title: Humanized FcRn mouse models for evaluating pharmacokinetics of human IgG antibodies.
abstract: A key element for the successful development of novel therapeutic antibodies is to fully understand their pharmacokinetic and pharmacodynamic behavior before performing clinical trials. While many in vitro modeling approaches exist, these simply cannot substitute for data obtained from appropriate animal models. It was established quite early that the unusual long serum half-life of immunoglobulin G's (IgGs) and Fc domains are due to their rescue and recycling by the neonatal Fc receptor (FcRn). The diverse roles of FcRn became apparent after isolation and cloning. Interesting are the significant species differences between rodent and human FcRn reactivity, rendering wild type rodents an inadequate model for studying IgG serum half-life. With the advance of genetic engineering mouse models have been established expressing human FcRn, and lacking mouse FcRn protein. These models have become highly relevant tools for serum half-life analysis of Fc-containing compounds.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA. Electronic address: gproetzel@earthlink.net.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Proetzel
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA. Electronic address: Derry.Roopenian@jax.org.
authors.forename: Derry C
authors.initials: DC
authors.lastname: Roopenian
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000235:genetics / Q000493:pharmacokinetics*; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000494:pharmacology*; D008252:Macaca fascicularis; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D011961:Receptors, Fc / Q000096:biosynthesis* / Q000235:genetics; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D000068878:Trastuzumab; C100688:Fc receptor, neonatal
keywords: B2M; EGFR; ES; Efficacy; FCGRT; Fab; Fc; Fc receptor IgG alpha chain transporter; FcRn; HSA; Humanized mice; IP; IV; Ig; MDCK; MHC; MSA; Madin-Darby canine kidney; Monoclonal antibody; Neonatal Fc receptor; P; PK; Pharmacokinetics; Serum half-life; VEGF; beta-2-microglobulin; embryonic stem; epidermal growth factor receptor; fragment crystallizable; fragment of antigen binding; human serum albumin; immunoglobulin; intraperitoneal; intravenous; mAb; major histocompatibility complex; monoclonal antibody; mouse serum albumin; neonatal Fc receptor; pharmacokinetics; probability value; vascular endothelial growth factor