Therapeutic factor XI blockade for sepsis

治疗败血症的 XI 因子阻断

• 批准号: 8467669
• 负责人: Andras Gruber
• 金额: $ 97.46万
• 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/8467669
• 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.

描述（由申请人提供）：该SBIR II期资助将支持可注射生物制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）申请。AXIMAB的主要适应症是严重细菌性脓毒症，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）导致器官灌注不足、缺血和全身炎症反应综合征（SIRS）。抗血栓药物可以有效地限制脓毒性DIC;然而，它们的抗血栓剂量可以产生严重的出血副作用。除了抗生素外，FDA批准的唯一治疗严重脓毒症的方法是抗凝酶重组活化蛋白C（APC，Xigris（R）），但APC的出血副作用往往超过其益处。对于更安全、更有效的治疗，存在着一个重大的未满足的医疗需求，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1A 6或14 E11进行抗凝治疗是安全和抗血栓形成的。我们的SBIR I期数据表明，使用我们的通用抗FXI抗体14 E11进行抗凝治疗可改善小鼠多微生物腹膜炎的存活率，同时降低对脓毒症的炎症和凝血反应，我们的II期初步研究显示，在脓毒性李斯特菌病期间使用14 E11治疗的小鼠具有存活获益。我们已经证明，14 E11选择性地抑制因子XIIa（FXIIa）激活因子XI（FXI）。由于FXIIa对FXI的激活不依赖于止血，因此使用14 E11阻断FXIIa对血栓前FXI的激活可转化为具有前所未有安全性的治疗性抗凝。由于不存在可比产品，AXIMAB 14 E11将与APC和其他正在开发的抗凝剂（包括活化的FXI抑制剂）成功竞争，因此具有非常大的市场潜力。具体目标是1。评价AXIMAB 14 E11治疗实验性微生物特异性脓毒症的疗效; 2.确定GMP级人源化重组AXIMAB批次的活性和稳定性;和3.在临床前研究中确定人源化AXIMAB的毒性。该II期项目的成功将支持AXIMAB进入临床研究。