Therapeutic factor XI blockade for sepsis

治疗败血症的 XI 因子阻断

基本信息

批准号：
7910359
负责人：
Andras Gruber
金额：
$ 29.75万
依托单位：
ARONORA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-10 至 2011-12-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7910359
关键词：
Abdomen Address Adult Respiratory Distress Syndrome Adverse effects Anti-Inflammatory Agents Anti-inflammatory Antibiotics Antibodies Anticoagulants Anticoagulation Aspirin Benign Biological Assay Biological Products Bleeding time procedure Bradykinin C57BL/6 Mouse Cell Line Cells Cessation of life Coagulation Process Data Development Disseminated Intravascular Coagulation Dose Drug Kinetics Enzymes FDA approved Factor XI Factor XI Deficiency Factor XIIa Funding Grant Hemorrhage Hemostatic Agents Hemostatic function Heparin Hour Hybridomas Impairment Inflammatory Injectable Intestines Investigational Drugs Investigational New Drug Application Ischemia Ischemic Stroke Lead Lilly brand of drotrecogin alfa activated Marketing Medical Methods Molecular Molecular Target Monoclonal Antibodies Mus Outcome Papio Pathogenesis Pathway interactions Patients Perforation Peritonitis Pharmaceutical Preparations Pharmacodynamics Phase Phenotype Plasma Primates Recombinants Safety Sepsis Sepsis Syndrome Small Business Innovation Research Grant Solid Tail Testing Therapeutic Therapeutic Monoclonal Antibodies Thrombin Thrombosis Time activated Protein C alternative treatment blood vessel occlusion cohort improved inhibitor/antagonist mortality neutralizing antibody pre-clinical product development public health relevance research study septic success

项目摘要

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.

描述（应用程序提供）：本I期SBIR赠款将支持单剂量注射生物学产品候选者的初步商业开发，重组人性化的抗因子XI单克隆单克隆治疗抗凝抗体，用于研究新药（IND）应用。铅指示是严重的细菌败血症，这是住院患者死亡的主要原因之一。缺血有助于败血症相关的散布性血管内凝血（DIC）和全身性炎症反应综合征（SIRS）的发病机理。抗血栓药物可能有效；但是，它们最有效的剂量会产生严重的出血副作用。除了抗生素外，严重败血症的唯一FDA批准的治疗方法是抗凝酶重组活化蛋白C（APC，Xigris（R）），但APC的出血副作用在不太严重的情况下大于其益处。我们的产品候选人以APC的安全有效替代方案解决了主要的医疗需求。分子靶标是凝结因子XI（FXI）。 FXI缺乏提高了小鼠实验性多因素性腹膜炎的存活，初步数据表明，通过FXI抗体抑制抗凝抗凝产生类似的益处。 FXI抑制作用也可能通过减少心动激肽释放而具有抗炎作用。 FXI的抗体抑制是一种从根本上开始的抗凝方法，因为FXI是接触途径的一部分，其中止血和血栓形成的分子机制会融合。在私有情况下，FXI抗体抑制作用抗血栓形成超过一周，而止血比肝素或阿司匹林更安全。不存在可比的药物，因此，如果成功开发出斧头示射，它将具有巨大的市场潜力。具体目的是1。制备中和小鼠抗小鼠FXI单克隆抗体（Maximab）； 2。确定马克西单抗在化粪池小鼠中的效率；和3。确定NA¿VE小鼠中马克昔单抗的止血安全。积极的结果将支持以下假设：FXI的药物抑制对败血症是有益的。公共卫生相关性：败血症原因缺血的血管阻塞，并导致严重的全身炎症反应综合征的高死亡率。可以有效产生严重的出血副作用的抗血栓形成药物，从而使它们少于有用。除抗生素外，唯一获得严重败血症的FDA批准的治疗方法是抗血栓性酶，重组活化蛋白C（APC，Xigris（r）），但在不太严重的败血症病例中出血副作用大于其益处。我们使用新的抗强化抗体产品候选者来满足这一主要医疗需求，以提供APC的安全有效替代品。