The AAPS Journal

, 11:553 | Cite as

Investigation of the Influence of FcRn on the Distribution of IgG to the Brain

  • Amit Garg
  • Joseph P. BalthasarEmail author
Research Article Theme: Investigation of the Role of FcRn on the Absorption, Distribution, and Elimination of IgG and Albumin


It has been suggested that the neonatal Fc receptor (FcRn) is a primary determinant of the distribution of IgG to the brain. In the present report, 125I-labeled 7E3, a monoclonal IgG1 antibody, was injected intravenously to groups of FcRn-deficient mice and C57BL/6J control mice. Sub-groups of three mice were sacrificed at several time points. Blood and brain tissue were harvested and radioactivity was assessed. Antibody concentrations in brain were corrected for residual blood using 51Cr-labeled red blood cells. Data were analyzed via WinNonlin, and areas under plasma and tissue concentration vs. time curves (AUCs) were assessed via the Bailer method. The apparent plasma elimination half-life and clearance of 7E3 were 13.61 ± 0.61 days and 6.5 ± 0.10 ml/day/kg in control mice and 0.70 ± 0.05 days and 63.5 ± 2.7 ml/day/kg in the knockout mice. Plasma and brain AUCs (0–10 days) were found to be 3,338.7 ± 50.4 and 7.46 ± 0.5 nM day in control animals and 781.2 ± 16.6 and 1.65 ± 0.1 nM day in FcRn-deficient animals. There was no significant difference between brain-to-plasma AUC ratios in control and FcRn-deficient mice (0.0022 ± 0.00015 vs. 0.0021 ± 0.00011, p = 0.3347). Two-way analysis of variance showed no significant differences, at any time point, between brain-to-plasma concentration ratios determined from control and knockout animals. The results suggest that FcRn does not contribute significantly to the “blood–brain barrier” for IgG in mice, and the data suggest that FcRn is not responsible for the low exposure of IgG in the brain relative to plasma.

Key words

antibody blood brain barrier FcRn IgG pharmacokinetics 



This study was supported by grant AI60687 from the National Institutes of Health. Amit Garg was supported by a pre-doctoral fellowship from Eli Lilly and Company.


