Novel Therapeutic Approaches for Lupus Nephritis

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。

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.