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Novel Therapeutic Approaches for Lupus Nephritis

狼疮性肾炎的新治疗方法

基本信息

批准号：
10033331
负责人：
Vernon Michael Holers
金额：
$ 44.09万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10033331
关键词：
Affect Affinity Antibodies Antibody Affinity Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Biology Bone Marrow CD19 gene Cellular biology Chimeric Proteins Complement Complement 3a Complement 3d Complement 3d Receptors Complement 5a Complement Activation Complement Inactivators Complement Membrane Attack Complex Complement Receptor Complex Deposition Development Disease Drug Targeting End stage renal failure Female Follicular Dendritic Cells Gene Targeting Generations Immune Inbred MRL lpr Mice Inflammation Inflammatory Injury Injury to Kidney Interferon-alpha Interferons Kidney Kidney Diseases Longevity Lupus Lupus Nephritis Lymphocyte Lymphoid Cell Mediator of activation protein Modeling Monoclonal Antibodies Morbidity - disease rate Mus Myelogenous Myeloid Cells Onset of illness Organ Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Population Process Production Proteinuria Public Health Receptors, Antigen, B-Cell Recombinants Renal glomerular disease Research Risk Role Safety Signal Transduction Site Spleen Systemic Lupus Erythematosus TLR7 gene Testing Therapeutic Therapeutic Agents Tissues Treatment Side Effects antigen binding base comparative efficacy complement system design efficacy testing experimental study immunoregulation improved improved outcome in vivo infection risk inhibitor/antagonist innovation link protein mortality novel novel drug class novel strategies novel therapeutic intervention novel therapeutics organ injury peripheral blood pharmacokinetics and pharmacodynamics prevent protective effect response sample fixation side effect systemic autoimmunity therapeutic evaluation tissue injury treatment effect

项目摘要

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that can affect multiple organs throughout the body. Unfortunately, the currently available drugs are not effective for all patients, and the drugs can have significant side effects. The complement system is integrally involved with several aspects of SLE. The classical pathway protects against the development of SLE. On the other hand, evidence suggests that C3d covalently bound to antigens lowers the threshold for developing autoimmunity through its interaction with complement receptor 2 (CR2). Complement activation is also a critical downstream mediator of target organ injury in SLE. We developed a monoclonal antibody, designated mAb 3d8b, that binds C3d and blocks autoantigen complex from ligating CR2. Furthermore, mAb 3d8b targets sites of complement activation and C3d fixation in vivo. We generated unique chimeric proteins that link 3d8b to molecules that inhibit the complement effector functions. These chimeric molecules are able to block the two key pathologic roles of complement in the development of SLE: they prevent the development of high affinity autoantibodies, and they inhibit pro-inflammatory complement activation in target organs. Because the drugs do not block the classical pathway, however, they do not interfere with complement's protective effects. Furthermore, the risk of infection with tissue-targeted drugs is expected to be less than with untargeted complement inhibitors. Based on these considerations, the overall hypothesis of this project is that the 3d8b-targeted complement inhibitors will be more protective in a model of SLE than untargeted complement inhibitors, through both modulation of autoantibody production and inhibition of the downstream pro-inflammatory effects. To test this hypothesis, the following specific aims will be pursued. Aim 1) Examine the effects of C3d-targeted complement inhibitors on autoimmunity in the (NZBxNZW)F1 model of lupus. We will determine the pharmacokinetics and pharmacodynamics of the targeted drugs compared to untargeted complement inhibitors, and we will test the effects of these drugs on systemic autoimmunity. Aim 2) Compare the efficacy of single and combined therapeutic complement inhibitors for treating kidney disease in the (NZBxNZW)F1 model of lupus. In this aim we will test the efficacy of the different strategies for preventing the pathologic effects of complement in lupus nephritis. Aim 3) Characterize the systemic immunomodulatory effects of single and combined therapeutic complement inhibitors. In this aim we will examine the effects of the targeted and untargeted complement inhibitors on myeloid and lymphoid cell populations from spleen, peripheral blood, and bone marrow of (NZBxNZW)F1 mice. The studies in this proposal are innovative, because they test novel molecules designed to block multiple mechanisms of autoimmunity and tissue injury in SLE. This project is significant, because it develops a new class of drugs that may improve outcomes in SLE while reducing treatment side effects.

系统性红斑狼疮(SLE)是一种严重的自身免疫性疾病，可累及多个器官遍及全身。不幸的是，目前可用的药物并不是对所有患者都有效，而且这些药物可能会有显著的副作用。补体系统与系统性红斑狼疮的几个方面密切相关。经典途径可预防SLE的发展。另一方面，有证据表明 C3d与抗原的共价结合降低了自身免疫的发展门槛补体受体2(CR2)。补体激活也是靶器官的关键下游调节因子系统性红斑狼疮中的损伤。我们开发了一种单抗，命名为mAb3d8b，可以结合C3d并阻断结合CR2的自身抗原复合体。此外，mAb3d8b针对补体激活和体内C3d固定。我们产生了独特的嵌合蛋白，将3d8b连接到抑制3d8b的分子补充效应器功能。这些嵌合分子能够阻断两个关键的病理作用补体在系统性红斑狼疮发展中的作用：它们可以防止高亲和力自身抗体的产生，而且它们抑制靶器官中促炎症补体的激活。因为这些药物不会阻断经典的然而，它们并不干扰补体的保护作用。此外，感染的风险使用组织靶向药物预计比使用非靶向补体抑制剂要少。基于这些考虑到，这个项目的总体假设是3d8b靶向的补体抑制剂将是在系统性红斑狼疮模型中比非靶向补体抑制剂更具保护作用，这是通过调节自身抗体的产生和下游促炎作用的抑制。为了检验这一假设，将实现以下具体目标。目的1)检测C3d靶向补体抑制剂对狼疮(NZBxNZW)F1模型的自身免疫我们将测定药物动力学和靶向药物与非靶向补体抑制剂的药效学比较，我们将测试这些药物对全身自身免疫的影响。目的2)比较单用与联合用药的疗效治疗狼疮(NZBxNZW)F1模型肾脏疾病的治疗性补体抑制剂。在这一目标中我们将测试在狼疮中预防补体病理效应的不同策略的有效性。肾炎。目的3)研究单一疗法和联合疗法的全身免疫调节作用。补体抑制剂。在这个目标中，我们将考察定向补语和非定向补语的效果抑制小鼠脾、外周血和骨髓中髓系和淋巴系细胞群的药物 (NZBxNZW)F1小鼠。这项提案中的研究是创新的，因为它们测试了设计的新分子阻断SLE自身免疫和组织损伤的多种机制。这个项目意义重大，因为它开发一类新的药物，可能会改善SLE的结果，同时减少治疗副作用。