Therapeutic factor XI blockade for sepsis

治疗败血症的 XI 因子阻断

• 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
• 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

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（由申请人提供）：该 I 期 SBIR 拨款将支持单剂量注射生物制品候选物（重组人源化抗 XI 因子单克隆治疗性抗凝抗体）的初步商业开发，以用于研究性新药 (IND) 应用。主要适应症是严重细菌性败血症，这是住院患者死亡的主要原因之一。缺血导致脓毒症相关的弥散性血管内凝血（DIC）和全身炎症反应综合征（SIRS）的发病机制。抗血栓药物可能有效；然而，它们最有效的剂量会产生严重的出血副作用。除抗生素外，FDA 批准的治疗严重脓毒症的唯一方法是抗凝酶重组激活蛋白 C（APC，Xigris(r)），但在不太严重的病例中，APC 的出血副作用超过了其益处。我们的候选产品通过安全有效的 APC 替代品解决了主要的医疗需求。分子靶标是凝血因子 XI (FXI)。 FXI 缺陷可提高小鼠实验性多种微生物腹膜炎的存活率，初步数据表明，通过抗体抑制 FXI 进行抗凝可产生类似的益处。 FXI 抑制也可能通过减少缓激肽释放而具有抗炎作用。 FXI 的抗体抑制代表了一种全新的抗凝方法，因为 FXI 是止血和血栓形成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 进行抗凝可抗血栓持续一周以上，并且止血比肝素或阿司匹林更安全。目前尚无可比药物，因此如果AXIMAB研发成功，将具有巨大的市场潜力。具体目标是 1. 制备中和小鼠抗小鼠 FXI 单克隆抗体（mAXIMAB）； 2.确定mAXIMAB对脓毒症小鼠的疗效； 3. 确定 mAXIMAB 在首次实验小鼠中的止血安全性。积极的结果将支持 FXI 的药理抑制对脓毒症有益的假设。 公共卫生相关性：败血症时血管血栓闭塞会导致缺血，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，从而使其失去作用。除抗生素外，FDA 批准的治疗严重脓毒症的唯一方法是抗血栓酶、重组激活蛋白 C（APC、Xigris(r)），但在不太严重的脓毒症病例中，出血副作用超过了其益处。我们通过一种新的抗血栓抗体候选产品来满足这一主要医疗需求，为 APC 提供安全有效的替代品。