Novel Therapeutic Approaches for Lupus Nephritis

狼疮性肾炎的新治疗方法

基本信息

批准号：
10403435
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/10403435
关键词：
Affect Affinity Antibodies Antibody Affinity Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity B-Cell Antigen Receptor 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 Immunosuppressive Agents 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 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 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，可影响多个器官遍布全身。不幸的是，目前可用的药物并非对所有患者都有效，并且这些药物可能会产生明显的副作用。补体系统与 SLE 的多个方面密切相关。经典途径可防止 SLE 的发展。另一方面，有证据表明 C3d 与抗原共价结合，通过与抗原相互作用降低发生自身免疫的阈值补体受体 2 (CR2)。补体激活也是靶器官的关键下游介质 SLE 中的损伤。我们开发了一种单克隆抗体，命名为 mAb 3d8b，它结合 C3d 并阻断来自连接 CR2 的自身抗原复合物。此外，mAb 3d8b 靶向补体激活位点， C3d 体内固定。我们生成了独特的嵌合蛋白，将 3d8b 连接到抑制补充效应器功能。这些嵌合分子能够阻断两个关键的病理作用 SLE 发展过程中的补充：它们可以防止高亲和力自身抗体的发展，并且它们抑制靶器官中促炎补体的激活。因为药物不能阻断经典然而，它们不会干扰补体的保护作用。此外，还有感染的风险预计组织靶向药物的疗效低于非靶向补体抑制剂。基于这些考虑到这一点，该项目的总体假设是，靶向 3d8b 的补体抑制剂将是通过调节 SLE 模型，比非靶向补体抑制剂更具保护性自身抗体的产生和下游促炎作用的抑制。为了检验这个假设，将追求以下具体目标。目标 1) 检查 C3d 靶向补体抑制剂对 (NZBxNZW)F1 狼疮模型中的自身免疫。我们将确定药代动力学和与非靶向补体抑制剂相比，靶向药物的药效学，我们将测试这些药物对系统性自身免疫的影响。目标2）比较单一和联合的功效用于治疗 (NZBxNZW)F1 狼疮模型中肾脏疾病的治疗性补体抑制剂。为了这个目标我们将测试不同策略预防狼疮补体病理效应的功效肾炎。目标 3) 表征单一和联合治疗的全身免疫调节作用补体抑制剂。为此，我们将检查靶向和非靶向补体的效果对来自脾脏、外周血和骨髓的骨髓和淋巴细胞群的抑制剂 (NZBxNZW)F1 小鼠。该提案中的研究具有创新性，因为它们测试了设计的新颖分子阻断 SLE 自身免疫和组织损伤的多种机制。这个项目意义重大，因为它开发了一类新的药物，可以改善系统性红斑狼疮的治疗结果，同时减少治疗副作用。