Therapeutic factor XI blockade for sepsis

治疗败血症的 XI 因子阻断

• 批准号: 8314635
• 负责人: Andras Gruber
• 金额: $ 100万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314635
• 关键词: Abdomen; Address; Adverse effects; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antibodies; Anticoagulants; Anticoagulation; Aspirin; Binding; Biological Products; Blood Clot; Blood Coagulation Disorders; Blood coagulation; Cause of Death; Cell Line; Chemistry; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Complication; Data; Development; Disease susceptibility; Disseminated Intravascular Coagulation; Dose; Enzymes; FDA approved; Factor XI; Factor XI Deficiency; Factor XIIa; Factor XIa; Gram-Positive Bacterial Infections; Grant; Guidelines; Hemorrhage; Hemostatic function; Heparin; Human; Hybridomas; Impairment; In Vitro; Incidence; Infection; Inflammatory; Influenza; Injectable; Intestines; Investigation; Investigational Drugs; Investigational New Drug Application; Ischemia; Ischemic Stroke; Lead; Life; Lilly brand of drotrecogin alfa activated; Listeriosis; Marketing; Medical; Methods; Microbe; Modeling; Monoclonal Antibodies; Mus; No-Observed-Adverse-Effect Level; Organ; Organ Specificity; Organism; Outcome; Pamphlets; Papio; Patients; Perforation; Perfusion; Peritoneal; Peritonitis; Pharmaceutical Preparations; Pharmacology; Phase; Pneumococcal Pneumonia; Primates; Process; Production; Protein C; Quality Control; Recombinants; Research Contracts; Research Personnel; Risk; Safety; Sepsis; Sepsis Syndrome; Small Business Innovation Research Grant; Solid; Staging; Sterility; Systemic infection; Testing; Therapeutic; Therapeutic antibodies; Thrombosis; Thrombus; Toxic effect; Translating; Vial device; Work; activated Protein C; antigen binding; base; blood vessel occlusion; effective therapy; experience; immunogenicity; improved; inhibitor/antagonist; meetings; microbial; mortality; pre-clinical; preclinical study; preclinical toxicity; prevent; product development; response; safety study; safety testing; septic; success

DESCRIPTION (provided by applicant): This SBIR Phase II grant will support the commercial development of an injectable biological product candidate, a unique proprietary recombinant humanized anti-factor XI monoclonal antibody (AXIMAB), towards an investigational new drug (IND) application. The lead indication for AXIMAB is severe bacterial sepsis, which is a major cause of mortality in hospitalized patients. Sepsis-associated disseminated intravascular coagulation (DIC) contributes to organ perfusion deficits, ischemia, and a systemic inflammatory response syndrome (SIRS). Antithrombotic drugs may effectively limit septic DIC; however, their antithrombotic 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 can often outweigh its benefits. There is a major unmet medical need for safer and more effective treatments, and our product candidate addresses this need by providing an alternative to APC. In primates, anticoagulation with our anti-FXI antibodies 1A6 or 14E11 is safe and antithrombotic. Our SBIR Phase I data demonstrate that anticoagulation with our universal anti-FXI antibody 14E11 improves the survival of polymicrobial peritonitis in mice, while reducing the inflammatory and coagulation responses to sepsis, and our Phase II preliminary studies show a survival benefit for mice treated with 14E11 during septic Listeriosis. We have demonstrated that 14E11 selectively inhibits factor XI (FXI) activation by factor XIIa (FXIIa). Since FXI activation by FXIIa is independent of hemostasis, using 14E11 for blocking prothrombotic FXI activation by FXIIa could translate into therapeutic anticoagulation with unprecedented safety. Since no comparable product exists, AXIMAB 14E11 would compete successfully with APC and other anticoagulants under development, including activated FXI inhibitors, and therefore has a very large market potential. The Specific Aims are to 1. Evaluate the efficacy of AXIMAB 14E11 treatment in experimental microbe-specific sepsis; 2. Determine the activity and stability of GMP-grade humanized recombinant AXIMAB batches; and 3. Determine the toxicity of humanized AXIMAB in preclinical studies. Success of this Phase II project will support the advancement of AXIMAB into clinical studies. PUBLIC HEALTH RELEVANCE: Occlusion of blood vessels by clots significantly contributes to the high mortality rate of sepsis, and drugs that are effective against blood clots in vessels (antithrombotic drugs or "blood thinners") have only limited utility because they also aggravate the bleeding tendency (coagulopathy) that characterizes severe sepsis. 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 often outweigh its benefits. The lack of safe and effective sepsis treatments represents a major unmet medical need that we address with the development of a new antithrombotic molecule, a therapeutic anti-factor XI antibody that does not cause bleeding and thus provides a safe alternative to APC for treating the coagulopathic complications of sepsis. 1

描述（由申请人提供）：这笔 SBIR II 期拨款将支持可注射生物产品候选物的商业开发，这是一种独特的专有重组人源化抗因子 XI 单克隆抗体 (AXIMAB)，用于研究性新药 (IND) 应用。 AXIMAB 的主要适应症是严重的细菌性败血症，这是住院患者死亡的主要原因。脓毒症相关的弥散性血管内凝血（DIC）会导致器官灌注不足、缺血和全身炎症反应综合征（SIRS）。抗血栓药物可有效限制脓毒症DIC；然而，它们的抗血栓剂量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方法是抗凝酶重组激活蛋白 C（APC，Xigris(R)），但 APC 的出血副作用往往超过其益处。对更安全、更有效的治疗的医疗需求尚未得到满足，我们的候选产品通过提供 APC 的替代品来满足这一需求。在灵长类动物中，使用我们的抗 FXI 抗体 1A6 或 14E11 进行抗凝治疗是安全且抗血栓的。我们的 SBIR I 期数据表明，使用我们的通用抗 FXI 抗体 14E11 进行抗凝可改善小鼠多种微生物腹膜炎的存活率，同时减少对脓毒症的炎症和凝血反应，而我们的 II 期初步研究表明，在脓毒症李斯特菌病期间用 14E11 治疗的小鼠具有存活获益。我们已经证明 14E11 选择性抑制因子 XIIa (FXIIa) 激活因子 XI (FXI)。由于 FXIIa 激活 FXI 与止血无关，因此使用 14E11 阻断 FXIIa 激活血栓前 FXI 可以转化为治疗性抗凝，具有前所未有的安全性。由于没有可比产品，AXIMAB 14E11将成功与APC和其他正在开发的抗凝剂（包括活化的FXI抑制剂）竞争，因此具有非常大的市场潜力。具体目标是 1. 评估 AXIMAB 14E11 治疗实验性微生物特异性败血症的疗效； 2. 测定GMP级人源化重组AXIMAB批次的活性和稳定性； 3. 在临床前研究中确定人源化 AXIMAB 的毒性。该二期项目的成功将支持 AXIMAB 进入临床研究。 公众健康相关性：血栓闭塞血管会导致脓毒症的高死亡率，而有效对抗血管血栓的药物（抗血栓药物或“血液稀释剂”）的作用有限，因为它们还会加重严重脓毒症的出血倾向（凝血病）。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)），但出血副作用往往超过其益处。缺乏安全有效的脓毒症治疗方法是一个未满足的主要医疗需求，我们通过开发一种新的抗血栓分子来解决这一需求，这是一种不会引起出血的治疗性抗因子 XI 抗体，因此为治疗脓毒症的凝血病并发症提供了 APC 的安全替代品。 1