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.
|Abuqayyas, Lubna; Zhang, Xiaoyan; Balthasar, Joseph P (2013) Application of knockout mouse models to investigate the influence of FcÃ½Ã½R on the pharmacokinetics and anti-platelet effects of MWReg30, a monoclonal anti-GPIIb antibody. Int J Pharm 444:185-92|
|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|
|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|
|Wang, W; Wang, E Q; Balthasar, J P (2008) Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 84:548-58|
|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; Tayab, Zia R; Balthasar, Joseph P (2005) Pharmacokinetic and pharmacodynamic effects of high-dose monoclonal antibody therapy in a rat model of immune thrombocytopenia. AAPS J 7:E895-902|
|Wang, Tanya; Yang, Zhiqiang; Emregul, Emel et al. (2005) Strategies for improving the functionality of an affinity bioreactor. Int J Pharm 306:132-41|
|Emregul, Emel; David, Allan; Balthasar, Joseph P et al. (2005) 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. J Biomed Mater Res A 75:648-55|
|Getman, Kate E; Balthasar, Joseph P (2005) 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. J Pharm Sci 94:718-29|
|Deng, Rong; Balthasar, Joseph P (2005) Investigation of antibody-coated liposomes as a new treatment for immune thrombocytopenia. Int J Pharm 304:51-62|
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