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Isomerization of Asp-Asp motif in model peptides and a Monoclonal Antibody Fab Fragment.
MedLine Citation:
PMID:  23280575     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Isomerization of aspartyl (Asp or D) residues is a critical degradation route to consider for stable monoclonal antibody formulations. Among the known hotspot sequences, the DD motif is relatively understudied. To gain mechanistic insights, we used model hexapeptides, YADXFK, YADDXK, and DIDDDM, as surrogates for the hotspots in a Fab protein (YADDFK and DIDDDM), to characterize the rate-pH profile of Asp isomerization. Compared with the YADGFK peptide, isomerization of D3 (the first D in the DD pair) in YADDFK was highly pH dependent. Comparison of rate-pH profiles of YADDFK, YADNFK, and YADHFK revealed a charge effect of the n + 1 residue-isomerization rate is accelerated by the positive side chain and reduced by negative side chain at n + 1 residue. Studies on YADDFK, YADDAK, and YADDGK indicated a mutual impact of D3 and D4 on their respective isomerization rates through charge effect. Comparison of rate-pH profile of DIDDDM sequence in peptide models with that in the complementary determining region of the Fab showed a faster rate in the Fab than in peptides, presumably because of contribution from structural factors in the former. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
Authors:
Li Yi; Nia Beckley; Benson Gikanga; Jennifer Zhang; Y John Wang; Hung-Wei Chih; Vikas K Sharma
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-12-20
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  -     ISSN:  1520-6017     ISO Abbreviation:  J Pharm Sci     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2013-1-2     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:
Early Stage Pharmaceutical Development, Genentech, South San Francisco, California 94080. yi.li@gene.com.
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