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.

说明（由申请人提供）：此 I/II 期快速通道申请正在根据 2016 财年 NHLBI 小企业特别关注主题 (HLS16-04) 某些挽救生命的干预措施（例如心肺搭桥）重新提交。 CPB）、体外膜肺氧合（ECMO）或心室辅助装置（VAD）泵需要使用高剂量肝素来维持通过装置的血流和/或一些其他侵入性血管手术也利用深度暂时抗凝，例如在人工血管移植物植入期间和之后，不幸的是，肝素等抗血栓药物无意中针对重要的止血分子机制，并可能产生严重的剂量限制性出血毒性。试验中，必须限制抗凝水平以平衡出血与血栓形成的风险，因此，我们最近的研究表明，血栓并发症可能很频繁且具有破坏性。凝血因子 XII (FXII) 有助于血栓形成的进展，因此是一类新型抗血栓药物的潜在靶点，因为数据表明 FXII 不有助于止血，并且 FXII 缺乏是哺乳动物的一种无症状病症，因此抑制 FXII 是一种有效的治疗方法。我们已经生成了一种针对人 FXII 的专有鼠单克隆抗体 15H8，该抗体是通过免疫 FXII 敲除而产生的。小鼠，并在初步灵长类动物实验中验证了其抗凝血和抗血栓作用。该拟议的 I/II 期快速通道项目将启动 15H8 (rh15H8) 的重组人源化版本的商业开发，这是一种可用作标准的候选产品。单独或作为辅助抗凝剂，以提高肝素的抗血栓功效，而不进一步增加肝素相关的出血风险。支持 15H8 开发以实现研究性新药 (IND) 应用的必要条件是：1) 在实验性体外膜氧合 (ECMO) 灵长类动物模型中评估鼠抗 FXII 抗体 (15H8) 的抗血栓形成作用，2) 确定重组人源化 15H8 (rh15H8) 的活性和功效，以及 3) 制造用于 GLP 毒性的 rh15H8 rh15H8 方法代表了一种全新的抗凝治疗概念，因为 FXII 抑制有望减少合成移植物和体外装置中接触引发的血栓形成，而不会影响危重患者的残余出血控制。该项目的成功并达到我们的关键里程碑将直接进入下一阶段的产品开发，其中包括 GLP 毒性和稳定性研究、IND 准备和备案，然后启动第一阶段人体安全性。我们的创新抗血栓候选药物的研究。