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dc.contributorNot Applicableen_US
dc.contributor.authorBALU-IYER, SATHY VENKAT Principal Investigatoren_US
dc.date31-Dec-11en_US
dc.date2010en_US
dc.date.accessioned2011-04-18T20:55:32Zen_US
dc.date.accessioned2011-04-19T18:30:22Z
dc.date.available1-Apr-02en_US
dc.date.available2011-04-18T20:55:32Zen_US
dc.date.available2011-04-19T18:30:22Z
dc.date.issued2011-04-18T20:55:32Zen_US
dc.identifier7751250en_US
dc.identifier5R01HL070227-08en_US
dc.identifier70227en_US
dc.identifier.urihttp://hdl.handle.net/10477/940
dc.descriptionA Mouse;Abbreviations;Antibodies;Antibody Formation;Antigen-Presenting Cells;Antigens;Area Under Curve;base;Binding (Molecular Function);Binding Sites;Blood Circulation;C2 Domain;Calcium ion;Cell Culture Techniques;Choline;Circular Dichroism;Complex;Complication;cytokine;Dendritic Cells;density;design;Development;dioleoyl-N-(monomethoxypolyethylene glycol succinyl)phosphatidylethanolamine;Disease Management;Dose;Drug Formulations;Drug Kinetics;Drug or chemical Tissue Distribution;Encapsulated;Epitopes;Ethanolamines;ethylene glycol;Ethylene Glycols;Exogenous Factors;Factor VIII;Frequencies (time pattern);Generations;Goals;Half-Life;Hemophilia A;Immune response;Immune system;immunogenic;immunogenicity;improved;In Vitro;in vivo;Inflammatory Response;inhibitor/antagonist;Injection of therapeutic agent;Knockout Mice;LDL-Receptor Related Protein 1;Lead;Lipid Binding;Lipids;Lipopolysaccharides;Liposomes;liver metabolism;Mediating;Micelles;Modification;Molecular;molecular assembly/self assembly;Molecular Sieve Chromatography;mouse model;Mus;nano;novel;particle;Particle Size;Particulate;Patients;Pharmacologic Substance;Pharmacology;Phosphatidic Acid;Phospholipids;Phosphoserine;Plasma;Play;Preparation;prevent;Process;programs;Property;protein aggregation;Protein Binding;protein complex;Protein Engineering;Proteins;receptor;receptor density;recombinant antihemophilic factor VIII;Recombinants;Replacement Therapy;Research Personnel;research study;Reticuloendothelial System;Role;Serine;Structure;Surface;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Therapeutic Agents;therapeutic protein;Time Factors;Treatment Efficacy;uptake;von Willebrand Factor;en_US
dc.descriptionAmount: $ 271422en_US
dc.description.abstractAdvances in protein engineering have led to the development of proteins as therapeutic agents. However, acommon complication is the reduction of efficacy due to antibody response. Factors that influence antibodyresponse include protein aggregation, immunogenic sequences within the protein and the frequency ofadministration. The broad objective of this proposal is to improve therapeutic efficacy of biopharmaceuticalsby developing lipid-protein complexes that will reduce immunogenicity and decrease the clearance of theprotein, thereby reducing frequency of administration. Factor VIII (FVIII) offers an excellent opportunity toinvestigate such approaches, as the administration of exogenous FVIII leads to development of inhibitoryantibody responses in 15-30% of Hemophilia A patients, complicating replacement therapy. The long termgoal of the project is to develop lipidic complexes of FVIII that positively modulate immunogenicity andclearance. During the previous project period, rational approaches led to the development of FVIII-Phosphoserine (PS)complexes that showed reduction in immune response against the protein following itsinjection in Hemophilia A mice and improved physical stability. The molecular interaction of PS with FVIII andCalcium ions was exploited to develop lipid based nano/micro particulates including liposomes and novelcondensed and nano-cochleate structures for FVIII delivery. In this proposal, we propose to investigate (1)the mechanism of reduction in immune response mediated by FVIM-PS complexes (2) the effect of lowdensity receptor related protein and von Willebrand factor mediated clearance of FVIII and FVIII-PScomplexes and (3) the effect of antibody response on clearance of FVIII and FVIII-PS complexes. Thestudies aimed at understanding the pharmacology of FVIII-PS complexes will be carried out in Hemophilia Amice model and in vitro with antigen presenting cells such as dendritic cells and T-cells. We propose toinvestigate key steps in the processing of protein antigen by the immune system in general, which includeuptake and processing of FVIII by antigen presenting cells and subsequent presentation and expansion of T-cells. We will investigate the role of PS in modulating the immunogenicity of FVIII (Specific Aim 1). Thepharmacokinetic properties of FVIII are complex due to intrinsic protein binding and we will investigate thedisposition of FVIII and FVIII-PS complexes mediated by liver metabolism and immune system. In specificaim 2, we will investigate the effect of PS binding and lipid molecular assemblies on pharmacokineticparameters such as half-life, area under the curve and clearance. Finally, in specific aim 3, we willinvestigate the effect of antibody response and disposition of FVIII. The results obtained from these studieswill be useful to develop optimal dosing and efficient management of the disease and therapy.en_US
dc.titleDEVELOPMENT AND PHARMACOLOGY OF NOVEL LIPIDIC RAHFen_US
dc.typeNIH Grant Awarden_US


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