Structure-based prediction of asparagine and aspartate degradation sites in antibody variable regions.
Monoclonal antibodies (mAbs) and proteins containing antibody domains are the most prevalent class of biotherapeutics in diverse indication areas. Today, established techniques such as immunization or phage display allow for an efficient generation of new mAbs. Besides functional properties, the sta...
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doaj-a05b1f718abd4f5d89a334e9fb4d432c2020-11-25T02:51:55ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0196e10073610.1371/journal.pone.0100736Structure-based prediction of asparagine and aspartate degradation sites in antibody variable regions.Jasmin F SydowFlorian LipsmeierVincent LarrailletMaximiliane HilgerBjoern MautzMichael MølhøjJan KuentzerStefan KlostermannJuergen SchochHans R VoelgerJoerg T RegulaPatrick CramerApollon PapadimitriouHubert KettenbergerMonoclonal antibodies (mAbs) and proteins containing antibody domains are the most prevalent class of biotherapeutics in diverse indication areas. Today, established techniques such as immunization or phage display allow for an efficient generation of new mAbs. Besides functional properties, the stability of future therapeutic mAbs is a key selection criterion which is essential for the development of a drug candidate into a marketed product. Therapeutic proteins may degrade via asparagine (Asn) deamidation and aspartate (Asp) isomerization, but the factors responsible for such degradation remain poorly understood. We studied the structural properties of a large, uniform dataset of Asn and Asp residues in the variable domains of antibodies. Their structural parameters were correlated with the degradation propensities measured by mass spectrometry. We show that degradation hotspots can be characterized by their conformational flexibility, the size of the C-terminally flanking amino acid residue, and secondary structural parameters. From these results we derive an accurate in silico prediction method for the degradation propensity of both Asn and Asp residues in the complementarity-determining regions (CDRs) of mAbs.http://europepmc.org/articles/PMC4069079?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jasmin F Sydow Florian Lipsmeier Vincent Larraillet Maximiliane Hilger Bjoern Mautz Michael Mølhøj Jan Kuentzer Stefan Klostermann Juergen Schoch Hans R Voelger Joerg T Regula Patrick Cramer Apollon Papadimitriou Hubert Kettenberger |
spellingShingle |
Jasmin F Sydow Florian Lipsmeier Vincent Larraillet Maximiliane Hilger Bjoern Mautz Michael Mølhøj Jan Kuentzer Stefan Klostermann Juergen Schoch Hans R Voelger Joerg T Regula Patrick Cramer Apollon Papadimitriou Hubert Kettenberger Structure-based prediction of asparagine and aspartate degradation sites in antibody variable regions. PLoS ONE |
author_facet |
Jasmin F Sydow Florian Lipsmeier Vincent Larraillet Maximiliane Hilger Bjoern Mautz Michael Mølhøj Jan Kuentzer Stefan Klostermann Juergen Schoch Hans R Voelger Joerg T Regula Patrick Cramer Apollon Papadimitriou Hubert Kettenberger |
author_sort |
Jasmin F Sydow |
title |
Structure-based prediction of asparagine and aspartate degradation sites in antibody variable regions. |
title_short |
Structure-based prediction of asparagine and aspartate degradation sites in antibody variable regions. |
title_full |
Structure-based prediction of asparagine and aspartate degradation sites in antibody variable regions. |
title_fullStr |
Structure-based prediction of asparagine and aspartate degradation sites in antibody variable regions. |
title_full_unstemmed |
Structure-based prediction of asparagine and aspartate degradation sites in antibody variable regions. |
title_sort |
structure-based prediction of asparagine and aspartate degradation sites in antibody variable regions. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
Monoclonal antibodies (mAbs) and proteins containing antibody domains are the most prevalent class of biotherapeutics in diverse indication areas. Today, established techniques such as immunization or phage display allow for an efficient generation of new mAbs. Besides functional properties, the stability of future therapeutic mAbs is a key selection criterion which is essential for the development of a drug candidate into a marketed product. Therapeutic proteins may degrade via asparagine (Asn) deamidation and aspartate (Asp) isomerization, but the factors responsible for such degradation remain poorly understood. We studied the structural properties of a large, uniform dataset of Asn and Asp residues in the variable domains of antibodies. Their structural parameters were correlated with the degradation propensities measured by mass spectrometry. We show that degradation hotspots can be characterized by their conformational flexibility, the size of the C-terminally flanking amino acid residue, and secondary structural parameters. From these results we derive an accurate in silico prediction method for the degradation propensity of both Asn and Asp residues in the complementarity-determining regions (CDRs) of mAbs. |
url |
http://europepmc.org/articles/PMC4069079?pdf=render |
work_keys_str_mv |
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