Targeting resitin and RELM-beta to treat pulmonary hypertension

靶向抵抗素和 RELM-β 治疗肺动脉高压

基本信息

批准号：
8931049
负责人：
Roger A Johns
金额：
$ 157.65万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2016-08-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8931049
关键词：
Animal Model Animals Antibodies Antibody Affinity Antigens Biological Assay Biological Availability Biological Markers Cardiac Cell Line Cells Chronic Clinical Common Epitope Data Development Diagnosis Disease Drug Formulations Drug Kinetics Etiology Fibroblasts Functional disorder Gene Expression Genetic Genetic Polymorphism Genomics Heart Heart Hypertrophy Heart failure Human Human Development Hypertension Hypoxia Image Inflammatory Interleukin-2 Investigational Drugs Investigational New Drug Application Knock-out Lead Lesion Lung Medical Genetics Modeling Muscle Cells Myocardial dysfunction Myofibroblast Pathway interactions Patients Pharmacodynamics Production Protein Family Proteins Pulmonary Hypertension Research Research Project Grants Right Ventricular Dysfunction Right ventricular structure Risk Rodent Rodent Model Role Sampling Sarcomeres Scleroderma Series Serum Severities Specialized Center Testing Therapeutic Therapeutic antibodies Toxicology Validation Vascular remodeling Virus Work base chemokine clinical efficacy coronary fibrosis cysteine-rich secreted protein FIZZ3 cytokine gain of function hemodynamics human data immunogenicity in vivo loss of function manufacturing scale-up monocyte mouse model novel overexpression patient population peripheral blood preclinical evaluation preclinical study prevent pulmonary arterial hypertension resistin response small hairpin RNA therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The resistin-like molecule (RELM) family of proteins comprises pleiotropic cytokines critically involved in the vascular remodeling and cardiac dysfunction seen in animal and human pulmonary arterial hypertension (PH). Our rodent and human work and the work of others strongly suggests that human resistin (hResistin) and human RELMß (hRELMß) are mechanistically important to the etiology of human PH and associated right ventricular dysfunction (RVD) and serve as potential biomarkers and therapeutic targets for this disease. IN the CADET I we accomplished target validation and developed a series of human antibodies against hResistin and against hRELMß including some that recognized both targets. The first aim (UH2) will identify an optimal lead antibody through biophysical and antigen-antibody interaction studies, antibody inhibition of target effects in cell based assays, and clinical efficacy studies of antibodies in our humanized overexpressing resistin and RELMß mouse models of PH. It will also include antibody affinity maturation and optimization as needed and initial GLP cell line selection and optimization. This aim will further assess the selectivity, functionality and "drugability" of our lead candidates. The second aim (UH3) will evaluate the in vivo pharmacokinetics and pharmacodynamics of our lead candidate(s), perform toxicology, immunogenicity and bioavailability studies in animal models, further optimize cell production efficiency of the lead antibody, and manufacture and scale-up GMP production of the lead antibody(ies). It will include pre-formulation development and clinical formulation development. It will end with creation and filing of our IND application with the FDA. The third aim (UH2, UH3) will explore and develop the biomarker potential of human resistin and RELMß to assess severity and progression of PH and to predict response to therapy, by studying the functional role of genetic polymorphisms, PBMC gene expression, and serum levels for these proteins, and integrating and correlating these findings with the demographic, hemodynamic, clinical, genetic and genomic data already obtained in our recent SCCOR grant on pulmonary arterial hypertension, with a primary focus on PH and cardiac function.

描述（由申请人提供）：抵抗素样分子（RELM）蛋白家族包含与动物和人类肺动脉高压（PH）中观察到的血管重塑和心脏功能障碍密切相关的多效性细胞因子。其他人强烈表明，人抵抗素 (hResistin) 和人 RELMß (hRELMß) 在机制上对于人类 PH 的病因学和相关右心室功能障碍很重要(RVD) 并作为该疾病的潜在生物标志物和治疗靶点，在 CADET I 中，我们完成了靶点验证，并开发了一系列针对 hResistin 和针对 hRELMß 的人类抗体，其中包括一些识别这两个靶点的抗体。通过生物物理和抗原抗体相互作用研究、基于细胞的测定中的抗体抑制靶效应以及我们的人源化过表达抵抗素和 RELMß PH 小鼠模型中抗体的临床功效研究，我们还将获得最佳的先导抗体。包括根据需要进行抗体亲和力成熟和优化以及初始 GLP 细胞系选择和优化。第二个目标（UH3）将评估我们的主要候选药物的选择性、功能性和“成药性”。我们的主要候选药物，在动物模型中进行毒理学、免疫原性和生物利用度研究，进一步优化先导抗体的细胞生产效率，以及制造和扩大先导抗体的 GMP 生产。第三个目标（UH2、UH3）将探索和开发人类抵抗素和 RELMß 的生物标志物潜力，以评估疾病的严重程度和进展。通过研究遗传多态性、PBMC 基因表达和这些蛋白质的血清水平的功能作用，并将这些发现与已获得的人口统计、血流动力学、临床、遗传和基因组数据进行整合和关联，来预测 PH 并预测治疗反应我们最近获得了关于肺动脉高压的 SCCOR 资助，主要关注肺动脉高压和心脏功能。