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.
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.
Suzuki
Takuo
T
Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Tokyo, Japan.
Ishii-Watabe
Akiko
A
Tada
Minoru
M
Kobayashi
Tetsu
T
Kanayasu-Toyoda
Toshie
T
Kawanishi
Toru
T
Yamaguchi
Teruhide
T
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*
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