Mutational approaches to improve the biophysical properties of human single-domain antibodies

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DOIResolve DOI: http://doi.org/10.1016/j.bbapap.2014.07.008
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TypeArticle
Journal titleBiochimica et Biophysica Acta - Proteins and Proteomics
ISSN1570-9639
Volume1844
Issue11
Pages19832001; # of pages: 19
SubjectAggregation; Mutation; Single-domain antibody; Stability; VH; VL
AbstractMonoclonal antibodies are a remarkably successful class of therapeutics used to treat a wide range of indications. There has been growing interest in smaller antibody fragments such as Fabs, scFvs and domain antibodies in recent years. In particular, the development of human VH and VL single-domain antibody therapeutics, as stand-alone affinity reagents or as "warheads" for larger molecules, are favored over other sources of antibodies due to their perceived lack of immunogenicity in humans. However, unlike camelid heavy-chain antibody variable domains (VHHs) which almost unanimously resist aggregation and are highly stable, human VHs and VLs are prone to aggregation and exhibit poor solubility. Approaches to reduce VH and VL aggregation and increase solubility are therefore very active areas of research within the antibody engineering community. Here we extensively chronicle the various mutational approaches that have been applied to human VHs and VLs to improve their biophysical properties such as expression yield, thermal stability, reversible unfolding and aggregation resistance. In addition, we describe stages of the VH and VL development process where these mutations could best be implemented. This article is part of a Special Issue entitled: Recent advances in molecular engineering of antibody.
Publication date
PublisherElsevier
LanguageEnglish
AffiliationNational Research Council Canada; Human Health Therapeutics
Peer reviewedYes
NRC numberNRC-HHT-53236
NPARC number21272777
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Record identifierb4fa8836-fbba-4941-8e5e-301b44d5e52c
Record created2014-12-03
Record modified2016-05-09
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