IgGA: a "cross-isotype" engineered human Fc antibody domain that displays both IgG-like and IgA-like effector functions

William Kelton; Nishant Mehta; Wissam Charab; Jiwon Lee; Chang-han Lee; Takaaki Kojima; Tae Hyun Kang; George Georgiou

doi:10.1016/j.chembiol.2014.10.017

IgGA: a "cross-isotype" engineered human Fc antibody domain that displays both IgG-like and IgA-like effector functions

Chem Biol. 2014 Dec 18;21(12):1603-9. doi: 10.1016/j.chembiol.2014.10.017. Epub 2014 Dec 11.

Authors

William Kelton¹, Nishant Mehta², Wissam Charab¹, Jiwon Lee¹, Chang-han Lee¹, Takaaki Kojima³, Tae Hyun Kang², George Georgiou⁴

Affiliations

¹ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
² Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
³ Laboratory of Molecular Biotechnology, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
⁴ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA; Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA; Section of Molecular Genetics and Microbiology, University of Texas at Austin, Austin, TX 78712, USA; Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA. Electronic address: [email protected].

PMID: 25500223
DOI: 10.1016/j.chembiol.2014.10.017

Abstract

All clinically approved antibodies are of the IgG isotype and mediate the clearance of target cells via binding to Fcγ receptors and complement (C1q). Even though IgA can elicit powerful cytotoxic action via FcαRI receptor binding, IgA antibodies have not been amenable to therapeutic development. Here, we report the engineering of a "cross-isotype" antibody, IgGA, which combines the effector functions of both IgG and IgA. IgGA binds to FcαRI with an affinity comparable to that of IgA, and to the activating Fcγ receptors, FcγRI and FcγRIIa, with high affinity, and displays increased binding to C1q compared to IgG. Unlike trastuzumab-IgG, trastuzumab-IgGA potently activates both neutrophils and macrophages to kill Her2(+) cancer cells. Furthermore, IgGA mediates greater complement-dependent cytotoxicity than IgG1 or IgA antibodies. The multitude of IgGA effector functions could be important for therapeutic purposes and highlights the concept of engineering antibodies that combine effector functions from multiple antibody isotypes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Cell Line, Tumor
Complement System Proteins / metabolism
Cross Reactions*
Humans
Immunoglobulin A / chemistry
Immunoglobulin A / genetics
Immunoglobulin A / immunology*
Immunoglobulin A / metabolism*
Immunoglobulin G / chemistry
Immunoglobulin G / genetics
Immunoglobulin G / immunology*
Immunoglobulin G / metabolism*
Models, Molecular
Molecular Sequence Data
Neutrophils / immunology
Protein Engineering*
Protein Structure, Tertiary
Receptors, Fc / metabolism*
Receptors, IgG / metabolism

Substances

Fc gamma receptor IIA
Immunoglobulin A
Immunoglobulin G
Receptors, Fc
Receptors, IgG
Complement System Proteins