Novel Therapeutic Approaches for Lupus Nephritis

狼疮性肾炎的新治疗方法

• 批准号: 10615186
• 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
• 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/10615186
• 关键词: Affect; Affinity; Antibodies; 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; Infiltration; Inflammation; Inflammatory; Injury; Injury to Kidney; Interferon alpha; Kidney; Kidney Diseases; Ligation; Longevity; Lupus; Lupus Nephritis; Lymphocyte; Lymphoid Cell; Mediator; 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; 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; protective pathway; response; sample fixation; side effect; systemic autoimmunity; therapeutic evaluation; tissue injury; treatment effect

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.

全身性红斑狼疮（SLE）是一种严重的自身免疫性疾病，可能影响多个器官 整个身体。不幸的是，当前可用的药物对所有患者都不有效，并且药物 可以产生重大的副作用。补体系统与SLE的几个方面都涉及。 经典途径可以防止SLE的发展。另一方面，有证据表明 C3D与抗原共价结合，通过与 补体受体2（CR2）。补体激活也是目标器官的关键下游介体 SLE受伤。我们开发了一种单克隆抗体，该抗体指定为MAB 3D8B，该抗体结合了C3D和块 连接CR2的自动抗原复合物。此外，MAB 3D8B的目标位点补体激活和 C3D固定在体内。我们生成了独特的嵌合蛋白，将3D8B与抑制的分子联系起来 补体效应子功能。这些嵌合分子能够阻止两个关键的病理作用 补充SLE的发展：它们可以防止高亲和力自身的发展，并且 抑制目标器官中促炎的补体激活。因为药物不会阻止经典 但是，途径不会干扰补充的保护作用。此外，感染的风险 靶向组织的药物的预计将小于未靶向补体抑制剂。基于这些 考虑到这一点，该项目的总体假设是，以3D8B为目标的补体抑制剂将是 通过调制 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， 将追求以下特定目标。目的1）检查C3D靶向补体抑制剂对 狼疮的（NZBXNZW）F1模型中的自身免疫性。我们将确定药代动力学和 与未靶向补体抑制剂相比，靶向药物的药效学，我们将测试 这些药物对全身自身免疫性的影响。目标2）比较单个和合并的功效 狼疮（NZBXNZW）F1模型中治疗肾脏疾病的治疗补体抑制剂。在这个目标中 我们将测试不同策略的功效，以防止狼疮中补体的病理影响 肾炎。目标3）表征单一治疗和联合治疗的全身免疫调节作用 补充抑制剂。在此目标中，我们将研究针对性和不靶向补充的影响 脾脏，外周血和骨髓的髓样和淋巴样细胞群的抑制剂 （NZBXNZW）F1小鼠。该提案中的研究是创新的，因为它们测试了设计的新分子 阻止SLE自身免疫和组织损伤的多种机制。这个项目很重要，因为它 开发一类新的药物，可以改善SLE的结果，同时减少治疗副作用。

项目成果

Highly pathogenic natural monoclonal antibody B4-IgM recognizes a post-translational modification comprised of acetylated N-terminal methionine followed by aspartic or glutamic acid.

高致病性天然单克隆抗体 B4-IgM 可识别由乙酰化 N 末端蛋氨酸和天冬氨酸或谷氨酸组成的翻译后修饰。

• DOI: 10.1016/j.molimm.2023.03.005
• 发表时间: 2023
• 期刊: Molecular immunology
• 影响因子: 3.6
• 作者: Kulik,Liudmila;Renner,Brandon;Laskowski,Jennifer;Thurman,JoshuaM;MichaelHolers,V
• 通讯作者: MichaelHolers,V