Targeting resitin and RELM-beta to treat pulmonary hypertension

描述（由申请人提供）：抵抗素样分子（RELM）蛋白家族包括多效细胞因子，在动物和人类肺动脉高压（PH）中观察到的血管重塑和心功能障碍中起重要作用。我们的啮齿动物和人类的工作以及其他人的工作强烈表明，人类抵抗素（hresisttin）和人类RELMß （hRELMß）在人类PH和相关右心室功能障碍（RVD）的病因学中具有重要的机制作用，并可作为该疾病的潜在生物标志物和治疗靶点。在CADET I中，我们完成了靶标验证，并开发了一系列针对hresisttin和hRELMß的人抗体，包括一些同时识别这两个靶标的抗体。第一个目标（UH2）将通过生物物理和抗原-抗体相互作用研究、基于细胞的抗体抑制靶标效应、人源化过表达抵抗素和RELMß小鼠ph模型中抗体的临床疗效研究来确定最佳的先导抗体。它还将包括抗体亲和成熟和优化，以及初始GLP细胞系的选择和优化。这一目标将进一步评估我们的主要候选药物的选择性、功能性和“可药性”。第二个目标（UH3）将评估我们的主要候选药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，进一步优化主要抗体的细胞生产效率，制造和扩大主要抗体的GMP生产。它将包括制剂前开发和临床制剂开发。它将以我们的IND申请的创建和向FDA提交结束。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，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，评估PH的严重程度和进展，并预测对治疗的反应，并将这些发现与我们最近在肺动脉高压SCCOR资助中已经获得的人口统计学、血流动力学、临床、遗传学和基因组数据整合和关联。主要关注PH和心脏功能。

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.