Fully Human VH Single Domains That Rival the Stability and Cleft Recognition of Camelid Antibodies.

The Journal of Biological Chemistry
Romain RouetDaniel Christ

Abstract

Human VH single domains represent a promising class of antibody fragments with applications as therapeutic modalities. Unfortunately, isolated human VH domains also generally display poor biophysical properties and a propensity to aggregate. This has encouraged the development of non-human antibody domains as alternative means of antigen recognition and, in particular, camelid (VHH) domains. Naturally devoid of light chain partners, these domains are characterized by favorable biophysical properties and propensity for cleft binding, a highly desirable characteristic, allowing the targeting of cryptic epitopes. In contrast, previously reported structures of human VH single domains had failed to recapitulate this property. Here we report the engineering and characterization of phage display libraries of stable human VH domains and the selection of binders against a diverse set of antigens. Unlike "camelized" human domains, the domains do not rely on potentially immunogenic framework mutations and maintain the structure of the VH/VL interface. Structure determination in complex with hen egg white lysozyme revealed an extended VH binding interface, with complementarity-determining region 3 deeply penetrating into the active site cl...Continue Reading

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Citations

Mar 31, 2017·Proceedings of the National Academy of Sciences of the United States of America·Romain RouetDaniel Christ
Jan 25, 2017·Journal of Structural Biology·Roberta B DaviesAlastair G Stewart
Jul 1, 2017·PLoS Pathogens·María Victoria HumbertMyron Christodoulides
Aug 23, 2016·F1000Research·Shane Miersch, Sachdev S Sidhu
Mar 1, 2019·Current Allergy and Asthma Reports·Geoffrey A MuellerLars C Pedersen
Apr 25, 2018·Nature Chemistry·Mahdi ZeraatiDaniel Christ
Sep 16, 2017·Angewandte Chemie·Dominik SchumacherChristian P R Hackenberger
Feb 2, 2020·Scientific Reports·Anne LjungarsMikael Mattsson
Jan 23, 2019·Frontiers in Immunology·Starlynn C ClarkeShelley Force Aldred
Sep 29, 2020·Frontiers in Immunology·Anna PomésMaksymilian Chruszcz
Oct 22, 2020·Nature Chemical Biology·Colton J BrackenJames A Wells
Dec 21, 2020·Protein Engineering, Design & Selection : PEDS·Alexander M SevyChung-Ming Hsieh
Apr 12, 2021·European Biophysics Journal : EBJ·Holly L BirchenoughThomas A Jowitt
May 16, 2021·Protein Engineering, Design & Selection : PEDS·Kasandra Bélanger, Jamshid Tanha
Jul 3, 2021·Viruses·Esen SokulluBenoit Coulombe

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