Immune thrombocytopenia (ITP), a common autoimmune disease, affects a large population of individuals worldwide; in the U.S. alone, as many as 33,000 new cases occur each year. Approximately 25-30 percent 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. Progress toward the development of new treatments has been impeded by difficulties associated with conducting investigations in ITP patients and by the unavailability of suitable animal models of the disease. A primary significance of this proposal lies in its potential to develop mechanistically relevant, quantitative animal models of immune thrombocytopenia. Extremely promising results have been obtained in our laboratory in the development of passive and active animal models of ITP. Further validation and complete development of these experimental models, as proposed in Aim number 1, will permit, for the first time, quantitative evaluation of the efficacy of existing and new therapies. The project plans to take the advantage of the animal models to examine hypotheses regarding the mechanisms of action of an effective, yet unfeasible therapy of chronic ITP, pooled immunoglobulin (IVIG, Aim number 2). Delineation of the pathways by which IVIG achieves effects may lead to the development of new therapies with improved pharmaceutical and therapeutic characteristics. Furthermore, the proposal plans to develop and test two new therapies for ITP: (1) a novel bioreactor for the antigen-specific removal of pathogenic antibodies (Aim number 3), which is expected to carry significant advantages over clinically approved methods for ITP treatment (e.g., Protein A immuno- adsorption); and (2) a new liposomal immunotherapy (Aim number 4), designed to improve upon anti-Rho(D) immunotherapy, which is approved for use in non-splenectomized ITP patients as an inhibitor of auto-antibody mediated elimination of platelets. Findings gathered from the body of proposed studies may offer insight in the design of effective combination therapy for treating ITP and other autoimmune diseases, which, as a group, affect over 50 million Americans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067347-03
Application #
6638775
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Ganguly, Pankaj
Project Start
2001-04-11
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
3
Fiscal Year
2003
Total Cost
$268,083
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
Abuqayyas, Lubna; Zhang, Xiaoyan; Balthasar, Joseph P (2013) Application of knockout mouse models to investigate the influence of FcýýR 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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