title: IgG2m4, an engineered antibody isotype with reduced Fc function.
abstract: The Fc region of an antibody mediates effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and plays a key role in the in vivo half-life of an antibody. In designing antibody therapeutics, it is sometimes desirable that the antibody has altered Fc-mediated properties. In the case of a "benign blocker" antibody, it is often desirable to diminish or abolish the ADCC and CDC functions while retaining its PK profile. Here, we report a novel engineered IgG isotype, IgG2m4, with reduced Fc functionality. IgG2m4 is based on the IgG2 isotype with four key amino acid residue changes derived from IgG4 (H268Q, V309L, A330S and P331S). An IgG2m4 antibody has an overall reduction in complement and Fc gamma receptor binding in in vitro binding analyses while maintaining the normal in vivo serum half-life in rhesus.
authors.affiliation: Department of Biologics Research, West Point, PA, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: An
authors.forename: Gail
authors.initials: G
authors.lastname: Forrest
authors.forename: Renee
authors.initials: R
authors.lastname: Moore
authors.forename: Michael
authors.initials: M
authors.lastname: Cukan
authors.forename: Peter
authors.initials: P
authors.lastname: Haytko
authors.forename: Lingyi
authors.initials: L
authors.lastname: Huang
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vitelli
authors.forename: Jing Zhang
authors.initials: JZ
authors.lastname: Zhao
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.forename: Jin
authors.initials: J
authors.lastname: Hua
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gibson
authors.forename: Barrett R
authors.initials: BR
authors.lastname: Harvey
authors.forename: Donna
authors.initials: D
authors.lastname: Montgomery
authors.forename: Dennis
authors.initials: D
authors.lastname: Zaller
authors.forename: Fubao
authors.initials: F
authors.lastname: Wang
authors.forename: William
authors.initials: W
authors.lastname: Strohl
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics / Q000276:immunology; D015922:Complement C1q / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006224:Cricetinae; D006207:Half-Life; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D015202:Protein Engineering; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D017452:Receptors, IgG; D015922:Complement C1q; C481642:eculizumab