Therapeutic factor XI blockade for sepsis

描述(由申请人提供)：这笔SBIR第二阶段拨款将支持一种可注射的候选生物制品的商业开发，这是一种独特的专利重组人源化抗XI因子单抗(AXIMAB)，用于研究新药(IND)应用。AXIMAB的主要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。脓毒症相关的弥漫性血管内凝血(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感染性DIC，但其抗血栓剂量会产生严重的出血副作用。除抗生素外，FDA批准的治疗严重脓毒症的唯一药物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。对于更安全和更有效的治疗，有一个重大的未得到满足的医疗需求，我们的候选产品通过提供APC的替代方案来满足这一需求。在灵长类动物中，使用我们的抗FXI抗体1A6或14E11进行抗凝是安全和抗血栓的。我们的SBIR I期数据表明，使用我们通用的抗FXI抗体14E11进行抗凝可以提高小鼠多菌腹膜炎的存活率，同时减少脓毒症的炎症和凝血反应，我们的II期初步研究表明，在败血症李斯特氏菌病期间使用14E11治疗对小鼠的存活率有好处。我们已经证明，14E11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，因此用14E11阻断FXIIa对血栓前状态FXI的激活可转化为具有前所未有的安全性的治疗性抗凝。由于没有类似的产品，AXIMAB 14E11将成功地与APC和其他正在开发的抗凝血剂竞争，包括活化的FXI抑制剂，因此具有非常大的市场潜力。具体目的是：1.评价AXIMAB 14E11治疗实验性微生物特异性脓毒症的疗效；2.测定GMP级人源化重组AXIMAB批次的活性和稳定性；3.在临床前研究中测定人源化AXIMAB的毒性。这一第二阶段项目的成功将支持AXIMAB进入临床研究。 公共卫生相关性：血栓阻塞血管是导致脓毒症高死亡率的重要原因，而有效对抗血管内血栓的药物(抗血栓药物或“血液稀释剂”)的效用有限，因为它们还会加重严重脓毒症的出血倾向(凝血障碍)。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激活蛋白C(APC，XIGRIS(R))，但出血副作用往往大于其益处。缺乏安全和有效的脓毒症治疗是一个主要的未得到满足的医疗需求，我们开发了一种新的抗血栓分子，一种不会导致出血的治疗性抗凝血因子XI抗体，从而为治疗脓毒症的凝血并发症提供了一种安全的替代方案。1

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