HLS- Factor XII Inhibitor for Surface Initiated Thrombosis

 描述(由申请人提供)：此第一阶段/第二阶段快速通道申请正在根据NHLBI 2016财年特别关注的小型企业主题(HLS16-04)重新提交。某些挽救生命的干预措施，如体外循环(CPB)、体外膜氧合(ECMO)或脑室辅助装置(VAD)泵，需要使用大剂量肝素来维持通过装置的血流和/或预防下游血栓栓塞症并发症。其他几种侵入性血管手术也利用了深刻的暂时性抗凝，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。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)参与了血栓形成的进展，因此是一类新的抗血栓药物的潜在靶点。由于数据表明FXII不有助于止血，而且FXII缺乏是哺乳动物的一种无症状状态，抑制FXII不太可能有显著的不良影响。我们已经通过免疫FXII基因敲除小鼠而产生了一种专有的抗人FXII的鼠单抗15H8，并在初步的灵长类动物实验中验证了它的抗凝和抗血栓作用。这个拟议的I/II阶段快速通道项目将启动15H8重组人源化版本(Rh15H8)的商业开发，该产品候选产品可以作为独立的或辅助抗凝剂使用，以增加肝素的抗血栓功效，而不会进一步增加肝素相关的出血风险。为支持15H8向研究新药(IND)应用方向发展所必需的该项目的具体目标是：1)在实验性体外膜氧合(ECMO)的灵长类动物模型中评估鼠抗FXII抗体(15H8)的抗血栓作用；2)确定重组人源化15H8(Rh15H8)的活性和有效性；以及3)制造用于GLP毒性研究的rh15H8。Rh15H8方法代表了一种全新的治疗抗凝概念，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液凝块的形成，而不会对危重患者的残余出血控制产生不利影响。 抗凝血的病人。该项目的成功和达到我们的关键里程碑将直接导致下一阶段的产品开发，这将包括GLP毒性和稳定性研究、IND准备和归档，然后启动我们创新的抗血栓候选药物的第一阶段人类安全性研究。

 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.