Therapeutic factor XI blockade for sepsis

描述(由申请人提供)：这笔第一阶段的SBIR赠款将支持单剂可注射生物制品候选产品--重组人源化抗凝血因子XI单抗的初步商业开发，以用于研究新药(IND)应用。主要的适应症是严重的细菌败血症，这是住院患者死亡的主要原因之一。脑缺血是脓毒症相关性弥散性血管内凝血(DIC)和全身炎症反应综合征(SIRS)的发病机制之一。抗血栓药物可能是有效的；然而，它们最有效的剂量可能会产生严重的出血副作用。除抗生素外，FDA批准的唯一治疗严重脓毒症的药物是抗凝酶重组活化蛋白C(APC，Xgris(R))，但在不太严重的病例中，APC的出血副作用大于其益处。我们的候选产品满足了主要的医疗需求，提供了一种安全有效的APC替代品。分子靶点是凝血因子XI(FXI)。FXI缺乏改善了实验性多菌性腹膜炎小鼠的存活率，初步数据表明，通过抗体抑制FXI进行抗凝也有类似的好处。抑制FXI也可能通过减少缓激肽的释放而起到抗炎作用。抗体抑制FXI代表了一种全新的抗凝方法，因为FXI是止血和血栓形成的分子机制汇聚的接触途径的一部分。在灵长类动物中，通过抗体抑制FXI的抗凝作用可持续一周以上，并且在止血方面比肝素或阿司匹林更安全。目前还不存在类似的药物，因此，如果AXIMAB成功开发，它将具有巨大的市场潜力。其具体目的是：1.制备中和鼠抗鼠FXI单抗(MAXIMAB)；2.测定mAXIMAB对脓毒症小鼠的疗效；3.测定mAXIMAB对NA小鼠的止血安全性。阳性结果将支持药物抑制FXI对脓毒症有益的假说。 公共卫生相关性：脓毒症患者血管血栓闭塞导致缺血，并导致严重全身炎症反应综合征的高死亡率。可能有效的抗血栓药物会产生严重的出血副作用，这使得它们没有多大用处。除抗生素外，FDA批准的治疗严重脓毒症的唯一药物是抗血栓酶，重组活化蛋白C(APC，XIGRIS(R))，但在不太严重的脓毒症病例中，出血副作用超过其益处。我们用一种新的抗血栓抗体候选产品满足了这一主要医学需求，为APC提供了一种安全有效的替代品。

DESCRIPTION (provided by applicant): This Phase I SBIR grant will support the initial commercial development of a single dose injectable biological product candidate, recombinant humanized anti-factor XI monoclonal therapeutic anticoagulant antibody, towards an investigational new drug (IND) application. The lead indication is severe bacterial sepsis, which is among the leading causes of mortality among hospitalized patients. Ischemia contributes to the pathogenesis of sepsis-associated disseminated intravascular coagulation (DIC) and systemic inflammatory response syndrome (SIRS). Antithrombotic drugs may be effective; however, their most potent doses can produce severe bleeding side effects. Apart from antibiotics, the only FDA-approved treatment for severe sepsis is the anticoagulant enzyme recombinant activated protein C (APC, Xigris(r)), but the bleeding side effects of APC outweigh its benefits in less severe cases. Our product candidate addresses a major medical need with a safe and effective alternative to APC. The molecular target is coagulation factor XI (FXI). FXI deficiency improves the survival of experimental polymicrobial peritonitis in mice, and preliminary data suggest that anticoagulation by antibody inhibition of FXI produces similar benefits. FXI inhibition may also be anti-inflammatory by reducing bradykinin liberation. Antibody inhibition of FXI represents a fundamentally new method of anticoagulation because FXI is part of the contact pathway where the molecular mechanisms of hemostasis and thrombosis converge. In primates, anticoagulation by antibody inhibition of FXI is antithrombotic for more than a week, and hemostatically safer than heparin or aspirin. No comparable drugs exist, and thus if AXIMAB is successfully developed, it would have significant market potential. The Specific Aims are to 1. Prepare neutralizing mouse anti-mouse FXI monoclonal antibody (mAXIMAB); 2. Determine the efficacy of mAXIMAB in septic mice; and 3. Determine the hemostatic safety of mAXIMAB in na¿ve mice. Positive results will support the hypothesis that pharmacological inhibition of FXI is beneficial in sepsis. PUBLIC HEALTH RELEVANCE: Thrombotic occlusion of blood vessels in sepsis causes ischemia and contributes to the high mortality rate of severe systemic inflammatory response syndrome. Antithrombotic drugs that could be effective produce severe bleeding side effects, which render them less than useful. Apart from antibiotics, the only FDA approved treatment for severe sepsis is the antithrombotic enzyme, recombinant activated protein C (APC, Xigris(r)), but bleeding side effects outweigh its benefits in less severe sepsis cases. We address this major medical need with a new antithrombotic antibody product candidate to provide a safe and effective alternative to APC.