Pharmacology and Bioengineering of New Treatment of ITP

Summary

Principal Investigator: JOSEPH BALTHASAR
Affiliation: University at Buffalo
Country: USA
Abstract: Immune thrombocytopenic purpura (ITP) is a common autoimmune disease that is associated with ~50,000 new cases each year in the United States. Approximately 25-30% of chronic ITP patients are refractory to standard therapy (corticosteroid immunosuppression and splenectomy) and are at high risk for fatal hemorrhage. No feasible alternative therapies are presently available, and progress toward the development of new treatments had been slowed be the lack of suitable animal models of the disease. However, work conducted on this project has led to the development of new, reproducible, quantitative rat and mouse models of ITP, which now allow the systematic evaluation of new treatment strategies. Experiments have been conducted to probe the mechanisms responsible for the effects of high-dose intravenous immunoglobulin (IVIG) therapy of ITP. This work demonstrated that much of the benefit provided by IVIG results from the competitive inhibition of the FcRn, which protects IgG from degradation. Additionally, we initiated the development and evaluation of three new therapeutic strategies for ITP (i.e., application of specific FcRn-inhibitors to increase the elimination of pathogenic antiplatelet antibodies, removal of antiplatelet antibodies with an antigen-specific extracorporeal bioreactor, and inhibition of platelet destruction through the use of antibody-coated liposomes as "decoy particles"). Extremely promising results were generated from each specific aim during the initial funding period. This competing renewal will build upon these results, testing proposed mechanisms of IVIG action in a splenectomized-mouse model of ITP (Aim #1), optimizing the formulation of antibody-coated liposomes for enhanced pharmacokinetic and pharmacodynamic properties, and testing hypotheses related to the mechanisms of effect of antibody-coated liposomes in ITP (Aim #2). Aim #3 will develop and evaluate a new immune complex therapy for ITP, and Aim #4 will optimize the construction of hollow fiber bioreactors for efficient and selective extracorporeal removal of pathogenic, antiplatelet antibodies. Findings gathered from the proposed studies are expected to lead toward the development of new treatments for refractory ITP. Additionally, work conducted on this project may offer insight in the design of effective strategies for the treatment of all autoimmune conditions, which collectively affect 14-22 million Americans.
Funding Period: 2001-04-11 - 2011-05-31
more information: NIH RePORT

Top Publications

  1. pmc Application of knockout mouse models to investigate the influence of FcγR on the pharmacokinetics and anti-platelet effects of MWReg30, a monoclonal anti-GPIIb antibody
    Lubna Abuqayyas
    Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA
    Int J Pharm 444:185-92. 2013
  2. pmc 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
    Xiaotao Duan
    The Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, NY 14260, USA
    J Chromatogr A 1251:63-73. 2012
  3. pmc 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
    Xiaotao Duan
    The Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York 14260, United States
    Anal Chem 84:4373-82. 2012
  4. ncbi Monoclonal antibody pharmacokinetics and pharmacodynamics
    W Wang
    Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, West Point, Pennsylvania, USA
    Clin Pharmacol Ther 84:548-58. 2008
  5. pmc Comparison of the effects of antibody-coated liposomes, IVIG, and anti-RBC immunotherapy in a murine model of passive chronic immune thrombocytopenia
    Rong Deng
    Department of Pharmaceutical Sciences, 457B Cooke Hall, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA
    Blood 109:2470-6. 2007
  6. pmc Pharmacokinetic and pharmacodynamic effects of high-dose monoclonal antibody therapy in a rat model of immune thrombocytopenia
    Feng Jin
    Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA
    AAPS J 7:E895-902. 2005
  7. ncbi Strategies for improving the functionality of an affinity bioreactor
    Tanya Wang
    College of Pharmacy, University of Michigan, Ann Arbor, MI 48109 1065, USA
    Int J Pharm 306:132-41. 2005
  8. ncbi Investigation of antibody-coated liposomes as a new treatment for immune thrombocytopenia
    Rong Deng
    Department of Pharmaceutical Sciences, 457B Cooke Hall, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA
    Int J Pharm 304:51-62. 2005
  9. ncbi A GPIIb/IIIa bioreactor for specific treatment of immune thrombocytopenic purpura, an autoimmune disease. Preparation, in vitro characterization, and preliminary proof-of-concept animal studies
    Emel Emregul
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109 1065, USA
    J Biomed Mater Res A 75:648-55. 2005
  10. ncbi Mechanisms of intravenous immunoglobulin action in immune thrombocytopenic purpura
    Feng Jin
    Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA
    Hum Immunol 66:403-10. 2005

