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Local dynamics and their alteration by excipients modulate the global conformational stability of an igg1 monoclonal antibody.
MedLine Citation:
PMID:  23060088     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
A molecular understanding of excipient effects on the interrelationship(s) between dynamics and conformational stability of proteins, such as monoclonal antibodies (mAbs), can be important for their pharmaceutical development. The current study examines stabilizing and destabilizing effects of excipients on the conformational stability and local dynamics of distinct solvent-exposed regions within an IgG1 monoclonal antibody (mAb-B). The principles of site-selective photoselection upon red-edge excitation, accompanied by acrylamide quenching of tryptophan fluorescence were employed in this study. The initiation of mAb-B thermal unfolding occurs by structural alterations in the more solvent-exposed regions of the antibody, which subsequently leads to a cascade of structural alterations in its relatively more solvent-shielded regions. In addition, an increase in internal dynamics of solvent-shielded regions made mAb-B more susceptible to thermally induced structural perturbations resulting in its global destabilization. Sucrose and arginine exert their stabilizing and destabilizing effects by predominantly influencing the conformational stability of solvent-exposed regions in mAb-B. The complex molecular effects of sucrose and arginine on local dynamics of different regions in mAb-B and their correlation with the protein's conformational stability are described within the pretransition range, at the onset temperature (T(onset) ) and at the thermal melting temperature (T(M) ). © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
Authors:
Santosh V Thakkar; Jae Hyun Kim; Hardeep S Samra; Hasige A Sathish; Steven M Bishop; Sangeeta B Joshi; David B Volkin; C Russell Middaugh
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-11
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  -     ISSN:  1520-6017     ISO Abbreviation:  J Pharm Sci     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
Affiliation:
Department of Pharmaceutical Chemistry, Macromolecule and Vaccine Stabilization Center, University of Kansas, Lawrence, Kansas 66047.
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