title: Application of human FcRn transgenic mice as a pharmacokinetic screening tool of monoclonal antibody.
abstract: 1. For drug discovery, useful screening tools are essential to select superior candidates. Here, we evaluated the applicability of transgenic mice expressing human neonatal Fc receptor (FcRn) (hFcRn Tgm) as a pharmacokinetic screening tool of therapeutic monoclonal antibodies (mAbs) and Fc-fusion proteins that overcomes the species difference in FcRn binding. 2. Marketed 11 mAbs and 2 Fc-fusion proteins were intravenously administered to hFcRn Tgm and WT mice. The half-lives in hFcRn Tgm and WT mice were compared with those in human obtained from literature. The linear half-lives in human and monkey were also calculated by nonlinear pharmacokinetic analysis. For comparison, correlations of half-lives between monkey and human were also evaluated. 3. The half-lives of mAbs and Fc-fusion proteins after intravenous administration ranged from 1.1 to 13.2 days in hFcRn Tgm and from 1.2 to 30.3 days in WT mice. The half-lives in human correlated more closely with those in hFcRn Tgm than in WT mice and monkey. 4. Our results suggest that hFcRn Tgm are a valuable and useful tool for pharmacokinetic screening of mAbs and Fc-fusion proteins in the preclinical stage. Furthermore, we believe that hFcRn Tgm are broadly applicable to preclinical pharmacokinetic screening of mAbs-based therapeutics.
authors.affiliation: Chugai Pharmabody Research Pte. Ltd. , Singapore and.
authors.forename: Kenta
authors.initials: K
authors.lastname: Haraya
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tachibana
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nanami
authors.forename: Masaki
authors.initials: M
authors.lastname: Ishigai
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000882:Haplorhini; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins; D013045:Species Specificity
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; D011994:Recombinant Proteins; C100688:Fc receptor, neonatal
keywords: FcRn; monoclonal antibody; preclinical pharmacokinetic screening; transgenic mice