Chimeric FVIIa

嵌合FVIIa

基本信息

批准号：
9195059
负责人：
Michael Griffith
金额：
$ 7.5万
依托单位：
CHIMERA BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-31 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195059
关键词：
Acute Address Animal Model Antithrombins Binding Biological Availability Biological Products Biomedical Engineering Biotechnology Blood Blood Coagulation Disorders Blood Coagulation Factor Canis familiaris Caring Cell Culture Techniques Cell Line Child Chimera organism Chimeric Proteins Chronic Clinical Clinical effectiveness Collagen Type IV Data Defect Development Dose Drug Kinetics Effectiveness Evaluation F8 gene Factor IX Factor VIII Factor VIIa Factor X Goals Half-Life Hemophilia A Hemophilia B Hemorrhage Hemostatic Agents Hemostatic function Heparin Hour Human Immune response Immunosuppression In Vitro Industry Injection of therapeutic agent Intellectual Property Intravenous Life Life Experience Limb structure Location Marketing Medical Methods Modeling Morphologic artifacts Mus North Carolina Patients Persons Pharmaceutical Preparations Pharmacodynamics Phase Phospholipids Plasma Post-Translational Protein Processing Preparation Prevention Property Prophylactic treatment Proteins Protocols documentation Publishing Quality of life Recombinants Recovery Regimen Replacement Therapy Safety Saphenous Vein Site Small Business Innovation Research Grant Staging Technology Therapeutic Therapeutic Agents Thromboplastin Time Transfection Universities Variant Work analog antibody inhibitor base compliance behavior cost drug candidate improved in vivo inhibitor/antagonist intravenous administration joint function joint injury mouse model neutralizing antibody novel prevent prophylactic protein distribution public health relevance response therapeutic effectiveness

项目摘要

DESCRIPTION (provided by applicant): In patients with hemophilia, intravenous administration of blood coagulation factors, e.g., factor VIII, is a safe and effective therapeutic approach for the treatment and prevention of bleeding episodes. However, up to 30% of the patients receiving factor VIII treatment develop an inhibitory immune response to the administered factor VIII such that subsequent treatment is no longer effective. For those inhibitor patients whose immune response cannot be suppressed, so-called inhibitor by-passing agents, e.g. recombinant human factor VIIa (rFVIIa), are used to treat bleeding episodes. To treat a severe bleeding episode with currently available by- passing agents requires multiple intravenous doses. Development of a by-passing agent with longer duration of effect such that fewer injections are required would be a major advance in therapy. The goal of the current application is to evaluate a novel bioengineered protein (Chimera) that consists of functionally important structural domains of blood coagulation factor IX (FIX) that replace the homologous domains of rFVIIa. In preliminary studies the Chimera has been found to be as effective as rFVIIa in treating bleeding in an animal model of hemophilia. The Chimera also displays a dramatically reduced thrombotic potential. The hypothesis of this application is that the Chimera will have an extended half-life of therapeutic effectiveness. The FIX structural properties of the Chimera are anticipated to reduce clearance by natural inhibitors. This is anticipated to increase the plasma half-life. Further, the FIX structural properties are expected to substantially increase distribution of the protein into the extravascular space where it is anticipated to persist in an active form even after plasma levels have returned to baseline. In the current application we propose to utilize readily available commercial technology to manufacture sufficient amounts of the Chimera to rigorously evaluate the structural and functional properties of the protein. Well characterized protein will be advanced to in vivo evaluation of the circulating half-life and prolonged hemostatic effectiveness in a well-established mouse model of bleeding in hemophilia. We anticipate that the proposed work will show a significant increase in the circulating half-life of the Chimera relative to rFVIIa. We also anticipate that hemostasis will be maintained in a bleeding model for even longer than the circulating half-life. Such results will suggest that it could be plausible for prophylactic dosing with the Chimera to be extended from daily to at most once every second day with the possibility of once weekly dosing while achieving breakthrough bleeding rates comparable to what has been observed with replacement therapy. This significant increase in effectiveness would warrant further commercial development of the chimera product under a Phase II SBIR application wherein cell line development would begin in order to produce representative clinical product for evaluation in the dog model of hemophilia. This canine model has been documented to correlate well with the clinical effectiveness of hemophilia products in humans.

描述（由应用提供）：在血友病患者中，静脉注射血液凝血因子，例如VIII因子，是一种安全有效的治疗治疗和预防出血发作的方法。但是，接受VIII因子治疗的患者中，多达30％对施用的因子VIII产生了抑制性免疫响应，因此随后的治疗不再有效。对于那些无法抑制免疫增强剂的抑制剂患者，由所谓的抑制剂通过抑制剂，例如重组人因子VIIA（RFVIIA）用于治疗出血发作。为了治疗严重的出血发作，目前可用的通过剂需要多种静脉注射剂量。开发具有更长效果持续时间的旁路剂，因此需要更少的注射将是治疗的重大进步。当前应用的目的是评估一种新型的生物工程蛋白（Chimera），该蛋白质由血液凝结因子IX（FIX）的功能重要的结构结构域组成，该结构域IX（FIX）取代了RFVIIA的同源结构域。初步研究已发现嵌合体与RFVIIA在血友病动物模型中治疗出血一样有效。嵌合体还显示动态降低的血栓势。该应用的假设是嵌合体具有延长的热有效性的半衰期。预计嵌合体的固定结构特性将减少自然抑制剂的清除。预计这会增加血浆半衰期。此外，预计固定结构特性将大大增加蛋白质在血管外空间中的分布，即使血浆水平恢复到基线后，预计即使在血管外空间中持续存在。在当前的应用中，我们建议利用随时可用的商业技术来制造足够数量的嵌合体来严格评估蛋白质的结构和功能性能。表征良好的蛋白质将在体内进行体内评估，以评估循环的半衰期和延长的止血有效性。我们还预计止血会在出血模型中保持比循环半衰期更长的时间。这样的结果将表明，与嵌合体的预防性给药可能是合理的，将每天从每天延伸至最多每天一次，并且可能每周一次给药，同时可以达到与替代治疗相当的突破性出血率。在II期SBIR应用下，有效性的显着提高将需要进一步的嵌合产物商业开发，其中细胞系的发展将开始，以生产代表性的临床产品，以评估血友病的狗模型。该犬模型已被证明与人类血友病产物的临床有效性很好地相关。