Abstract
Recombinant human monoclonal antibodies have become important protein-based therapeutics for the treatment of various diseases. An IgG1 molecule, which is now mainly used for antibody preparation, consists of a total of 12 immunoglobulin domains. Each domain has one disulfide bond. The CH3 domain is the C-terminal domain of the heavy chain of IgG1. The disulfide bonds of some of the CH3 domains are known to be reduced in recombinant human monoclonal antibodies. The lack of intramolecular disulfide bonds may decrease the stability and increase the aggregation propensity of an antibody molecule. To investigate the effects of a reduced disulfide bond in the CH3 domain on conformational stability and aggregation propensity, we performed several physicochemical measurements including circular dichroism, differential scanning calorimetry (DSC), and 2D NMR. DSC measurements showed that both the stability and reversibility of the reduced form were lower than those of the oxidized form. In addition, detailed analyses of the thermal denaturation data revealed that, although a dominant fraction of the reduced form retained a stable dimeric structure, some fractions assumed a less-specifically associated oligomeric state between monomers. ...Continue Reading
References
Jul 13, 1976·Biochemistry·J W LongworthA Solomon
Jun 5, 1987·Journal of Molecular Biology·D J StatesM Karplus
Mar 5, 1981·Journal of Molecular Biology·Y Goto, K Hamaguchi
Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
Mar 26, 1998·Protein Engineering·T R KimC A Batt
Sep 4, 2001·Biotechnology & Genetic Engineering Reviews·R L FahrnerG S Blank
Jan 25, 2002·Blood·Guillaume CartronHervé Watier
Jun 8, 2002·Biotechnology Progress·Wei Zhang, Marta J Czupryn
Jun 24, 2004·Pharmaceutical Research·Suzanne HermelingWim Jiskoot
May 5, 2005·The Journal of Biological Chemistry·Yoshihisa HagiharaNoboru Yumoto
Jul 20, 2005·Pharmaceutical Research·Gary D PipesGerd R Kleemann
Oct 13, 2007·The Journal of Biological Chemistry·Yoshihisa HagiharaKoichi Uegaki
Nov 30, 2007·The Journal of Biological Chemistry·Pierre A BarthelemySachdev S Sidhu
Oct 1, 2008·Journal of Pharmaceutical Sciences·Hanns-Christian MahlerSylvia Kiese
May 13, 2009·Proteins·Koichi MatsuoKunihiko Gekko
Aug 20, 2009·Journal of Pharmaceutical Sciences·Stephen R BrychMasazumi Matsumura
Jan 13, 2010·MAbs·Xiaoling WangSandeep Kumar
Nov 16, 2011·The Journal of Biological Chemistry·Ramil F LatypovDingjiang Liu
Jun 30, 2012·Proceedings of the National Academy of Sciences of the United States of America·Kip DudgeonDaniel Christ
May 18, 2013·Biophysics Reviews·Peter Schuck
Dec 3, 2014·Journal of Molecular Biology·Pietro SormanniMichele Vendruscolo
Citations
Dec 24, 2015·Drug Testing and Analysis·Pavel PostnikovGrigory Rodchenkov
Oct 18, 2018·The Journal of Biological Chemistry·Fang ZengRui Gong
Aug 16, 2017·Scientific Reports·Pietro SormanniBojana Popovic
Jan 30, 2018·Frontiers in Immunology·Chunpeng YangRui Gong