2007 Fiscal Year Final Research Report Summary
Studies on molecular basis of the pharmacokinetic regulation of protein drugs consisting of immunoglobulin Fc region
| Project/Area Number |
18590163
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | National Institute of Health Sciences |
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Principal Investigator |
KAWANISHI Toru National Institute of Health Sciences, Division of Drugs, Head (40124383)
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| Co-Investigator(Kenkyū-buntansha) |
ISHII Akiko (渡部 明子) National Institute of Health Sciences, Division of Biological Chemistry and Biologicals, Section chief (50291117)
SUZUKI Takuo National Institute of Health Sciences, Division of Biological Chemistry and Biologicals, Senior Researcher (10415466)
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| Project Period (FY) |
2006 – 2007
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| Keywords | FcRn / Fc domain / receptor / protein drugs / serum half life |
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| Research Abstract |
The neonatal Fc receptor (FcRn) is a receptor that protects IgG from catabolism and is important in maintaining high serum antibody levels. In order to elucidate the role of FcRn in pharmacokinetics of Fc domain-containing protein drugs, this study focused on (1) establishment of Surface Plasmon Resonance (SPR) analysis that can measure the affinity of Fc domain-containing protein drugs to FcRn; (2) evaluation of the affinity between FcRn and Fc domain-containing protein drugs by SPR analysis; (3) establishment of in vitro method to measure the protein recycling via FcRn; and (4) regulation of FcRn expression by inflammatory cytokines.
(1) SPR analysis method using extracellular domain of FcRn as the ligand was established. (2)The affinity of Fc domain-containing protein drugs to FcRn was almost correlated with the serum half lives in humans, suggesting the importance of FcRn in regulating serum half lives of these drugs. The analytes used were human antibody (Adalimumab), humanized antibodies (Daclizumab and Omalizumab), chimeric antibody (Infliximab), and Fe-fusion proteins (Etanercept and Alefacept). (3) ELISA method to quantify the 0.1〜10ng/ml of biotinylated Infliximab was established. Concentrations of biotinylated Infliximab in culture supernatant of human umbilical vein endothelial cells (HUVECs) those were pulse-labeled with it was measured. (4) In HUVECs, FcRn expression was suppressed by TNFα, IL-1β, or IL-6. The possibility of regulating the FcRn expression level by these inflammatory cytokines was suggested.
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