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（由申请人提供）：该项目的假设是，一种新型化合物，补体 C1 肽抑制剂（PIC1），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，补体是最有效的炎症。人类中的级联反应是由在许多炎症性疾病中驱动经典途径激活和宿主细胞破坏的抗体引发的，其中一种疾病是急性血管内溶血性输血反应（AIHTR），这是一种高度致命的输血反应，由于出现针对次要红细胞抗原的抗体，经常输血的人群（例如镰状细胞病）患 AIHTR 的风险大大增加。因此，代表了一个关键的未满足的医疗需求，包括镰状细胞病患者等服务不足的人群。我们在大鼠中开发了一种简单而强大的 AIHTR 模型，我们将用它来测试我们当前的先导化合物。 PIC1 (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成分 C1 结合，有效阻断抗体启动的补体激活。级联反应的第一步是通过盐水载体进行递送，并且在多次给药研究中重复显示，该抑制作用是快速、有效的，持续时间为 30 秒。在我们的异种输血方案中，我们使用 PIC1 抑制不匹配红细胞的溶血，其效果达到 90% 以上，并且在高剂量下可显着抑制补体介导的血管内溶血。作为金标准眼镜蛇毒因子（CVF），因此，该初步实验证明 PIC1 可以完全阻止抗体引发的经典补体介导的细胞破坏。 PIC1 的剂量，然后进行全面的研究，以评估 PIC1 在大鼠模型中抑制 AIHTR 的功效。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拟患者的临床情况。处于高风险的 AIHTR 患者可能在输血前接受 PIC1。此外，干预治疗策略将模拟输血开始时患者出现发烧、出汗和低血压的临床情况。除了接受肾上腺素来支持血压外，患者还可以接受 PIC1 来抑制发病机制并防止进一步溶血和急性肾损伤。拟议研究的成功将为 PIC1 可以预防补体介导的疾病提供重要的概念验证。这将为通过药代动力学和毒理学研究推动 PIC1 的未来临床前开发提供必要的证据。