Peptide inhibition of complement-mediated hemolysis after xenotransfusion.

异种输血后补体介导的溶血的肽抑制。

基本信息

批准号：
9129167
负责人：
KENJI Mason CUNNION
金额：
$ 14.99万
依托单位：
CHILDREN'S SPECIALTY GROUP, PLLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9129167
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Aftercare Alternative Complement Pathway American Amino Acids Animal Disease Models Animal Model Anti-Inflammatory Agents Anti-inflammatory Antibodies Antigens Autoimmune Process Automobile Driving Binding Blocking Antibodies Blood Pressure Cells Classical Complement Pathway Clinical Complement Complement Activation Complement Inactivators Complement Membrane Attack Complex Cytolysis Data Development Disease Dose Drug Design Drug Kinetics Epinephrine Erythrocytes Evaluation FDA approved Fever Flow Cytometry Future Goals Gold Graft Rejection Hemoglobin Hemolysis Human Human body Hypotension Immunologic Surveillance Immunology In Vitro Increased sweating Inflammation Inflammatory Intellectual Property Intervention Lead Legal patent Measurement Mediating Medical Medicine Methods Minor Modeling Organ Orphan Drugs Outcome Pathogenesis Pathway interactions Patients Peptides Pharmaceutical Preparations Phase Physician Executives Pilot Projects Play Population Prophylactic treatment Proteins Protocols documentation Rattus Reaction Red Cross Reperfusion Injury Research Project Grants Risk Role Saline Serum Sickle Cell Anemia Small Business Innovation Research Grant Supportive care Symptoms Technology Testing Tissues Toxic effect Toxicology Transfusion Underserved Population Wistar Rats cobra venom factor complement system efficacy testing high risk human disease inhibiting antibody novel phase 2 study pre-clinical prevent prophylactic public health relevance research study success treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The hypothesis for this project is that a novel compound, Peptide Inhibitor of complement C1 (PIC1), will inhibit antibody-initiated, complement-mediated cell destruction in a xenotransfusion animal model. Complement is the most potent inflammatory cascade in humans and is initiated by antibodies driving classical pathway activation and host cell destruction in many inflammatory diseases. One such disease is Acute Intravascular Hemolytic Transfusion Reaction (AIHTR), which is a highly lethal form of transfusion reaction. Frequently transfused populations (e.g., sickle cell disease) are at greatly increased risk of AIHTR, due to development of antibodies against minor erythrocyte antigens. Currently, no treatment exists to prevent or treat AIHTR besides supportive care and thus, represents a critical unmet medical need including underserved populations like sickle cell disease patients. We have developed a simple and robust model of AIHTR in rats, which we will use to test PIC1. Our current lead compound of PIC1 (PA-CPEG), is the product of years of rational drug design yielding a 15 amino acid peptide conjugated with PEG. Our compound binds to the initiating component of the classical pathway, C1, efficiently blocking antibody-initiated complement activation at the first step in the cascade. PIC1 is delivered in a saline vehicle and has reproducibly shown in multiple dosing studies to block classical complement activation in rats. This inhibition is rapid, 30 seconds, and potent, >90% inhibition of classical complement activation. We have performed a pilot experiment using PIC1 to inhibit hemolysis of mismatched erythrocytes in our xenotransfusion protocol. PIC1 demonstrated a dose- dependent effect and at high dose profoundly inhibited complement-mediated intravascular hemolysis to the same degree as the gold-standard cobra venom factor (CVF). Thus, this pilot experiment demonstrated that PIC1 can completely block antibody-initiated classical complement-mediated cell destruction. The proposed studies will refine the dosing of PIC1 and then conduct fully powered studies to evaluate the efficacy of PIC1 in inhibiting AIHTR in the rat model. We will test PIC1 in both a prophylactic strategy and an intervention treatment strategy. The prophylactic treatment strategy will mimic the clinical scenario of the patient at high risk fo AIHTR who could potentially receive PIC1 prior to transfusion. The intervention treatment strategy will mimic the clinical scenario where the transfusion begins and the patient develops fever, diaphoresis and hypotension. In addition to receiving epinephrine to support blood pressure, the patient could also receive PIC1 to inhibit the mechanism of pathogenesis and prevent further hemolysis and acute kidney injury. The success of the proposed studies will provide critical proof-of-concept that PIC1 can prevent complement- mediated pathogenesis in an animal model of human disease. This will provide the necessary evidence to propel the future pre-clinical development of PIC1 through pharmacokinetic and toxicology studies.

描述（由适用提供）：该项目的假设是一种新颖的化合物，C1（PIC1）的肽抑制剂（PIC1），将抑制异种转移动物模型中的抗体引起的补体，补体介导的细胞破坏。补体是人类中最潜在的炎症性级联反应，是通过驱动经典途径激活和许多炎症性疾病的宿主细胞破坏的抗体引发的。一种这样的疾病是急性血管内溶血输血反应（AIHTR），这是一种高度致命的翻译反应形式。由于对较小的红细胞抗原的抗体发展，经常翻译的种群（例如镰状细胞疾病）大大增加了AIHTR的风险。目前，除了支持性护理外，还没有治疗可以预防或治疗AIHTR，因此代表了关键的未满足的医疗需求，包括服务不足的人群，例如镰状细胞病患者。我们已经在大鼠中开发了一种简单且强大的AIHTR模型，我们将使用该模型来测试PIC1。我们目前的PIC1（PA-CPEG）铅化合物是多年合理药物设计的产物，产生了与PEG结合的15个氨基酸肽。我们的化合物与经典途径C1的启动组件结合，有效地阻止了级联的第一步。 PIC1在盐水中递送，并在多种剂量研究中可重复显示，以阻止大鼠的经典补体激活。这种抑制作用是快速的，30秒，潜力> 90％的经典补体激活抑制作用。我们已经使用PIC1进行了试点实验，以抑制异种输血方案中不匹配的红细胞的溶血。 PIC1表现出剂量依赖性的作用，并且在高剂量下，与金标准的眼镜蛇毒液因子（CVF）相同，深刻抑制补体介导的血管内溶血。该试验实验表明，PIC1可以完全阻止抗体引起的经典补体介导的细胞破坏。拟议的研究将完善PIC1的剂量，然后进行完全动力的研究，以评估PIC1在抑制大鼠模型中AIHTR中的有效性。我们将在预防策略和干预治疗策略中测试PIC1。预防性治疗策略将模仿患者高风险的患者的临床情况，后者可能会在转移之前接受PIC1。干预治疗策略将模仿转移开始的临床方案，并且患者会出现发烧，发汗和低血压。除了接受肾上腺素以支持血压外，患者还可以接收PIC1以抑制发病机理的机理，并防止进一步的溶血和急性肾脏损伤。拟议的研究的成功将提供关键的概念概念，即PIC1可以防止在人类疾病的动物模型中完成介导的发病机理。这将提供必要的证据，以通过药代动力学和毒理学研究来推动PIC1的未来临床前开发。