Approximately 20 million Americans are affected by autoimmune conditions, where the immune system mounts an attack directed against self-antigens. For many of the approximately 80 autoimmune diseases, the immune attack is mediated by self-reactive antibodies (i.e., autoantibodies). Recent work conducted in this laboratory has shown that high-dose intravenous immunoglobulin (IVlG), an effective therapy for many autoimmune conditions, increases the rate of clearance of pathogenic antibody in an animal model of autoimmune disease. Studies conducted in FcRn-knockout mice and pharmacokinetic-pharmacodynamic analyses have supported the hypothesis that IVlG enhances antibody elimination via competitive inhibition of FcRn, a transport protein that protects immune gamma globulin (IgG) from intracellular catabolism. Based on these findings, we have hypothesized that FcRn-inhibitors (e.g., anti-FcRn antibodies) may serve as a novel immunosuppressant therapy with broad utility for treatment of antibody-mediated immune conditions. Preliminary studies have shown that anti-FcRn antibodies are much more potent and much more effective in increasing the clearance of pathogenic antibodies in vivo (i.e., relative to IVIG). The present proposal will investigate the pharmacology of anti-FcRn antibodies, testing hypotheses related to: (a) the effects of anti-FcRn therapy in an animal model of autoimmunity (Aim #1), (b) the influence of FcRn and FcRn inhibitors on the tissue disposition of IgG (Aim #2), and (c) the effects of anti-human-FcRn antibodies on FcRn-mediated transport of human IgG in vitro (Aim #3). Findings gathered from the proposed studies may demonstrate the utility of FcRn inhibition in an animal model of disease, improve our understanding of the influence of FcRn on IgG disposition, and also develop new agents, inhibitors of human FcRn, with potential for use in future clinical studies

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI060687-04
Application #
7224222
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Esch, Thomas R
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2007
Total Cost
$327,007
Indirect Cost
Name
State University of New York at Buffalo
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Guimond, David M; Cam, Nicholas R; Hirve, Nupura et al. (2013) Regulation of immune responsiveness in vivo by disrupting an early T-cell signaling event using a cell-permeable peptide. PLoS One 8:e63645
Duan, Xiaotao; Dai, Lipeng; Chen, Shang-Chiung et al. (2012) Nano-scale liquid chromatography/mass spectrometry and on-the-fly orthogonal array optimization for quantification of therapeutic monoclonal antibodies and the application in preclinical analysis. J Chromatogr A 1251:63-73
Chen, Yang; Balthasar, Joseph P (2012) Evaluation of a catenary PBPK model for predicting the in vivo disposition of mAbs engineered for high-affinity binding to FcRn. AAPS J 14:850-9
Duan, Xiaotao; Abuqayyas, Lubna; Dai, Lipeng et al. (2012) High-throughput method development for sensitive, accurate, and reproducible quantification of therapeutic monoclonal antibodies in tissues using orthogonal array optimization and nano liquid chromatography/selected reaction monitoring mass spectrometry. Anal Chem 84:4373-82
Garg, Amit; Balthasar, Joseph P (2009) Investigation of the influence of FcRn on the distribution of IgG to the brain. AAPS J 11:553-7
Wang, W; Wang, E Q; Balthasar, J P (2008) Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 84:548-58
Garg, Amit; Balthasar, Joseph P (2007) Physiologically-based pharmacokinetic (PBPK) model to predict IgG tissue kinetics in wild-type and FcRn-knockout mice. J Pharmacokinet Pharmacodyn 34:687-709
Deng, Rong; Balthasar, Joseph P (2007) Pharmacokinetic/pharmacodynamic modeling of IVIG effects in a murine model of immune thrombocytopenia. J Pharm Sci 96:1625-37
Deng, Rong; Balthasar, Joseph P (2007) Comparison of the effects of antibody-coated liposomes, IVIG, and anti-RBC immunotherapy in a murine model of passive chronic immune thrombocytopenia. Blood 109:2470-6
Jin, Feng; Balthasar, Joseph P (2005) Mechanisms of intravenous immunoglobulin action in immune thrombocytopenic purpura. Hum Immunol 66:403-10

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