Preprint Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 14 May 2018 / Approved: 15 May 2018 / Online: 15 May 2018 (07:51:15 CEST)

A peer-reviewed article of this Preprint also exists.

Su, C. .-T.; Lua, W.-H.; Ling, W.-L.; Gan, S. .-E. Allosteric Effects between the Antibody Constant and Variable Regions: A Study of IgA Fc Mutations on Antigen Binding. Antibodies 2018, 7, 20. Su, C. .-T.; Lua, W.-H.; Ling, W.-L.; Gan, S. .-E. Allosteric Effects between the Antibody Constant and Variable Regions: A Study of IgA Fc Mutations on Antigen Binding. Antibodies 2018, 7, 20.

Journal reference: Antibodies 2018, 7, 20
DOI: 10.3390/antib7020020

Abstract

Therapeutics antibodies have increasingly 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. In fact, the constant region can govern effects that might be useful in reducing the unwanted consequences resulted from systemic circulation. For this reason, apart from the commonly used IgG isotypes, IgA antibodies are promising therapeutics drugs, given its localized mucosal effects. While the antibody Fc effector cell activity has been well explored, recent research has shown evidences that the constant region of the antibody can also influence antigen binding, challenging the conventional idea of region-specific antibody functions. To further investigate this, we analyzed the IgA antibody constant and its allosteric effects onto the antigen binding regions, using recombinant Pertuzumab IgA1 and IgA2 variants. We found mutations in the C-region to reduce Her2 binding, and our computational structural analysis showed that such allosteric communications were highly dependent on the antibody hinge, providing the evidence to consider antibodies as a whole protein rather than a sum of functional regions.

Subject Areas

antibody; Isotype IgA; Pertuzumab; allosteric; biologics; constant region; variable region

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