期刊
JOURNAL OF IMMUNOLOGY
卷 184, 期 4, 页码 1968-1976出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0903296
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资金
- Ministry of Education, Culture, Sports. Science and Technology [21790172]
- Japan Society for the Promotion of Science [18590163, 20590167]
- Grants-in-Aid for Scientific Research [18590163, 20590167, 21790172] Funding Source: KAKEN
The neonatal FeR (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 Fe-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 Fc gamma RI binding region of the Fc domain. The Journal of Immunology, 2010, 184: 1968-1976.
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