Detail Information

Publications11

  1. pmc Application of knockout mouse models to investigate the influence of FcγR on the pharmacokinetics and anti-platelet effects of MWReg30, a monoclonal anti-GPIIb antibody
    Lubna Abuqayyas
    Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA
    Int J Pharm 444:185-92. 2013
    ..inhibitory FcγR in processing immune complexes (i.e., MWReg30-platelets), while also providing an example where monoclonal antibody pharmacokinetics are not substantially influenced by FcγR expression...
  2. pmc 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
    Xiaotao Duan
    The Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, NY 14260, USA
    J Chromatogr A 1251:63-73. 2012
    ..The strategy employed in this study can be easily adapted to the sensitive and accurate analysis of other mAb and therapeutic proteins...
  3. pmc 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
    Xiaotao Duan
    The Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York 14260, United States
    Anal Chem 84:4373-82. 2012
    ..This work represents the first extensive quantification of mAb in tissues by an LC/MS-based method...
  4. ncbi Monoclonal antibody pharmacokinetics and pharmacodynamics
    W Wang
    Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, West Point, Pennsylvania, USA
    Clin Pharmacol Ther 84:548-58. 2008
    ..This article attempts to provide a brief overview of the main determinants of antibody pharmacokinetics and pharmacodynamics. Clinical Pharmacology & Therapeutics (2008); 84, 5, 548-558 doi:10.1038/clpt.2008.170...
  5. pmc Comparison of the effects of antibody-coated liposomes, IVIG, and anti-RBC immunotherapy in a murine model of passive chronic immune thrombocytopenia
    Rong Deng
    Department of Pharmaceutical Sciences, 457B Cooke Hall, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA
    Blood 109:2470-6. 2007
    ....
  6. pmc Pharmacokinetic and pharmacodynamic effects of high-dose monoclonal antibody therapy in a rat model of immune thrombocytopenia
    Feng Jin
    Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA
    AAPS J 7:E895-902. 2005
    ..72 +/- 0.08 mL h(-1) kg(-1), P < .05). Consequently, high-dose monoclonal antibody therapy attenuated thrombocytopenia and produced a moderate increase in the clearance of antiplatelet antibodies in a rat model of ITP...
  7. ncbi Strategies for improving the functionality of an affinity bioreactor
    Tanya Wang
    College of Pharmacy, University of Michigan, Ann Arbor, MI 48109 1065, USA
    Int J Pharm 306:132-41. 2005
    ..Indeed, efforts have been made recently in utilizing these approaches to develop a clinically usable GPIIb/IIIa bioreactor for the treatment of immune thrombocytopenic purpura (ITP)-an autoimmune disease...
  8. ncbi Investigation of antibody-coated liposomes as a new treatment for immune thrombocytopenia
    Rong Deng
    Department of Pharmaceutical Sciences, 457B Cooke Hall, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA
    Int J Pharm 304:51-62. 2005
    ..The results suggest that antibody-coated liposomes may be used as 'decoy particles' to competitively inhibit the destruction of antibody-coated platelets; thus, antibody-coated liposomes may have value in the treatment of ITP...
  9. ncbi A GPIIb/IIIa bioreactor for specific treatment of immune thrombocytopenic purpura, an autoimmune disease. Preparation, in vitro characterization, and preliminary proof-of-concept animal studies
    Emel Emregul
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109 1065, USA
    J Biomed Mater Res A 75:648-55. 2005
    ..In addition, a rapid restoration of WBC counts in the treated rats was also found. These preliminary findings shed light of promise of using the GPIIb/IIIa bioreactor approach in achieving highly improved ITP therapy...
  10. ncbi Mechanisms of intravenous immunoglobulin action in immune thrombocytopenic purpura
    Feng Jin
    Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA
    Hum Immunol 66:403-10. 2005
    ..This review provides an overview and critical discussion of mechanisms that may be responsible of IVIG effects in ITP...
  11. ncbi Pharmacokinetic effects of 4C9, an anti-FcRn antibody, in rats: implications for the use of FcRn inhibitors for the treatment of humoral autoimmune and alloimmune conditions
    Kate E Getman
    Department of Pharmaceutical Sciences, University at Buffalo, The State University at New York, Buffalo, New York 14260, USA
    J Pharm Sci 94:718-29. 2005
    ..The results suggest that FcRn inhibitors may have utility in the treatment of antibody-mediated autoimmune and alloimmune conditions...