Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies.
The MHC class I-related receptor, neonatal Fc receptor (FcRn), plays a central role in regulating the transport and in vivo persistence of immunoglobulin G (IgG). IgG-FcRn interactions can be targeted for engineering to modulate the in vivo longevity and transport of an antibody, and this has implications for the successful application of therapeutic IgGs. Although mice are widely used to preclinically test antibodies, human and mouse FcRn have significant differences in binding specificity. Here we show that an engineered human IgG1 has disparate properties in murine and human systems. The mutant shows improved transport relative to wild-type human IgG1 in assays of human FcRn function but has short in vivo persistence and competitively inhibits FcRn activity in mice. These studies indicate potential limitations of using mice as preclinical models for the analysis of engineered antibodies. Alternative assays are proposed that serve as indicators of the properties of IgGs in humans.
Vaccaro
Carlos
C
Center for Immunology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9093, USA.
Bawdon
Roger
R
Wanjie
Sylvia
S
Ober
Raimund J
RJ
Ward
E Sally
ES
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001666:Binding Sites, Antibody; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D015202:Protein Engineering; D011961:Receptors, Fc / Q000276:immunology / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C100688:Fc receptor, neonatal