Neutralizing Antibodies for Complement Inhibition

描述(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，有时甚至导致死亡。血液供应中断会导致缺血，从而迅速损害代谢活跃的组织。矛盾的是，血流恢复到缺血组织会引发一连串的病理变化，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)激活的有效诱导者，AP是一种诱导额外的细胞或组织损伤的事件。在再灌注过程中，死亡细胞被先天免疫系统，特别是AP清除，然而，在这个过程中，正常的健康细胞(无辜的旁观者)也被破坏。心脏、肠道、肾脏、四肢和肝脏的临床和实验研究表明，I/R导致AP激活，随后产生补体因子C3a、C5a和膜攻击复合体(MAC)。Mac促进缺血组织中的细胞溶解，而C3a和C5a是强有力的促炎介质，激活先天免疫系统的细胞，并上调其促炎细胞因子的产生。通过这种方式，AP激活导致大量炎症介质的产生，从而进一步促进细胞死亡和组织损伤。我们的工作重点是防止当血流重新储存在组织缺血区时发生的再灌注损伤和细胞死亡。NovelMed已经开发出一种新的单抗治疗方法，可以特异性地防止AP的激活和AP介导的炎症，后者在再灌注时会导致进一步的组织损伤。NovelMed的主要候选药物结合并中和AP的一种关键蛋白质，以防止AP激活。NovelMed有强大的体外和体外数据表明，单抗抑制C3a和C5a的产生，下调中性粒细胞、单核细胞和血小板的激活，并阻止这些激活的细胞产生促炎介质。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。这一阶段SBIR的目标是完成可行性研究，证明开发这种尖端的单抗技术来预防IRI的治疗价值。由于目前还没有有效的药物疗法来预防或治疗IRI，这种新型的生物抑制剂可能会在临床上得到广泛的应用。。 与公共健康相关：基于单抗的疗法是已知的尖端技术。缺血再灌注(I/R)损伤是一种常见的临床事件，可对患者健康造成不利影响，并可导致患者死亡。血液供应中断会导致缺血，从而迅速损害代谢活跃的组织。矛盾的是，血流恢复到缺血组织会引发一连串的病理变化，导致额外的细胞或组织损伤，称为缺血再灌注损伤(IRI)。导致额外的细胞和组织损伤的病理级联在很大程度上是由补体激活和补体激活的抑制剂阻止IRI解释的。NovelMed打算开发一种替代途径补体激活抑制剂YalcioMab，作为一种治疗方法，以预防与IRI相关的严重且往往危及生命的并发症。

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.