title: Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies.
abstract: Therapeutic antibodies continue to develop as an emerging drug class, with a need for preclinical tools to better predict in vivo characteristics. Transgenic mice expressing human neonatal Fc receptor (hFcRn) have potential as a preclinical pharmacokinetic (PK) model to project human PK of monoclonal antibodies (mAbs). Using a panel of 27 mAbs with a broad PK range, we sought to characterize and establish utility of this preclinical animal model and provide guidance for its application in drug development of mAbs. This set of mAbs was administered to both hemizygous and homozygous hFcRn transgenic mice (Tg32) at a single intravenous dose, and PK parameters were derived. Higher hFcRn protein tissue expression was confirmed by liquid chromatography-high resolution tandem mass spectrometry in Tg32 homozygous versus hemizygous mice. Clearance (CL) was calculated using non-compartmental analysis and correlations were assessed to historical data in wild-type mouse, non-human primate (NHP), and human. Results show that mAb CL in hFcRn Tg32 homozygous mouse correlate with human (r(2) = 0.83, r = 0.91, p < 0.01) better than NHP (r(2) = 0.67, r = 0.82, p < 0.01) for this dataset. Applying simple allometric scaling using an empirically derived best-fit exponent of 0.93 enabled the prediction of human CL from the Tg32 homozygous mouse within 2-fold error for 100% of mAbs tested. Implementing the Tg32 homozygous mouse model in discovery and preclinical drug development to predict human CL may result in an overall decreased usage of monkeys for PK studies, enhancement of the early selection of lead molecules, and ultimately a decrease in the time for a drug candidate to reach the clinic.
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Andover , MA , USA.
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Avery
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Andover , MA , USA.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Wang
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Andover , MA , USA.
authors.forename: Mania S
authors.initials: MS
authors.lastname: Kavosi
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Andover , MA , USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Joyce
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Andover , MA , USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Kurz
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Andover , MA , USA.
authors.forename: Yao-Yun
authors.initials: YY
authors.lastname: Fan
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Andover , MA , USA.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Dowty
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Andover , MA , USA.
authors.forename: Minlei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Andover , MA , USA.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: b Pharmaceutical Sciences Analytical R&D, Pfizer Inc. , Andover , MA , USA.
authors.forename: Aili
authors.initials: A
authors.lastname: Cheng
authors.affiliation: c PharmaTherapeutics Clinical R&D, Pfizer Inc. , Technology Square, Cambridge , MA , USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Hua
authors.affiliation: d Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Andover , MA , USA.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Neubert
authors.affiliation: d Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Polzer
authors.affiliation: a Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Andover , MA , USA.
authors.forename: Denise M
authors.initials: DM
authors.lastname: O'Hara
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D055808:Drug Discovery / Q000379:methods*; D057898:Hemizygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D011237:Predictive Value of Tests; D011961:Receptors, Fc / Q000235:genetics*; D053719:Tandem Mass Spectrometry
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; C100688:Fc receptor, neonatal
keywords: Allometric scaling; FcRn; Human PK prediction; IgG; Neonatal Fc Receptor; PK; clearance; hFcRn transgenic mice; mAb; monoclonal antibody; pharmacokinetics