title: Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn).
abstract: We describe here the functional implications of an increase in IgG binding to the neonatal Fc receptor. We have defined in a systematic fashion the relationship between enhanced FcRn binding of a humanized anti-respiratory syncytial virus (RSV) monoclonal antibody (MEDI-524) and the corresponding biological consequences in cynomolgus monkeys. The triple mutation M252Y/S254T/T256E (YTE) was introduced into the Fc portion of MEDI-524. Whereas these substitutions did not affect the ability of MEDI-524 to bind to its cognate antigen and inhibit RSV replication, they resulted in a 10-fold increase in its binding to both cynomolgus monkey and human FcRn at pH 6.0. MEDI-524-YTE was efficiently released from FcRn at pH 7.4 in both cases. We show that MEDI-524-YTE consistently exhibited a nearly 4-fold increase in serum half-life in cynomolgus monkeys when compared with MEDI-524. This constituted the largest half-life improvement described to date for an IgG in a primate. For the first time, we demonstrate that these sustained serum levels resulted in an up to 4-fold increase in lung bioavailability. Importantly, we also establish that our non-human primate model is relevant to human. Finally, we report that the YTE triple substitution provided a means to modulate the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of a humanized IgG1 directed against the human integrin alpha(v)beta3. Therefore, the YTE substitutions allow the simultaneous modulation of serum half-life, tissue distribution and activity of a given human IgG1.
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune, Inc., Gaithersburg, Maryland 20878, USA. dall'acquaw@medimmune.com
authors.forename: William F
authors.initials: WF
authors.lastname: Dall'Acqua
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kiener
authors.forename: Herren
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D061067:Antibodies, Monoclonal, Humanized; D000916:Antibody Diversity; D000920:Antibody-Dependent Cell Cytotoxicity; D001666:Binding Sites, Antibody; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D008252:Macaca fascicularis; D009928:Organ Specificity; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods; D011961:Receptors, Fc / Q000097:blood / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C496124:FCGR3A protein, human; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D017452:Receptors, IgG; C506968:motavizumab; C100688:Fc receptor, neonatal