Targeting resitin and RELM-beta to treat pulmonary hypertension

靶向抵抗素和 RELM-β 治疗肺动脉高压

• 批准号: 8757198
• 负责人: Roger A Johns
• 金额: $ 156.28万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757198
• 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; Dependovirus; Development; Diagnosis; Disease; Drug Formulations; Drug Kinetics; Etiology; Fibroblasts; Fibrosis; 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; Modeling; Muscle Cells; 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; Work; abstracting; base; chemokine; clinical efficacy; 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

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 RELM¿ (hRELM¿) 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 hRELM¿ 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 RELM¿ 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 RELM¿ 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. (End of Abstract)

描述（由申请人提供）：抵抗素样分子（RELM）蛋白家族包括多效性细胞因子，其与动物和人肺动脉高压（PH）中观察到的血管重塑和心功能障碍密切相关。我们的啮齿动物和人类工作以及其他人的工作强烈表明，人抗酸蛋白（hResistin）和人RELM <$（hRELM <$）对人类PH和相关右心室功能障碍（RVD）的病因学具有重要的机制，并可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hRELM的人抗体，包括一些识别两种靶点的抗体。第一个目标（UH 2）将通过生物物理学和抗原-抗体相互作用研究，抗体对细胞中靶效应的抑制， 本研究还将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。这一目标将进一步评估我们的主要候选物的选择性、功能性和“可药用性”。第二个目标（UH 3）将评估我们的先导候选物的体内药代动力学和药效学，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。它将包括处方前开发和临床处方开发。它将随着我们向FDA提交IND申请而结束。第三个目标（UH 2，UH 3）将探索和开发人类β-内酰胺酶和RELM的生物标志物潜力。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，并将这些发现与人口统计学、血流动力学、临床、在我们最近的SCCOR基金中已经获得了关于肺动脉高压的遗传和基因组数据，主要关注PH和心脏功能。 (End摘要）