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Allosteric Effects between the Antibody Constant and Variable Regions: A Study of IgA Fc Mutations on Antigen Binding

1
Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore
2
p53 Laboratory, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
*
Author to whom correspondence should be addressed.
Authors equally contributed to the work.
Antibodies 2018, 7(2), 20; https://doi.org/10.3390/antib7020020
Received: 14 May 2018 / Revised: 2 June 2018 / Accepted: 5 June 2018 / Published: 7 June 2018
(This article belongs to the Collection Computational Antibody and Antigen Design)
Therapeutic antibodies have shifted the paradigm of disease treatments from small molecules to biologics, especially in cancer therapy. Despite the increasing number of antibody candidates, much remains unknown about the antibody and how its various regions interact. Recent findings showed that the antibody constant region can govern localization effects that are useful in reducing side effects due to systemic circulation by the commonly used IgG isotypes. Given their localized mucosal effects, IgA antibodies are increasingly promising therapeutic biologics. While the antibody Fc effector cell activity has been a focus point, recent research showed that the Fc could also influence antigen binding, challenging the conventional idea of region-specific antibody functions. To investigate this, we analysed the IgA antibody constant region and its distal effects on the antigen binding regions using recombinant Pertuzumab IgA1 and IgA2 variants. We found that mutations in the C-region reduced Her2 binding experimentally, and computational structural analysis showed that allosteric communications were highly dependent on the antibody hinge, providing strong evidence that we should consider antibodies as whole proteins rather than a sum of functional regions. View Full-Text
Keywords: antibody; isotype IgA; Pertuzumab; allosteric; biologics; constant region; variable region antibody; isotype IgA; Pertuzumab; allosteric; biologics; constant region; variable region
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Su, C.T.-T.; Lua, W.-H.; Ling, W.-L.; Gan, S.K.-E. Allosteric Effects between the Antibody Constant and Variable Regions: A Study of IgA Fc Mutations on Antigen Binding. Antibodies 2018, 7, 20.

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