دورية أكاديمية
The impact of proline isomerization on antigen binding and the analytical profile of a trispecific anti-HIV antibody
العنوان: | The impact of proline isomerization on antigen binding and the analytical profile of a trispecific anti-HIV antibody |
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المؤلفون: | Alessandro Masiero, Lechat Nelly, Gentric Marianne, Sourrouille Christophe, Laville Florian, Crépin Ronan, Borel Claire, Ziegler Cornelia, Bisch Grégoire, Leclerc Eric, Laurent Ludovic, Brault Dominique, Alexandre Sylvie, Gagnaire Marie, Duffieux Francis, Soubrier Fabienne, Capdevila Cécile, Arnould Isabelle, Dumas Jacques, Dabin Jérôme, Genet Bruno, Radošević Katarina, Menet Jean-Michel, Prades Catherine |
المصدر: | mAbs, Vol 12, Iss 1 (2020) |
بيانات النشر: | Taylor & Francis Group, 2020. |
سنة النشر: | 2020 |
المجموعة: | LCC:Therapeutics. Pharmacology LCC:Immunologic diseases. Allergy |
مصطلحات موضوعية: | Proline isomerization, antibody conformers, chemical equilibrium, developability, Therapeutics. Pharmacology, RM1-950, Immunologic diseases. Allergy, RC581-607 |
الوصف: | Proline cis-trans conformational isomerization is a mechanism that affects different types of protein functions and behaviors. Using analytical characterization, structural analysis, and molecular dynamics simulations, we studied the causes of an aberrant two-peak size-exclusion chromatography profile observed for a trispecific anti-HIV antibody. We found that proline isomerization in the tyrosine-proline-proline (YPP) motif in the heavy chain complementarity-determining region (CDR)3 domain of one of the antibody arms (10e8v4) was a component of this profile. The pH effect on the conformational equilibrium that led to these two populations was presumably caused by a histidine residue (H147) in the light chain that is in direct contact with the YPP motif. Finally, we demonstrated that, due to chemical equilibrium between the cis and trans proline conformers, the antigen-binding potency of the trispecific anti-HIV antibody was not significantly affected in spite of a potential structural clash of 10e8v4 YPtransPtrans conformers with the membrane-proximal ectodomain region epitope in the GP41 antigen. Altogether, these results reveal at mechanistic and molecular levels the effect of proline isomerization in the CDR on the antibody binding and analytical profiles, and support further development of the trispecific anti-HIV antibody. |
نوع الوثيقة: | article |
وصف الملف: | electronic resource |
اللغة: | English |
تدمد: | 19420862 1942-0870 1942-0862 |
Relation: | https://doaj.org/toc/1942-0862; https://doaj.org/toc/1942-0870 |
DOI: | 10.1080/19420862.2019.1698128 |
URL الوصول: | https://doaj.org/article/557558a041934ac8a558f2aca973256c |
رقم الأكسشن: | edsdoj.557558a041934ac8a558f2aca973256c |
قاعدة البيانات: | Directory of Open Access Journals |
تدمد: | 19420862 19420870 |
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DOI: | 10.1080/19420862.2019.1698128 |