Neutralizing Antibodies for Complement Inhibition

描述（由申请人提供）：缺血再灌注（I/R）损伤是一种常见的临床事件，有可能严重影响患者，有时甚至导致患者死亡。血液供应中断导致缺血，从而迅速损害代谢活跃的组织。矛盾的是，缺血组织血流的恢复引发了一系列病理反应，导致额外的细胞或组织损伤，称为缺血再灌注损伤（IRI）。I/R是替代途径补体（AP）激活的有效诱导剂，AP激活可诱导额外的细胞或组织损伤。在再灌注过程中，死亡细胞被先天免疫系统，特别是AP靶向清除，但在此过程中，正常健康细胞（无辜的旁观者）也被破坏。心脏、肠道、肾脏、肢体和肝脏的临床和实验研究表明，I/R导致AP活化，随后产生补体因子C3a、C5a和膜攻击复合物（MAC）。MAC促进缺血组织的细胞裂解，而C3a和C5a是有效的促炎介质，激活先天免疫系统细胞，上调其促炎细胞因子的产生。通过这种方式，AP激活导致许多炎症介质的产生，这些炎症介质进一步促进细胞死亡和组织损伤。我们的工作重点是防止再灌注损伤和细胞死亡发生时，血流重新储存在组织的缺血区域。NovelMed开发了一种新的单克隆抗体治疗方法，可以特异性地阻止AP和AP介导的炎症的激活，而AP介导的炎症会在再灌注时引起进一步的组织损伤。NovelMed的主要候选药物结合并中和AP的关键蛋白，以防止AP激活。NovelMed有大量的体外和离体数据表明，单克隆抗体抑制C3a和C5a的产生，下调中性粒细胞、单核细胞和血小板的激活，并阻止这些活化细胞产生的促炎介质的产生。初步数据还表明，在心脏IRI动物模型中，这种生物治疗可以减少IRI。该I期SBIR的目标是完成可行性研究，证明开发这种尖端单克隆抗体技术预防IRI的治疗价值。由于目前还没有有效的药物治疗来预防或治疗IRI，这种新型生物抑制剂可能会有广泛的临床应用。

DESCRIPTION (provided by applicant): Ischemia-reperfusion (I/R) injury is a common clinical event, which has the potential to seriously affect, and sometimes result in death, of the patient. Interruption of the blood supply causes ischemia, which rapidly damages metabolically active tissues. Paradoxically, restoration of blood flow to the ischemic tissues initiates a cascade of pathology that leads to additional cell or tissue injury, termed ischemic reperfusion injury (IRI). I/R is a potent inducer of alternative pathway complement (AP) activation, an event that induces additional cell or tissue injury. In the process of reperfusion, dead cells are targeted for removal by the innate immune system, particular the AP, however, in this process normal healthy cells (innocent bystanders) are also destroyed. Clinical and experimental studies in heart, gut, kidney, limb and liver have shown that I/R results in AP activation with subsequent production of the complement factors, C3a, C5a and membrane attack complex (MAC). MAC promotes cell lysis in the ischemic tissue, while C3a and C5a are potent pro-inflammatory mediators that activate cells of the innate immune system and up regulate their production of proinflammatory cytokines. In this manner, AP activation results in the production of a number of inflammatory mediators that further promote cell death and tissue injury. Our work focuses on preventing the reperfusion injury and cell death that occurs when the blood flow is re-stored in the ischemic area of tissues. NovelMed has developed a novel monoclonal antibody therapeutic that specifically prevents activation of the AP and AP-mediated inflammation that induces further tissue damage with reperfusion. NovelMed's lead drug candidate binds and neutralizes a critical protein of the AP to prevent AP activation. NovelMed has strong in vitro and ex vivo data demonstrating that the monoclonal antibody inhibits C3a and C5a production, down regulates neutrophil, monocyte, and platelet activation and prevent production of proinflammatory mediators that these activated cells produce. Preliminary data also indicate that this biologic treatment reduces IRI in a heart IRI animal model. The goals of this phase I SBIR is to complete feasibility studies demonstrating the therapeutic value of developing this cutting-edge monoclonal antibody technololgy to prevent IRI. This novel biologic inhibitor may find wide clinical applications,as there are no effective drug therapies currently available to prevent or treat IRI. . PUBLIC HEALTH RELEVANCE: Monoclonal antibody based therapeutics are known to be cutting-edge technology. Ischemia-reperfusion (I/R) injury is a common clinical event, which can adversely affect patient health and can result in patient death. Interruption of the blood supply causes ischemia, which rapidly damages metabolically active tissues. Paradoxically, restoration of blood flow to the ischemic tissues initiates a cascade of pathology that leads to additional cell or tissue injury, termed ischemic reperfusion injury (IRI). The cascade of pathology that leads to additional cell and tissue injury is largely explained by complement activation and inhibitor of complement activation prevents IRI. NovelMed intends to develop it lead biologic, YalcioMab, an alternative pathway complement activation inhibitor, as a treatment to prevent the serious and often life-threatening complications associated with IRI.