Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn).
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.
Dall'Acqua
William F
WF
Department of Antibody Discovery and Protein Engineering, MedImmune, Inc., Gaithersburg, Maryland 20878, USA. dall'acquaw@medimmune.com
Kiener
Peter A
PA
Wu
Herren
H
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
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