IL-13 Fusion Cytotoxin as a Targeted Therapeutic for IIP

IL-13 融合细胞毒素作为 IIP 的靶向治疗

• 批准号: 6801929
• 负责人: Cory M Hogaboam
• 金额: $ 26.78万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6801929
• 关键词: Pseudomonas; biopsy; bronchoscopy; cell line; clinical research; clinical trial phase I; cytokine receptors; drug screening /evaluation; exotoxins; fiber optic microscopy; fibroblasts; human subject; idiopathic pulmonary fibrosis; inhalation drug administration; interleukin 13; interleukin 4; molecular pathology; patient oriented research; receptor expression; respiratory disorder chemotherapy

DESCRIPTION (provided by applicant): The factors that initiate and maintain chronic idiopathic interstitial pneumonias (lIP) remain enigmatic thereby severely limiting the treatment options available to these patients. Pulmonary biopsies from lIP patients exhibit several unique characteristics not shared by similar biopsies from non-lIP patients, one of which is the exaggerated presence of type-2 cytokines such as interleukin-4 (IL-4) and IL-13. Experimental data suggest that both cytokines are potent pro-fibrotic mediators in the lung. Preliminary data provided in this proposal shows that primary lIP pulmonary fibroblasts derived from surgical lung biopsies (SLBs) and transbronchial biopsies (TBBs) exhibit increased levels of receptor subunits that bind IL-4 and IL-13. In addition, lIP pulmonary fibroblasts exhibit heightened responsive to both ligands as evidenced by exuberant fibroblast activation, proliferation and fibrosis. Few strategies currently exist that concomitantly modulate the in vivo activities of both type-2 cytokines, aside from a chimeric protein comprised of IL-13 and a truncated version of the Pseudomonas exotoxin A (IL13-PE). IL13-PE and other immunotoxins have been employed clinically to specifically eliminate brain tumor cells over-expressing receptors for IL-4 and IL-13. The working hypothesis of the present proposal is that an effective treatment strategy in lIP involves employing IL13-PE to eliminate IL-4- and IL-13-responsive lIP pulmonary cells, primarily fibroblasts, consequently ridding the lung of instigators of pulmonary remodeling. This hypothesis will be addressed by focusing on SLB and TBBs, and primary pulmonary SLB- and TBB-derived fibroblast lines from IIP and non-IIP patients, and demonstrating the specificity, safety and therapeutic efficacy of IL13-PE clinically. Specific areas to be addressed in this proposal include: 1) to characterize the IL-4 and IL-13 receptor subunits in primary fibroblast lines from IIP and non-IIP patients and determine the effects of IL13-PE on these cell lines; 2) to characterize the cellular expression of IL-4 and IL-13 and their respective receptor subunits in SLBs and TBBs from IIP and non-IIP patients; 3) To characterize the IL-4, IL-13, IL-4Ra, IL-13Ra1, and IL-13Ra2 expression profiles in fibrotic foci in lung biopsies (SLBs) from IIP patients.; 4) to determine the safety of aerosolized IL13-PE treatment in a consenting and informed IIP patient population. The proposed studies will critically evaluate a pathophysiologic paradigm in IIP that has not been thoroughly examined to date.

描述（由申请人提供）： 引发和维持慢性特发性肺炎（唇）的因素仍然神秘，从而严重限制了这些患者可用的治疗选择。来自唇部患者的肺活检表现出了几种独特的特征，这些特征不是由非脂肪患者的类似活检共享的，其中一种是夸张的2型细胞因子（例如介绍性列鲁金4（IL-4）和IL-13）的存在。实验数据表明，两种细胞因子都是肺中有效的促纤维化介质。该提案中提供的初步数据表明，源自手术肺活检（SLB）和经支气管活检（TBB）的原发性唇肺成纤维细胞（TBB）表现出结合IL-4和IL-13的受体亚基水平的增加。此外，唇肺成纤维细胞表现出对这两种配体的反应性增强，这可以通过旺盛的成纤维细胞激活，增殖和纤维化证明。目前，很少有策略同时调节两种2型细胞因子的体内活性，除了由IL-13组成的嵌合蛋白和假单胞菌Exotoxin A（IL13-PE）的截断版本。 IL13-PE和其他免疫毒素已在临床上已用于特异性消除IL-4和IL-13过度表达受体的脑肿瘤细胞。本提案的工作假设是，嘴唇中的有效治疗策略涉及使用IL13-PE消除IL-4-和IL-13反应性的唇肺细胞，主要是成纤维细胞，因此消除了肺化重塑的Instigators的肺。该假设将通过关注SLB和TBB，以及IIP和非IIP患者的原发性肺SLB和TBB衍生的成纤维细胞系，并在临床上证明IL13-PE的特异性，安全性和治疗性。该提案中要解决的特定区域包括：1）表征来自IIP和非IIP患者的原代成纤维细胞系中IL-4和IL-13受体亚基，并确定IL13-PE对这些细胞系的影响； 2）表征来自IIP和非IIP患者的SLB和TBB中IL-4和IL-13及其各自的受体亚基的细胞表达； 3）表征IIP患者的肺活活检（SLB）中IL-4，IL-13，IL-4RA，IL-13RA和IL-13RA2表达谱。 4）在同意并告知IIP患者人群中，确定雾化IL13-PE治疗的安全性。拟议的研究将批判性地评估IIP中尚未对IIP的病理生理范式进行评估。