title: Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR.
abstract: The neonatal FcR (FcRn) binds to the Fc domain of IgG at acidic pH in the endosome and protects IgG from degradation, thereby contributing to the long serum half-life of IgG. To date, more than 20 mAb products and 5 Fc-fusion protein products have received marketing authorization approval in the United States, the European Union, or Japan. Many of these therapeutic proteins have the Fc domain of human IgG1; however, the serum half-lives differ in each protein. To elucidate the role of FcRn in the pharmacokinetics of Fc domain-containing therapeutic proteins, we evaluated the affinity of the clinically used human, humanized, chimeric, or mouse mAbs and Fc-fusion proteins to recombinant human FcRn by surface plasmon resonance analysis. The affinities of these therapeutic proteins to FcRn were found to be closely correlated with the serum half-lives reported from clinical studies, suggesting the important role of FcRn in regulating their serum half-lives. The relatively short serum half-life of Fc-fusion proteins was thought to arise from the low affinity to FcRn. The existence of some mAbs having high affinity to FcRn and a short serum half-life, however, suggested the involvement of other critical factor(s) in determining the serum half-life of such Abs. We further investigated the reason for the relatively low affinity of Fc-fusion proteins to FcRn and suggested the possibility that the receptor domain of Fc-fusion protein influences the structural environment of the FcRn binding region but not of the FcgammaRI binding region of the Fc domain.
authors.affiliation: Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Suzuki
authors.forename: Akiko
authors.initials: A
authors.lastname: Ishii-Watabe
authors.forename: Minoru
authors.initials: M
authors.lastname: Tada
authors.forename: Tetsu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Toshie
authors.initials: T
authors.lastname: Kanayasu-Toyoda
authors.forename: Toru
authors.initials: T
authors.lastname: Kawanishi
authors.forename: Teruhide
authors.initials: T
authors.lastname: Yamaguchi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000627:therapeutic use; D000915:Antibody Affinity / Q000276:immunology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D007074:Immunoglobulin G / Q000097:blood / Q000627:therapeutic use*; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011961:Receptors, Fc / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; C100688:Fc receptor, neonatal