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

项目摘要/摘要 广谱中和抗体(BNAbs)的载体传递有可能a)实现严格和 对艾滋病毒个体的持久抑制，以及b)是一种成功和有力的预防方法。对.的使用 重组腺相关病毒载体(AAV)在许多方面都是理想的递送应用。 AAV在临床试验中具有出色的安全性记录，只要所传递的蛋白质被视为自身，它 可以导致转基因产品的持续持久表达。不幸的是，由于多年的亲和力 成熟时，bNAbs表现出异常高的体细胞超突变水平，并可能具有不寻常的特征 这可以被接受者的免疫系统视为“非我”。事实上，尽管展示了巨大的希望， 这种方法，我们小组和其他人的猴子试验表明，对交付的抗体反应 BNAbs可严重限制其浓度和功能。在我们之前猴子试验的基础上，有什么 我们在这里提出了一种免疫调节方法，旨在避免宿主抗抗体反应(也 称为抗药物抗体或ADA)。我们的目标是诱导对所传递的抗体的免疫耐受 在接种AAV之前，以便在循环中能够稳定地达到所需浓度。我们计划 通过以树突状细胞为靶点来做到这一点。树突状细胞作为免疫反应的中央协调者，决定了 它们所遇到的抗原的命运。如果它们触发T细胞的激活和抗体的产生，抗原 设置为清除或移除。或者，树突状细胞可以产生无能和耐受。抗原性是 然后被视为‘自我’并保持不变。我们将使用一种针对体内树突状细胞的免疫调节疗法， 在AAV介导的抗体传递之前诱导抗体特异性耐受(目标1)。到时候我们会的 研究我们的方法在艾滋病病毒感染期间的表现：一项针对SHIV感染的治疗试验 将尝试猕猴，在与AAV一起交付之前，将容忍bNAbs的组合 (目标2)。通过根除或最小化宿主抗抗体反应，我们的目标是使AAV-递送 抗体是对抗艾滋病毒的安全可靠的方法.如果找到令人满意的交付方法，它将成为 有可能设想a)在没有抗逆转录病毒治疗的情况下通过以下方式长期控制病毒载量 在人群中提供bNAbs和b)当这种方法用于 预防设置。

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.