  1. 1.
    Borvak J, Richardson J, Medesan C, Antohe F, Radu C, Simionescu M, et al. Functional expression of the MHC class I-related receptor, FcRn, in endothelial cells of mice. Int Immunol. 1998;10(9):1289–98.PubMedCrossRefGoogle Scholar
  2. 2.
    Israel EJ, Taylor S, Wu Z, Mizoguchi E, Blumberg RS, Bhan A, et al. Expression of the neonatal Fc receptor, FcRn, on human intestinal epithelial cells. Immunology. 1997;92(1):69–74.PubMedCrossRefGoogle Scholar
  3. 3.
    Spiekermann GM, Finn PW, Ward ES, Dumont J, Dickinson BL, Blumberg RS, et al. Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: functional expression of FcRn in the mammalian lung. [erratum appears in J Exp Med. 2003 Jun 2;197(11):1601]. J Exp Med. 2002;196(3):303–10.PubMedCrossRefGoogle Scholar
  4. 4.
    Blumberg RS, Koss T, Story CM, Barisani D, Polischuk J, Lipin A, et al. A major histocompatibility complex class I-related Fc receptor for IgG on rat hepatocytes. J Clin Invest. 1995;95(5):2397–402.PubMedCrossRefGoogle Scholar
  5. 5.
    Zhu X, Meng G, Dickinson BL, Li X, Mizoguchi E, Miao L, et al. MHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, intestinal macrophages, and dendritic cells. J Immunol. 2001;166(5):3266–76.PubMedGoogle Scholar
  6. 6.
    Kristoffersen EK, Matre R. Co-localization of beta 2-microglobulin and IgG in human placental syncytiotrophoblasts. Eur J Immunol. 1996;26(2):505–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Leach JL, Sedmak DD, Osborne JM, Rahill B, Lairmore MD, Anderson CL. Isolation from human placenta of the IgG transporter, FcRn, and localization to the syncytiotrophoblast: implications for maternal–fetal antibody transport. J Immunol. 1996;157(8):3317–22.PubMedGoogle Scholar
  8. 8.
    Story CM, Mikulska JE, Simister NE. A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus. J Exp Med. 1994;180(6):2377–81.PubMedCrossRefGoogle Scholar
  9. 9.
    Schlachetzki F, Zhu C, Pardridge WM. Expression of the neonatal Fc receptor (FcRn) at the blood–brain barrier. J Neurochem. 2002;81(1):203–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang Y, Pardridge WM. Mediated efflux of IgG molecules from brain to blood across the blood–brain barrier. J Neuroimmunol. 2001;114(1–2):168–72.PubMedCrossRefGoogle Scholar
  11. 11.
    Boado RJ, Zhang Y, Zhang Y, Xia CF, Pardridge WM. Fusion antibody for Alzheimer's disease with bidirectional transport across the blood–brain barrier and abeta fibril disaggregation. Bioconjug Chem. 2007;18(2):447–55.PubMedCrossRefGoogle Scholar
  12. 12.
    Deane R, Sagare A, Hamm K, Parisi M, LaRue B, Guo H, et al. IgG-assisted age-dependent clearance of Alzheimer's amyloid beta peptide by the blood–brain barrier neonatal Fc receptor. J Neurosci. 2005;25(50):11495–503.PubMedCrossRefGoogle Scholar
  13. 13.
    Hansen RJ, Balthasar JP. Pharmacokinetics, pharmacodynamics, and platelet binding of an anti-glycoprotein IIb/IIIa monoclonal antibody (7E3) in the rat: a quantitative rat model of immune thrombocytopenic purpura. J Pharmacol Exp Ther. 2001;298(1):165–71.PubMedGoogle Scholar
  14. 14.
    Varner JA, Nakada MT, Jordan RE, Coller BS. Inhibition of angiogenesis and tumor growth by murine 7E3, the parent antibody of c7E3 Fab (abciximab; ReoPro). Angiogenesis. 1999;3(1):53–60.PubMedCrossRefGoogle Scholar
  15. 15.
    Jensenius JC, Williams AF. The binding of anti-immunoglobulin antibodies to rat thymocytes and thoracic duct lymphocytes. Eur J Immunol. 1974;4(2):91–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Garg A, Balthasar JP. Physiologically-based pharmacokinetic (PBPK) model to predict IgG tissue kinetics in wild-type and FcRn-knockout mice. J Pharmacokinet Pharmacodyn. 2007;34(5):687–709.PubMedCrossRefGoogle Scholar
  17. 17.
    International Committee for Standardization in Hematology (ICSH) Panel on Diagnostic Applications of Radioisotopes in Haematology. Standard techniques for the measurement of red-cell and plasma volume. Br J Haematol. 1973;25(6):801–14.CrossRefGoogle Scholar
  18. 18.
    International Committee for Standardization in Haematology (ICSH). Recommended methods for measurement of red-cell and plasma volume. J Nucl Med. 1980;21(8):793–800.Google Scholar
  19. 19.
    Gore CJ, Hopkins WG, Burge CM. Errors of measurement for blood volume parameters: a meta-analysis. J Appl Physiol. 2005;99(5):1745–58.PubMedCrossRefGoogle Scholar
  20. 20.
    Bernareggi A, Rowland M. Physiologic modeling of cyclosporin kinetics in rat and man. J Pharmacokinet Biopharm. 1991;19(1):21–50.PubMedCrossRefGoogle Scholar
  21. 21.
    Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health. 1997;13(4):407–84.PubMedGoogle Scholar
  22. 22.
    Bailer AJ. Testing for the equality of area under the curves when using destructive measurement techniques. J Pharmacokinet Biopharm. 1988;16(3):303–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Nedelman JR, Gibiansky E, Lau DT. Applying Bailer’s method for AUC confidence intervals to sparse sampling. Pharm Res. 1995;12(1):124–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Hansen RJ, Balthasar JP. Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor. [see comment]. Thromb Haemost. 2002;88(6):898–9.PubMedGoogle Scholar
  25. 25.
    Brambell FW, Hemmings WA, Morris IG. A theoretical model of gamma-globulin catabolism. Nature. 1964;203:1352–4.PubMedCrossRefGoogle Scholar
  26. 26.
    Rodewald R, Kraehenbuhl JP. Receptor-mediated transport of IgG. J Cell Biol. 1984;99(1 Pt 2):159s–64.PubMedCrossRefGoogle Scholar
  27. 27.
    Simister NE, Mostov KE. An Fc receptor structurally related to MHC class I antigens. Nature. 1989;337(6203):184–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Simister NE, Rees AR. Isolation and characterization of an Fc receptor from neonatal rat small intestine. Eur J Immunol. 1985;15(7):733–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Raghavan M, Bjorkman PJ. Fc receptors and their interactions with immunoglobulins. Annu Rev Cell Dev Biol. 1996;12:181–220.PubMedCrossRefGoogle Scholar
  30. 30.
    Dickinson BL, Badizadegan K, Wu Z, Ahouse JC, Zhu X, Simister NE, et al. Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line. J Clin Invest. 1999;104(7):903–11.PubMedCrossRefGoogle Scholar
  31. 31.
    Gallo JM, Li S, Guo P, Reed K, Ma J. The effect of P-glycoprotein on paclitaxel brain and brain tumor distribution in mice. Cancer Res. 2003;63(16):5114–7.PubMedGoogle Scholar
  32. 32.
    Kemper EM, van Zandbergen AE, Cleypool C, Mos HA, Boogerd W, Beijnen JH, et al. Increased penetration of paclitaxel into the brain by inhibition of P-glycoprotein. Clin Cancer Res. 2003;9(7):2849–55.PubMedGoogle Scholar
  33. 33.
    Mayer U, Wagenaar E, Beijnen JH, Smit JW, Meijer DK, van Asperen J, et al. Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr 1a P-glycoprotein. Br J Pharmacol. 1996;119(5):1038–44.PubMedGoogle Scholar
  34. 34.
    Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell. 1994;77(4):491–502.PubMedCrossRefGoogle Scholar
  35. 35.
    Schinkel AH, Wagenaar E, Mol CA, van Deemter L. P-glycoprotein in the blood–brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996;97(11):2517–24.PubMedCrossRefGoogle Scholar
  36. 36.
    van Asperen J, Schinkel AH, Beijnen JH, Nooijen WJ, Borst P, van Tellingen O. Altered pharmacokinetics of vinblastine in Mdr1a P-glycoprotein-deficient mice. J Natl Cancer Inst. 1996;88(14):994–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Ghetie V, Hubbard JG, Kim JK, Tsen MF, Lee Y, Ward ES. Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice. Eur J Immunol. 1996;26(3):690–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Israel EJ, Wilsker DF, Hayes KC, Schoenfeld D, Simister NE. Increased clearance of IgG in mice that lack beta 2-microglobulin: possible protective role of FcRn. Immunology. 1996;89(4):573–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Junghans RP, Anderson CL. The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor. Proc Natl Acad Sci U S A. 1996;93(11):5512–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Roopenian DC, Christianson GJ, Sproule TJ, Brown AC, Akilesh S, Jung N, et al. The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol. 2003;170(7):3528–33.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2009

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesUniversity at Buffalo, The State University of New YorkBuffaloUSA

Personalised recommendations