A tolerogenic approach for the long-term delivery of antibodies with AAV

AAV 长期递送抗体的致耐受方法

• 批准号: 10013459
• 负责人: Jose Maria Martinez-Navio
• 金额: $ 20.58万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-06 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013459
• 关键词: Affinity; Animals; Anti-Retroviral Agents; Antibodies; Antibody Formation; Antibody Response; Antigens; Antiviral Agents; Blood Circulation; Bypass; Chronic Phase; Clinical Trials; Code; Cost efficiency; Dendritic Cells; Detection; Development; Disease remission; Ensure; Excision; Exhibits; Future; Gene Delivery; Generations; Goals; HIV; HIV Antibodies; HIV Infections; Immune Tolerance; Immune response; Immune system; Immunoglobulin Somatic Hypermutation; Individual; Infection; Injections; Macaca; Measurement; Mediating; Methods; Monitor; Monkeys; Mus; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Plasma; Production; Property; Prophylactic treatment; Proteins; Recombinant Antibody; Recombinant adeno-associated virus (rAAV); Regulatory T-Lymphocyte; Safety; Sirolimus; T cell differentiation; T-Cell Activation; Testing; Therapy trial; Time; Transgenes; Viral; Viral Load result; Viremia; Virus Diseases; adeno-associated viral vector; anergy; antiretroviral therapy; cytokine; design; experimental study; immune activation; immunogenicity; immunomodulatory strategy; immunomodulatory therapies; immunoregulation; in vivo; lymphoid organ; nanoparticle; neutralizing antibody; novel strategies; organ transplant rejection; prevent; prophylactic; simian human immunodeficiency virus; targeted treatment; transgene expression; vector; virology

Project Summary/Abstract Vectored delivery of broadly neutralizing antibodies (bnAbs) has the potential to a) achieve stringent and durable suppression in HIV individuals and b) be a successful and robust prophylactic approach. The use of recombinant adeno-associated virus vectors (AAV) for such delivery applications is ideal in many respects. AAV has an outstanding safety record in clinical trials and, as long as the delivered protein is viewed as self, it can result in continuous durable expression of the transgene product. Unfortunately, due to years of affinity maturation, bnAbs exhibit unusually high levels of somatic hypermutation and may have uncommon features that can be seen as `non-self' by the recipient's immune system. In fact, despite showing the huge promise of this approach, monkey trials from our group and others have revealed that antibody responses to the delivered bnAbs can severely limit their concentration and functionality. Building up on our previous monkey trials, what we propose here is an immunomodulatory approach aimed at avoiding the host anti-antibody responses (also known as anti-drug antibodies or ADA). Our goal is to induce immune tolerance to the delivered antibodies prior to AAV inoculation so that the desired concentrations can be consistently achieved in circulation. We plan to do this by targeting dendritic cells. Dendritic cells, as central orchestrators of the immune responses, decide the fate of the antigens they encounter. If they trigger activation of T-cells and antibody production, the antigen is set for clearance or removal. Alternatively, dendritic cells can generate anergy and tolerance. The antigen is then seen as `self' and remains. We will use an immunomodulatory therapy that targets dendritic cells in vivo, to induce antibody-specific tolerance prior to the AAV-mediated delivery of antibodies (Aim 1). We will then investigate the performance of our approach during AIDS-virus infection: a therapy trial with SHIV-infected macaques will be attempted in which a combination of bnAbs will be tolerized before being delivered with AAV (Aim 2). By eradicating or minimizing the host anti-antibody responses, we aim at making the AAV-delivery of antibodies a safe and reliable approach against HIV. If satisfactory delivery methods are found, it becomes possible to envision a) long-term control of the viral loads in the absence of antiretroviral treatment by delivering a combination of bnAbs in people and b) long-lasting protection when this approach is used in a prophylactic setting.

项目总结/摘要 广泛中和抗体（bnAb）的载体化递送具有以下潜力：a）实现严格和有效的抗体递送， 在HIV个体中的持久抑制和B）是成功和稳健的预防方法。使用 用于这种递送应用的重组腺相关病毒载体（AAV）在许多方面是理想的。 AAV在临床试验中具有出色的安全记录，并且只要递送的蛋白质被视为自身， 可以导致转基因产物的连续持久表达。不幸的是，由于多年的亲密关系 在成熟过程中，bnAb表现出异常高水平的体细胞超突变， 可以被接受者的免疫系统视为“非自我”。事实上，尽管显示出巨大的希望， 通过这种方法，我们小组和其他人的猴子试验表明， bnAb会严重限制其浓度和功能。基于我们之前的猴子试验， 我们在此提出了一种免疫调节方法，旨在避免宿主抗抗体应答（也 称为抗药物抗体或ADA）。我们的目标是诱导免疫耐受的交付抗体 在AAV接种之前，使所需的浓度可以在循环中一致地达到。我们计划 通过靶向树突状细胞来实现。树突状细胞作为免疫反应的中央指挥官， 它们所遇到的抗原的命运。如果它们触发了T细胞的激活和抗体的产生， 被设置为清除或移除。或者，树突状细胞可以产生无反应性和耐受性。述抗原是 然后被视为“自我”并保持不变。我们将使用体内靶向树突细胞的免疫调节疗法， 以在AAV介导的抗体递送之前诱导抗体特异性耐受（目的1）。然后我们将 研究我们的方法在艾滋病病毒感染期间的性能：一项SHIV感染者的治疗试验 将尝试在猕猴中，在用AAV递送之前，将耐受bnAb的组合 (Aim 2）。通过消除或最小化宿主抗抗体应答，我们的目标是使AAV-递送 抗体是一种安全可靠的抗艾滋病毒方法。如果找到令人满意的交付方法， 可以设想a）在不存在抗逆转录病毒治疗的情况下， 在人体中提供bnAbs的组合，以及B）当这种方法用于治疗时的持久保护 预防性设置。