Development of an Anti-P-selectin Antibody for the Treatment of Sickle Cell Disea

开发用于治疗镰状细胞病的抗 P-选择素抗体

基本信息

批准号：
7769486
负责人：
SCOTT A ROLLINS
金额：
$ 209.12万
依托单位：
SELEXYS PHARMACEUTICALS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2012-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7769486
关键词：
Address Adhesions Affect Affinity African American Animals Antibodies Binding Biological Assay Blood Blood Platelets Blood Vessels Cell Culture Techniques Cell Line Cell model Cells Chronic Clinical Clinical Research Clinical Trials Contracts Data Development Disease Dose Drug Kinetics Enzyme-Linked Immunosorbent Assay Erythrocytes Goals Grant Hematological Disease Human In Vitro Inflammation Inflammatory Inherited Lead Leukocyte Rolling Leukocytes Macaca fascicularis Mammalian Cell Measures Mediating Medical Methotrexate Monitor Orphan Disease P-Selectin Pain Patients Persons Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Pharmacology and Toxicology Phase Phase I/II Trial Phase II Clinical Trials Prevention Primates Property Qualifying Role Safety Sampling Serum Sickle Cell Sickle Cell Anemia Site Specificity Surrogate Markers Testing Therapeutic Therapeutic Monoclonal Antibodies Toxic effect Toxicology Work antibody engineering base cell bank design effective therapy humanized antibody humanized monoclonal antibodies immunogenic immunogenicity in vivo innovation intravenous administration monocyte nonhuman primate novel therapeutics preclinical study prevent programs public health relevance response safety study sickling

项目摘要

DESCRIPTION (provided by applicant): Selexys Pharmaceuticals is developing a humanized monoclonal antibody drug directed against P-selectin for the treatment of vasoocclusive crisis in patients with sickle cell disease. P-selectin mediates the first step in the recruitment of white blood cells to sites of inflammation. Vasoocclusion is precipitated by a P- selectin-mediated adhesion of sickled red cells and leukocytes. These cells bind to and block blood vessels precipitating painful crises, a hallmark of the disease. In preclinical studies in sickle cell models, administration of an antibody to P-selectin prevents vasoocclusion. The major aims of this proposal are the development of pharmacokinetic, pharmacodynamic, and immunogenicity assays to support an animal toxicology study and a Phase I/II trial in patients with sickle cell disease. In Phase 1 of this Fast Track Proposal, an ex vivo pharmacodynamic (PD) assay will be developed to measure the ability of a humanized antibody to P-selectin to block adhesion of monocytes to activated platelets using human/primate serum. The assay will allow us to establish a surrogate marker of drug activity. A pharmacokinetic (PK) ELISA based assay will be developed to measure the concentration of the humanized antibody in blood. This assay will allow us to monitor blood levels of the P-selectin antibody in primate and human studies. An immunogenicity assay will be developed to monitor the formation of human anti-humanized antibodies (HAHA) in human clinical studies. A primate safety/toxicity study will be conducted in a dose ranging study in cynomolgus monkey (Macaca fascicularis) to assess safety, toxicity, PK, PD of the humanized anti-P selectin antibody. In Phase 2 of this proposal a Phase I/II clinical study will be conducted in sickle cell patients to assess safety and the PK, PD and immunogenicity of a humanized antibody to P-selectin. The primary goal of the proposed study is to characterize the antibody prior to commencing a Phase II chronic dosing trial. The overarching goal of our program is to develop and commercialize a humanized antibody to P-selectin to treat vasoocclusive crisis in sickle cell patients. In doing so we are addressing a critical unmet medical need for a rare, debilitating orphan disease which currently has no effective approved treatment. PUBLIC HEALTH RELEVANCE: This proposal supports development of a humanized antibody to P-selectin to treat vasoocclusive crisis in sickle cell patients. Sickle cell disease is an inherited blood disorder that affects over 70,000 persons, primarily African-Americans, in the U.S. The drug being developed addresses a critical unmet medical need for a rare, debilitating orphan disease which currently lacks an effective treatment.

描述（申请人提供）：Selexys Pharmaceuticals 正在开发一种针对 P-选择素的人源化单克隆抗体药物，用于治疗镰状细胞病患者的血管闭塞危象。 P-选择素介导白细胞募集到炎症部位的第一步。血管闭塞是由 P-选择素介导的镰状红细胞和白细胞粘附引起的。这些细胞结合并阻塞血管，引发痛苦的危机，这是该疾病的一个标志。在镰状细胞模型的临床前研究中，给予 P-选择素抗体可预防血管闭塞。该提案的主要目标是开发药代动力学、药效学和免疫原性测定，以支持动物毒理学研究和镰状细胞病患者的 I/II 期试验。在该快速通道提案的第一阶段，将开发一种离体药效学 (PD) 测定，以测量 P-选择素人源化抗体使用人/灵长类动物血清阻断单核细胞与活化血小板粘附的能力。该测定将使我们能够建立药物活性的替代标记。将开发基于药代动力学 (PK) ELISA 的测定法来测量血液中人源化抗体的浓度。该测定将使我们能够在灵长类动物和人类研究中监测 P-选择素抗体的血液水平。将开发免疫原性测定来监测人类临床研究中人类抗人源化抗体（HAHA）的形成。灵长类动物安全性/毒性研究将在食蟹猴（Macaca fasciculis）中进行剂量范围研究，以评估人源化抗 P 选择蛋白抗体的安全性、毒性、PK、PD。在该提案的第二阶段中，将在镰状细胞患者中进行 I/II 期临床研究，以评估 P-选择素人源化抗体的安全性以及 PK、PD 和免疫原性。拟议研究的主要目标是在开始 II 期慢性给药试验之前表征抗体。我们项目的总体目标是开发 P-选择素人源化抗体并将其商业化，以治疗镰状细胞患者的血管闭塞危机。在此过程中，我们正在解决一种罕见的、使人衰弱的孤儿疾病的未得到满足的关键医疗需求，该疾病目前尚无有效的批准治疗方法。公共健康相关性：该提案支持开发 P-选择素人源化抗体，以治疗镰状细胞病患者的血管闭塞危象。镰状细胞病是一种遗传性血液疾病，在美国影响着超过 70,000 人，主要是非裔美国人。正在开发的药物解决了一种罕见的、使人衰弱的孤儿疾病的未得到满足的关键医疗需求，该疾病目前缺乏有效的治疗方法。