HLS- Factor XII Inhibitor for Surface Initiated Thrombosis

HLS-表面引发血栓形成的因子 XII 抑制剂

基本信息

批准号：
9137247
负责人：
Erik Ian Tucker
金额：
$ 29.96万
依托单位：
ARONORA, 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：
2016-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9137247
关键词：
2-arachidonylglycerol Address Adjuvant Adverse effects Affect Antibodies Anticoagulants Anticoagulation Antithrombins Binding Bleeding time procedure Blood Blood Platelets Blood Vessels Blood coagulation Blood flow Businesses Cardiac Surgery procedures Cardiopulmonary Bypass Cell Line Chemistry Clinical Research Clinical Trials Collaborations Complement 5a Critical Illness Data Deposition Development Devices Dose Dose-Limiting Drug Compounding Drug Kinetics Effectiveness Equilibrium Experimental Models Extracorporeal Membrane Oxygenation Factor XII Factor XII Deficiency Factor Xa Fibrin Fibrinolytic Agents Generations Guidelines Healthcare Hemorrhage Hemostatic Agents Hemostatic function Heparin Human Hybridomas In Vitro Injectable Intervention Investigational Drugs Investigational New Drug Application Knockout Mice Lead Letters Leukocyte Elastase Life Link Lung Mammals Marketing Medical Membrane Modeling Molecular Monoclonal Antibodies Mus National Heart, Lung, and Blood Institute Papio Pathway interactions Patients Perfusion Pharmaceutical Preparations Pharmacodynamics Phase Platelet Activation Primates Procedures Process Prosthesis Publishing Pump Quality Control Recombinants Research Research Contracts Residual state Risk Safety Small Business Innovation Research Grant Staging Sterility Surface TNFSF5 gene Therapeutic Therapeutic Index Therapeutic antibodies Thrombin Thrombosis Thrombus Toxic effect Toxicity Tests Toxicology Vascular Graft Vial device Work antigen binding base cell bank drug candidate experience humanized antibody implantation improved in vitro activity in vitro testing industry partner inflammatory marker inhibitor/antagonist innovation interest murine monoclonal antibody novel therapeutics preclinical toxicity prevent product development public health relevance research study safety study stability testing success ventricular assist device

项目摘要

DESCRIPTION (provided by applicant): This Phase I/II Fast-Track application is being re-submitted under the NHLBI Small Business Topics of Special Interest for Fiscal Year 2016 (HLS16-04). Certain life-saving interventions such as cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), or ventricular assist device (VAD) pump require the use of high dose heparin to maintain blood flow through the devices and/or to prevent downstream thromboembolic complications. Several other invasive vascular procedures also utilize profound temporal anticoagulation, such as during and after prosthetic vascular graft implantation. Unfortunately, antithrombotic agents such as heparin inadvertently target vital hemostatic molecular mechanisms and can produce severe dose-limiting hemorrhagic toxicity. Consequently, the level of anticoagulation must be limited to balance the risk of bleeding with thrombosis. As a result, thrombotic complications can be frequent and devastating. Our recent studies suggest that coagulation factor XII (FXII) contributes to the progression of thrombosis, and thereby is a potential target for a new class of antithrombotic drugs. Since data suggests that FXII does not contribute to hemostasis, and FXII deficiency is an asymptomatic condition in mammals, FXII inhibition is unlikely to have significant adverse effects. We have generated a proprietary murine monoclonal antibody, 15H8, against human FXII that was created by immunizing FXII knockout mice, and verified its anticoagulant and antithrombotic effects in preliminary primate experiments. This proposed Phase I/II Fast-Track project will initiate the commercial development of a recombinant humanized version of 15H8 (rh15H8), a product candidate that could be used as a stand alone or as an adjuvant anticoagulant to increase the antithrombotic efficacy of heparin without further increasing heparin-associated bleeding risks. The Specific Aims for this project that will be necessary to support 15H8 development towards an investigational new drug (IND) application are to: 1) Evaluate the antithrombotic effect of the murine anti-FXII antibody (15H8) in a primate model of experimental extracorporeal membrane oxygenation (ECMO), 2) Determine the activity and efficacy of recombinant humanized 15H8 (rh15H8), and 3) Manufacture rh15H8 for use in GLP toxicity studies. The rh15H8 approach represents a fundamentally new therapeutic anticoagulation concept since FXII inhibition is expected to reduce the formation of contact-initiated blood clots in synthetic grafts and extracorporeal devices without a detrimental effect on residual bleeding control in critically ill, anticoagulated patients. Success of this project and reaching our critical milestones will lead directly to the next stage of product development that will consist of GLP toxicity and stability studies, IND preparation and filing, followed by the initiation of phase 1 first- in-human safety studies of our innovative antithrombotic drug candidate.

描述（由应用程序提供）：根据NHLBI小型企业主题，该阶段I/II阶段的快速申请正在2016财年特殊兴趣（HLS16-04）。某些挽救生命的干预措施，例如心肺旁路（CPB），体外膜氧合（ECMO）或心室辅助装置（VAD）泵需要使用高剂量的肝素来维持通过设备和/或防止下游势力势力势力来维持血液流动。其他几种侵入性血管手术也利用了深刻的临时抗凝治疗，例如肢体血管移植物植入。不幸的是，抗血栓形成剂（例如肝素）无意中靶向重要的止血分子机制，可以产生严重的限制剂量的出血毒性。因此，必须限制抗凝水平以平衡血栓形成出血的风险。结果，血栓形成并发症可能经常是毁灭性的。我们最近的研究表明，凝血因子XII（FXII）有助于血栓形成的进展，从而有可能成为新的抗强化药物的潜在靶标。由于数据表明FXII不会导致止血，而FXII缺乏是哺乳动物的不对称条件，因此FXII抑制不太可能产生重大的不良影响。我们已经通过免疫FXII基因敲除小鼠产生了一种针对人FXII的专有鼠单克隆抗体，15H8，并在初步的灵长类动物实验中验证了其抗凝剂和抗血栓形成效应。该提议的I/II期快速轨道项目将启动重组人源化版本的15H8（RH15H8）的商业开发，该版本可以单独使用，也可以用作可调节的抗凝剂，以提高肝素的抗强化效率，而无需进一步增加肝素相关的散布散布的风险。该项目的具体目的是支持15H8开发针对研究的新药（IND）的应用是：1）评估鼠抗FXII抗体（15H8）在实验性体外膜外膜氧合（ECMO）的私人模型中的抗血栓形成效应（15H8），2）确定了重新和有效性15H8的活性和有效性15H8（RH1）。 RH15H8用于GLP毒性研究。 RH15H8方法代表了一种从根本上具有新的治疗性抗凝概念抗凝患者。该项目的成功并达到我们的关键里程碑将直接导致产品开发的下一个阶段，该阶段将包括GLP毒性和稳定性研究，IND制备和归档，然后是第一阶段第一阶段的第一阶段 - 对我们创新的抗血栓形成药物候选者的首个人类安全研究。