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Neutralizing Antibodies for Complement Inhibition

补体抑制的中和抗体

基本信息

批准号：
7801452
负责人：
Rekha Bansal
金额：
$ 30万
依托单位：
NOVELMED THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-11 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7801452
关键词：
Affect Alternative Complement Pathway Animal Model Animals Area Binding Blood Blood Platelets Blood flow Blood specimen Cardiac Cell Death Cells Cessation of life Chest Clinical Clinical Trials Complement Complement 3a Complement 5a Complement Activation Complement Membrane Attack Complex Cytolysis Data Deposition Disease Doctor of Philosophy Dose Drug Kinetics Elastases Ensure Euthanasia Event Excision Feasibility Studies Goals Health Heart Housing Human Immune system In Vitro Infarction Infection Inflammation Inflammation Mediators Injury Interruption Intestines Intravenous Ischemia Kidney Laboratories Lead Leukocytes Life Limb structure Liver Lung Measures Mediating Mediator of activation protein Modeling Monoclonal Antibodies Morbidity - disease rate Multiple Organ Failure Myocardial Infarction Myocardial Ischemia Neutrophil Activation Organ Oryctolagus cuniculus Pathologic Processes Pathology Pathway interactions Patients Perfusion Peroxides Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Phase Phase I Clinical Trials Plasma Platelet Activation Play Positioning Attribute Preparation Procedures Process Production Properdin Proteins Qualifying Reperfusion Injury Reperfusion Therapy Role Safety Schedule Scientist Skeletal Muscle Small Business Innovation Research Grant Stroke Technology Testing Therapeutic Therapeutic Monoclonal Antibodies Time Tissue Transplantation Tissues Toxic effect Trauma Treatment Efficacy Troponin T Tumor Necrosis Factor-alpha Tumor Necrosis Factors Vascular blood supply Work base clinical application cytokine drug candidate experience in vivo inhibitor/antagonist meetings monocyte myocardial infarct sizing neutralizing antibody neutrophil novel phase 1 study phase 2 study prevent prophylactic public health relevance research study restoration statistics

项目摘要

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.

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。血液供应的中断会导致局部缺血，这会迅速损害代谢活性组织。特别地，血流恢复到缺血组织引发一系列病理学，导致额外的细胞或组织损伤，称为缺血再灌注损伤（IRI）。I/R是旁路途径补体（AP）激活的有效诱导剂，这是一种诱导额外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靶向清除，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活化，随后产生补体因子C3 a、C5 a和膜攻击复合物（MAC）。MAC促进缺血组织中的细胞溶解，而C3 a和C5 a是有效的促炎介质，其激活先天免疫系统的细胞并上调其促炎细胞因子的产生。以这种方式，AP激活导致产生许多炎症介质，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时发生的血流重新存储在组织的缺血区域。NovelMed开发了一种新型单克隆抗体治疗剂，可特异性预防AP和AP介导的炎症激活，从而诱导再灌注引起的进一步组织损伤。NovelMed的主要候选药物结合并中和AP的关键蛋白质，以防止AP激活。NovelMed具有强有力的体外和离体数据，证明单克隆抗体抑制C3 a和C5 a的产生，下调中性粒细胞、单核细胞和血小板活化，并防止这些活化细胞产生的促炎介质的产生。初步数据还表明，这种生物治疗减少了心脏IRI动物模型中的IRI。第一阶段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。这种新型的生物抑制剂可能会发现广泛的临床应用，因为目前没有有效的药物疗法可用于预防或治疗IRI。. 公共卫生相关性：已知基于单克隆抗体的治疗是尖端技术。缺血再灌注（I/R）损伤是一种常见的临床事件，会对患者健康产生不利影响并可能导致患者死亡。血液供应的中断会导致局部缺血，这会迅速损害代谢活性组织。特别地，血流恢复到缺血组织引发一系列病理学，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反应在很大程度上由补体激活和补体激活抑制剂预防IRI来解释。NovelMed打算开发其领先的生物制剂YalcioMab，一种替代途径补体激活抑制剂，作为预防与IRI相关的严重且通常危及生命的并发症的治疗方法。