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Global and Local Conformation of Human IgG Antibody Variants Rationalizes Loss of Thermodynamic Stability
Author(s) -
Edgeworth Matthew J.,
Phillips Jonathan J.,
Lowe David C.,
Kippen Alistair D.,
Higazi Daniel R.,
Scrivens James H.
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201507223
Subject(s) - hydrogen–deuterium exchange , antibody , chemistry , monoclonal antibody , chemical stability , molecular dynamics , computational biology , biophysics , mass spectrometry , biology , immunology , computational chemistry , chromatography , organic chemistry
Immunoglobulin G (IgG) monoclonal antibodies (mAbs) are a major class of medicines, with high specificity and affinity towards targets spanning many disease areas. The antibody Fc (fragment crystallizable) region is a vital component of existing antibody therapeutics, as well as many next generation biologic medicines. Thermodynamic stability is a critical property for the development of stable and effective therapeutic proteins. Herein, a combination of ion‐mobility mass spectrometry (IM‐MS) and hydrogen/deuterium exchange mass spectrometry (HDX‐MS) approaches have been used to inform on the global and local conformation and dynamics of engineered IgG Fc variants with reduced thermodynamic stability. The changes in conformation and dynamics have been correlated with their thermodynamic stability to better understand the destabilising effect of functional IgG Fc mutations and to inform engineering of future therapeutic proteins.