In-depth analysis of subclass-specific conformational preferences of IgG antibodies

Xinsheng Tian, Bente Vestergaard, Matthias Thorolfsson, Zhiru Yang, Hanne B. Rasmussen, Annette Eva Langkilde

Research output: Contribution to journalJournal articleResearchpeer-review

55 Citations (Scopus)

Abstract

IgG subclass-specific differences in biological function and in vitro stability are
often referred to variations in the conformational flexibility, while this flexibility
has rarely been characterized. Here, small-angle X-ray scattering data from
IgG1, IgG2 and IgG4 antibodies, which were designed with identical variable
regions, were thoroughly analysed by the ensemble optimization method. The
extended analysis of the optimized ensembles through shape clustering reveals
distinct subclass-specific conformational preferences, which provide new insights
for understanding the variations in physical/chemical stability and biological
function of therapeutic antibodies. Importantly, the way that specific differences
in the linker region correlate with the solution structure of intact antibodies is
revealed, thereby visualizing future potential for the rational design of
antibodies with designated physicochemical properties and tailored effector
functions. In addition, this advanced computational approach is applicable to
other flexible multi-domain systems and extends the potential for investigating
flexibility in solutions of macromolecules by small-angle X-ray scattering.
Original languageEnglish
JournalIUCrJ
Volume2
Issue number1
Pages (from-to)9-18
Number of pages10
ISSN2052-2525
DOIs
Publication statusPublished - 1 Jan 2015

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