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

• Published in: The Journal of immunology (1950) 2010-02, Vol.184 (4), p.1968-1976
• Main Authors: Suzuki, Takuo, Ishii-Watabe, Akiko, Tada, Minoru, Kobayashi, Tetsu, Kanayasu-Toyoda, Toshie, Kawanishi, Toru, Yamaguchi, Teruhide
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - therapeutic use; Antibody Affinity - immunology; CHO Cells; Cricetinae; Cricetulus; Half-Life; Histocompatibility Antigens Class I - blood; Histocompatibility Antigens Class I - metabolism; Histocompatibility Antigens Class I - physiology; Humans; Immunoglobulin Fc Fragments - blood; Immunoglobulin Fc Fragments - chemistry; Immunoglobulin Fc Fragments - metabolism; Immunoglobulin G - blood; Immunoglobulin G - therapeutic use; Infant, Newborn; Molecular Sequence Data; Protein Structure, Tertiary; Receptors, Fc - blood; Receptors, Fc - metabolism; Receptors, Fc - physiology; Recombinant Fusion Proteins - blood; Recombinant Fusion Proteins - isolation & purification; Recombinant Fusion Proteins - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0903296

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.