Peptide inhibition of complement-mediated hemolysis after xenotransfusion.

异种输血后补体介导的溶血的肽抑制。

• 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
• 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

 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（由申请方提供）：本项目的假设是一种新型化合物，补体C1肽抑制剂（PIC 1），将在异种输血动物模型中抑制抗体引发的补体介导的细胞破坏。补体是人类中最有效的炎症级联反应，并且在许多炎症性疾病中由驱动经典途径活化和宿主细胞破坏的抗体启动。一种这样的疾病是急性血管内溶血性输血反应（AIHTR），这是一种高度致命形式的输血反应。经常输血的人群（例如，镰状细胞病）由于产生了针对次要红细胞抗原的抗体而大大增加了AIHTR的风险。目前，除了支持性护理外，还没有预防或治疗AIHTR的治疗方法，因此，代表了一个关键的未满足的医疗需求，包括服务不足的人群，如镰状细胞病患者。我们已经在大鼠中开发了一种简单而强大的AIHTR模型，我们将使用它来测试PIC 1。我们目前的先导化合物PIC 1（PA-CPEG）是多年合理药物设计的产物，产生了与PEG缀合的15个氨基酸肽。我们的化合物与经典途径的起始组分C1结合，在级联反应的第一步有效阻断抗体引发的补体激活。PIC 1在生理盐水载体中递送，并且在多次给药研究中可重复地显示出阻断大鼠中的经典补体激活。这种抑制是快速的，30秒，并且是有效的，>90%的经典补体激活抑制。我们已经在异种输血方案中使用PIC 1进行了一项试验性实验，以抑制不匹配红细胞的溶血。PIC 1表现出剂量依赖性效应，并且在高剂量下显著抑制补体介导的血管内溶血，达到与金标准眼镜蛇毒因子（CVF）相同的程度。因此，该初步实验证明PIC 1可以完全阻断抗体引发的经典补体介导的细胞破坏。拟议的研究将完善PIC 1的剂量，然后进行充分的研究，以评估PIC 1在大鼠模型中抑制AIHTR的疗效。我们将在预防策略和干预治疗策略中测试PIC 1。预防性治疗策略将模拟可能在输血前接受PIC 1的AIHTR高风险患者的临床情况。干预治疗策略将模拟输血开始时患者出现发热、出汗和低血压的临床情况。除了接受肾上腺素以支持血压外，患者还可以接受PIC 1以抑制发病机制并防止进一步溶血和急性肾损伤。所提出的研究的成功将提供关键的概念验证，即PIC 1可以在人类疾病的动物模型中预防补体介导的发病机制。这将为通过药代动力学和毒理学研究推动PIC 1的未来临床前开发提供必要的证据。