HLS- Factor XII Inhibitor for Surface Initiated Thrombosis

 描述（由申请人提供）：此I/II期快速通道申请将根据2016财年特别关注的NHLBI小企业主题（HLS 16 -04）重新提交。某些挽救生命的干预措施，如心肺转流（CPB）、体外膜氧合（ECMO）或心室辅助装置（VAD）泵，需要使用高剂量肝素来维持血流通过装置和/或预防下游血栓栓塞并发症。其他几种侵入性血管手术也使用了深度时间抗凝，例如在假体血管移植物植入期间和之后。不幸的是，抗血栓药物如肝素无意中靶向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。因此，必须限制抗凝水平，以平衡出血和血栓形成的风险。因此，血栓性并发症可能是频繁和毁灭性的。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，因此是一类新的抗血栓药物的潜在目标。由于数据表明FXII不有助于止血，并且FXII缺乏是哺乳动物中的无症状病症，因此FXII抑制不太可能具有显著的不良作用。我们已经产生了一种专有的鼠单克隆抗体，15 H8，针对人FXII，是通过免疫FXII基因敲除小鼠，并验证其抗凝血和抗血栓形成的初步灵长类动物实验的影响。这个拟议的I/II期快速通道项目将启动重组人源化版本15 H8（rh 15 H8）的商业开发，这是一种候选产品，可用作独立或辅助抗凝剂，以增加肝素的抗血栓疗效，而不会进一步增加肝素相关的出血风险。该项目的具体目标是支持15 H8开发以实现研究性新药（IND）申请，这是必要的：1）在实验性体外膜氧合（ECMO）的灵长类动物模型中评价鼠抗FXII抗体（15 H8）的抗血栓形成作用，2）测定重组人源化15 H8（rh 15 H8）的活性和功效，和3）制备用于GLP毒性研究的rh 15 H8。rh 15 H8方法代表了一种全新的治疗性抗凝概念，因为FXII抑制预期可减少合成移植物和体外装置中接触引发的血凝块的形成，而不会对危重患者的残余出血控制产生有害影响， 抗凝患者该项目的成功和达到我们的关键里程碑将直接导致产品开发的下一阶段，包括GLP毒性和稳定性研究、IND制备和备案，随后启动我们的创新抗血栓候选药物的1期首次人体安全性研究。

 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.