title: Correlations between pharmacokinetics of IgG antibodies in primates vs. FcRn-transgenic mice reveal a rodent model with predictive capabilities.
abstract: Transgenic mice expressing human neonatal Fc receptor (FcRn) instead of mouse FcRn are available for IgG antibody pharmacokinetic (PK) studies. Given the interest in a rodent model that offers reliable predictions of antibody PK in monkeys and humans, we set out to test whether the PK of IgG antibodies in such mice correlated with the PK of the same antibodies in primates. We began by using a single research antibody to study the influence of: (1) different transgenic mouse lines that differ in FcRn transgene expression; (2) homozygous vs. hemizygous FcRn transgenic mice; (3) the presence vs. absence of coinjected high-dose human intravenous immunoglobulin (IVIG), and (4) the presence vs. absence of coinjected high-dose human serum albumin (HSA). Results of those studies suggested that use of hemizygous Tg32 mice (Tg32 hemi) not treated with IVIG or HSA offered potential as a predictive model for PK in humans. Mouse PK studies were then done under those conditions with a panel of test antibodies whose PK in mice and primates is not significantly affected by target binding, and for which monkey or human PK data were readily available. Results from the studies revealed significant correlations between terminal half-life or clearance values observed in the mice and the corresponding values reported in humans. A significant relationship in clearance values between mice and monkeys was also observed. These correlations suggest that the Tg32 hemi mouse model, which is both convenient and cost-effective, can offer value in predicting antibody half-life and clearance in primates.
authors.affiliation: Biologics Research; Janssen Research & Development, LLC; Spring House, PA USA.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Tam
authors.affiliation: Biologics Research; Janssen Research & Development, LLC; Spring House, PA USA.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: McCarthy
authors.affiliation: Biologics Toxicology; Janssen Research & Development, LLC; Spring House, PA USA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Brosnan
authors.affiliation: Nonclinical Statistics & Computing; Janssen Research & Development, LLC; Spring House, PA USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Goldberg
authors.affiliation: Biologics Research; Janssen Research & Development, LLC; Spring House, PA USA.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Scallon
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D005260:Female; D006207:Half-Life; D000882:Haplorhini; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage*; D007074:Immunoglobulin G / Q000008:administration & dosage*; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage; D008657:Metabolic Clearance Rate / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011237:Predictive Value of Tests; D011961:Receptors, Fc / Q000235:genetics*; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D012709:Serum Albumin / Q000008:administration & dosage; D014760:Viral Fusion Proteins / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D011961:Receptors, Fc; D012709:Serum Albumin; D014760:Viral Fusion Proteins; C100688:Fc receptor, neonatal
keywords: FcRn; HSA; IVIG; PK; Tg276; Tg32; antibody; correlations; primates; transgenic mice
references.citation: J Immunol. 2003 Apr 1;170(7):3528-33
references.pmid: 12646614
references.citation: Drug Metab Pharmacokinet. 2009;24(4):318-32
references.pmid: 19745559
references.citation: Drug Metab Dispos. 2011 Sep;39(9):1469-77
references.pmid: 21610128
references.citation: J Biol Chem. 2001 Mar 2;276(9):6591-604
references.pmid: 11096108
references.citation: Drug Metab Dispos. 2007 Jan;35(1):86-94
references.pmid: 17050651
references.citation: J Clin Pharmacol. 2009 Dec;49(12):1382-402
references.pmid: 19837907
references.citation: Int Immunol. 2001 Dec;13(12):1551-9
references.pmid: 11717196
references.citation: Clin Pharmacokinet. 2010 Aug;49(8):493-507
references.pmid: 20608753
references.citation: Int Immunol. 2006 Dec;18(12):1759-69
references.pmid: 17077181
references.citation: Biochemistry. 2006 Apr 18;45(15):4983-90
references.pmid: 16605266
references.citation: Clin Exp Immunol. 1969 Jan;4(1):101-12
references.pmid: 4182354
references.citation: Ther Deliv. 2011 Mar;2(3):359-68
references.pmid: 22834006
references.citation: Nat Rev Immunol. 2007 Sep;7(9):715-25
references.pmid: 17703228
references.citation: J Immunol. 2006 Jan 1;176(1):346-56
references.pmid: 16365427
references.citation: Immunol Today. 1997 Dec;18(12):592-8
references.pmid: 9425738
references.citation: Mamm Genome. 2012 Apr;23(3-4):259-69
references.pmid: 22193411
references.citation: Clin Pharmacol Ther. 1996 Jun;59(6):662-7
references.pmid: 8681491
references.citation: J Pharm Biomed Anal. 2009 May 1;49(4):1003-8
references.pmid: 19250787
references.citation: J Exp Med. 2003 Feb 3;197(3):315-22
references.pmid: 12566415