Modified Human Anti-a(3) IV Antibodies for Drug Delivery in Nephritis

用于肾炎药物输送的修饰人抗 a(3) IV 抗体

• 批准号: 7937993
• 负责人: MICHAEL P MADAIO
• 金额: $ 22.05万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937993
• 关键词: Adverse effects; Anti-Glomerular Basement Membrane Disease; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Area; Autoantibodies; Binding; Chimeric Proteins; Cochlea; Collagen Type IV; Deposition; Disease; Drug Delivery Systems; Engineering; Epitopes; Evaluation; Event; Experimental Models; Fibrosis; Future; Genes; Glomerulonephritis; Goals; Hand; Health; Human; Immune; Immunization; Immunoglobulin G; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Kidney; Location; Lung; Modification; Mus; Nature; Nephritis; Patients; Pharmaceutical Preparations; Physiological; Production; Protein Binding; Reagent; Recombinant Proteins; Recombinants; Research; Serum; Signal Transduction; Technology; Testing; Testis; Therapeutic; Therapeutic Agents; antigen binding; base; experience; glomerular basement membrane; human disease; human monoclonal antibodies; in vivo; man; novel; protein expression; public health relevance; targeted delivery; translational approach

DESCRIPTION (provided by applicant): The long-term aim of to limit disease in man. Toward this goal, we will take advantage of: the restricted nature of 13(IV) collagen (13(IV) and its available epitopes with the kidney; the availability of a unique panel of human monoclonal antibodies (mAb) that bind to 13(IV) within glomeruli in vivo, and our experience in Ab engineering, protein expression, and experimental models of nephritis, to create human fusion proteins that bind to the kidney, in vivo. The experimental approach will involve modification of human m anti-13(IV) Ab, whereby their antigen binding for 13(IV) is maintained, so that they bind to the GBM in vivo, in mice. However their Fc regions will be altered, so that instead of promoting inflammation, they will constructed so that they have the potential to deliver either anti-inflammatory or anti-fibrotic signals to glomeruli. Initially, this will involve, selection expression and purification of candidate human m anti-13(IV) minibodies, in vitro. Subsequently, further selection and optimization of candidates will be carried out in normal, and then in nephritic mice, to identify the ideal reagents for delivery to glomeruli, with the long-term goal to deliver disease modifying agents. These technologies, along with the aforementioned panel of reagents, will be used to pursue the following Specific Aims: 1: To produce and characterize recombinant human anti-13(IV)Ab fragments with linkers, and 2: To evaluate the capacity of the human Ab fragments to deliver reagents to the kidney, in vivo, during health and disease. Once conditions are optimized, the reagents will be used in future studies to test the hypothesis that modified human anti-13 (IV) Ab will efficiently deliver drugs to the kidney to limit local inflammation, without systemic side effects. If successful, a major advantage of this approach and technology is that it will have application to all forms of glomerulonephritis. Furthermore, since the reagents are derived from human Ab sequences, they have the potential of being directly evaluated to treat human glomerulonephritis, with limited modification. PUBLIC HEALTH RELEVANCE: The overall goal of these studies is develop more effective, less toxic therapy for glomerulonephritis. For this purpose, human antibodies that bind to the kidney will be modified, so they have the potential to localize in the kidney and deliver anti- inflammatory and anti-fibrotic agents, to modify the course of nephritis. Although the proposed studies will be performed in mice, since the reagents will be based on human sequences, they will have the potential to be directly applied to various forms of human glomerulonephritis in the future.

描述（由申请人提供）：限制人类疾病的长期目标。为了实现这一目标，我们将利用：13（IV）胶原蛋白（13（IV））的限制性性质及其与肾脏的可用表位;一组独特的人单克隆抗体（mAb）在体内肾小球内与13（IV）结合的可用性，以及我们在Ab工程，蛋白质表达，以及肾炎的实验模型，以在体内产生与肾脏结合的人类融合蛋白。实验方法将涉及人抗13（IV）Ab的修饰，由此维持其与13（IV）的抗原结合，使得它们在小鼠体内结合至GBM。然而，它们的Fc区将被改变，因此它们将被构建成具有向肾小球递送抗炎或抗纤维化信号的潜力，而不是促进炎症。最初，这将涉及在体外选择表达和纯化候选人抗13（IV）微抗体。随后，将在正常小鼠中进行候选物的进一步选择和优化，然后在肾炎小鼠中进行，以鉴定用于递送到肾小球的理想试剂，其长期目标是递送疾病修饰剂。这些技术，沿着上述试剂组，将用于实现以下特定目的：1：生产和表征具有接头的重组人抗13（IV）Ab片段，以及2：评价人Ab片段在健康和疾病期间体内将试剂递送至肾脏的能力。一旦条件得到优化，这些试剂将用于未来的研究，以检验修饰的人抗13（IV）抗体将有效地将药物递送到肾脏以限制局部炎症，而不会产生全身副作用的假设。如果成功的话，这种方法和技术的一个主要优点是它将适用于所有形式的肾小球肾炎。此外，由于试剂来源于人Ab序列，因此它们具有直接评价以治疗人肾小球肾炎的潜力，仅进行有限的修饰。公共卫生相关性：这些研究的总体目标是为肾小球肾炎开发更有效、毒性更低的治疗方法。为此目的，将修饰与肾脏结合的人抗体，因此它们具有定位于肾脏中并递送抗炎剂和抗纤维化剂的潜力，以改变肾炎的病程。虽然拟议的研究将在小鼠中进行，但由于试剂将基于人类序列，因此它们将有可能在未来直接应用于各种形式的人类肾小球肾炎。

项目成果

Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy.

• DOI: 10.4049/jimmunol.1500277
• 发表时间: 2015-06-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Chaudhary K;Shinde R;Liu H;Gnana-Prakasam JP;Veeranan-Karmegam R;Huang L;Ravishankar B;Bradley J;Kvirkvelia N;McMenamin M;Xiao W;Kleven D;Mellor AL;Madaio MP;McGaha TL
• 通讯作者: McGaha TL

Lupus Nephritis: Animal Modeling of a Complex Disease Syndrome Pathology.

• DOI: 10.1016/j.ddmod.2014.08.002
• 发表时间: 2014
• 期刊: Drug discovery today. Disease models