title: IgGA: a "cross-isotype" engineered human Fc antibody domain that displays both IgG-like and IgA-like effector functions.
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.
authors.affiliation: Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: William
authors.initials: W
authors.lastname: Kelton
authors.affiliation: Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Nishant
authors.initials: N
authors.lastname: Mehta
authors.affiliation: Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Wissam
authors.initials: W
authors.lastname: Charab
authors.affiliation: Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Chang-han
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Biotechnology, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Kang
authors.affiliation: 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: gg@che.utexas.edu.
authors.forename: George
authors.initials: G
authors.lastname: Georgiou
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D003165:Complement System Proteins / Q000378:metabolism; D003429:Cross Reactions; D006801:Humans; D007070:Immunoglobulin A / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000276:immunology; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D011961:Receptors, Fc / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism
chemical_list: C080568:Fc gamma receptor IIA; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D011961:Receptors, Fc; D017452:Receptors, IgG; D003165:Complement System Proteins