017

pii

S0022-3549(18)30041-8

journal_volume

107

pub_type

杂志文章

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