Targeting complement inhibitors to the human proximal tubule

将补体抑制剂靶向人类近曲小管

基本信息

批准号：
7244042
负责人：
RICHARD J. QUIGG
金额：
$ 25.81万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7244042
关键词：
Antigens Apical Binding Biological Models Cell Line Cells Characteristics Clinical Research Cloning Complement Complement 3d Receptors Complement Activation Complement Inactivators Complement Membrane Attack Complex Complement Receptor Condition Data Dipeptidyl-Peptidase IV Disease Disease model Epidemic Epithelial Cells Experimental Models Exposure to Generations Homologous Gene Human In Vitro Injury Kidney Diseases Life Link Modeling Monoclonal Antibodies Outcome Pathology Plasma Proteins Proteins Proteinuria Rattus Recombinant Proteins Recombinants Renal glomerular disease Research Risk Site Standards of Weights and Measures Surface System Technology Time Tissues Tubular formation Ursidae Family Work activation product cell injury cost follow-up genetic regulatory protein human disease in vivo inhibitor/antagonist response therapy design

项目摘要

DESCRIPTION (provided by applicant): Nearly all glomerular diseases are accompanied by tubulointerstitial (Tl) pathology that is inextricably linked to outcome. Such Tl injury may occur because the abnormal glomerular ultrafiltrate contains potentially injurious proteins, including those of the spontaneously active complement system. Although most host cells bear complement regulatory proteins (CRPs), these are not well expressed by proximal tubular epithelial cells (PTECs). There are strong data supporting that deleterious C5b-9 activation occurs on PTECs in proteinuric conditions. We have used exogenous CRPs to limit complement activation on cells and in tissues, including in renal disease models, and have recently used recombinant monoclonal antibodies (mAbs) and C3-binding complement receptors (CR2) to selectively target CRPs to relevant cells undergoing complement attack, including the rat PTEC in proteinuria-induced Tl injury. The research proposed here will apply this approach to target the specific C5b-9 inhibitor, CD59, to the human PTEC. The first aim will be to study a human PTEC culture that retains native characteristics, including expression of antigens that can be targeted, the repertoire of CRPs, and the functional response to C5b-9. Complement activation as is likely to occur upon exposure to recently filtered plasma proteins will be modeled on these cells, and the phenotypic response determined, including parallels to what occurs over time in progressive renal disease. We will then evaluate PTEC antigens that can be used for targeted therapy. Candidate antigens will be studied, including those with human homologues from our recent studies in the rat, and those upregulated in human PTEC injury. In addition, the potential of using CR2 to target sites of complement activation on the PTEC will be evaluated. Once we have created a model system and identified viable targets to deliver CRPs, we will create mAb/CR2-CD59 chimers to target human PTECs. The work proposed here applies fundamental principles and research derived from experimental models of proteinuria-induced Tl injury to develop therapy for the analogous human diseases. Kidney disease has reached epidemic proportions, costing us in lives and money. The work proposed here uses modern technology to design treatment for these disorders. Although these are considered pilot and high-risk studies, successful completion could give us treatments for immediate use in clinical studies.

描述（由申请人提供）：几乎所有肾小球疾病都伴随着与结局密不可分的tubulointerstitial（TL）病理学。由于异常的肾小球超滤含有潜在的有害蛋白质，包括自发活跃的补体系统，因此可能会发生这种TL损伤。尽管大多数宿主细胞都具有补体调节蛋白（CRP），但这些宿主细胞并未通过近端管状上皮细胞（PTEC）表达。有强大的数据支持在蛋白尿条件下PTEC上发生有害的C5B-9激活。我们已经使用了外源性CRP来限制细胞和组织中的补体激活，包括肾脏疾病模型，并且最近使用了重组单克隆抗体（MAB）和C3结合补体受体（CR2），以选择性地将CRP靶向CRP到相关细胞受到相关细胞，包括蛋白质尿液中的大鼠PTEC，包括蛋白质尿液诱导的TL诱导的TLEL诱导的TLEL诱导。此处提出的研究将采用这种方法将特定的C5B-9抑制剂CD59靶向人类PTEC。第一个目的是研究保留天然特征的人类PTEC培养物，包括可以靶向的抗原的表达，CRP的曲目以及对C5B-9的功能反应。在暴露于最近过滤的血浆蛋白时可能发生的补体激活将在这些细胞上进行建模，并且确定的表型反应，包括与渐进性肾脏疾病中发生的情况相似。然后，我们将评估可用于靶向治疗的PTEC抗原。将研究候选抗原，包括我们最近在大鼠研究中具有人类同源物的抗原，以及在人类PTEC损伤中上调的抗原。另外，将评估使用CR2对PTEC上补体激活的靶向位点的潜力。一旦我们创建了一个模型系统并确定了提供CRP的可行目标，我们将创建MAB/CR2-CD59 Chimers以瞄准人PTEC。此处提出的工作采用了源自蛋白尿诱导的TL损伤的实验模型得出的基本原理和研究，以开发针对类似的人类疾病的治疗。肾脏疾病已达到流行病的比例，使我们在生活和金钱上造成了损失。这里提出的工作使用现代技术为这些疾病设计治疗方法。尽管这些被认为是试验和高风险研究，但成功完成可以使我们立即在临床研究中使用。