Protein depleting pre-existing antibodies for viral gene therapy

项目摘要： 这是一个快速通道SBIR赠款提案。作为使用腺相关病毒的有效基因治疗（GT）产品， 随着腺相关病毒（AAV）载体进入临床应用，其翻译面临着高流行率的严峻挑战 αAA）抗体（Abs）。目前，只有α AAV-Ab阴性的个体才有资格进行AAV GT 治疗该SBIR项目的目标是开发一种能够有效消耗 为了使潜在的挽救生命的AAV GT走向临床应用和商业化， 所有需要给药和再给药的患者均可获得产品。 为了解决预先存在的α AAV-Ab的挑战，我们开发了一种新的有效的Ab消耗蛋白， 产品，抗体切割剂（AbC），基于已证实的链球菌IgG降解酶（IdeS）。 IdeS特异性切割人、灵长类动物、绵羊和兔（但不是小鼠）来源的IgG。大量研究 在动物和人类中证明了IdeS的有效瞬时IgG降解，没有可检测的剂量 限制毒性。我们的初步研究表明，通过IV AbC输注可有效消除Ab，导致 预先存在的α AAV 9-Ab的瞬时清除并允许在兔化α AAV 9-Ab中有效转导。 在IV scAAV 9-hGSH递送后的阳性MPS IIIA小鼠中。我们认为，IV ABC管理提供了一个 克服预先存在的α AAV-Ab用于翻译rAAV GT以治疗人类疾病的重要工具。 该建议是进一步开发和建立用于全身性rAAV 9的最佳AbC Ab耗尽方案。 基因传递在I期研究中，我们将确定最佳的AbC产品。一旦得到验证，在第二阶段， 将在动物模型的临床前研究中评价最佳Ab-C产品（目标#2、3），以评估 AbC瞬时Ab耗竭的功效和治疗潜力。在第二阶段，我们还将优化 用于临床应用和商业化的规模化生产的AbC生产程序（Aim #4）。值得注意的是，II期研究将导致IND和随后的临床试验，以桥接AbC 在MPS患者中施用全身性scAAV 9-hSGSH基因替代疗法的临床试验 IIIA，最近提交了IND。更重要的是，AbC抗体的耗尽可能会提供答案， 针对预先存在的Ab对使用AAV和其他病毒载体的基因治疗产品构成的挑战， 将军

Project Summary: This is a fast-track SBIR grant proposal. As effective gene therapy (GT) products using adeno-associated viral (AAV) vectors advance to clinical applications, the translation faces critical challenge of high prevalence of αAA) antibodies (Abs) in humans. Currently, only individuals negative of αAAV-Abs are eligible for AAV GT treatment. The goal of this SBIR project is to develop a therapeutic product capable of effectively depleting Abs towards clinical application and commercialization, in order to make potentially life-saving AAV GT products available to all patients in need of administration and re-administration. To address the challenge of pre-existing αAAV-Abs, we have developed a new effective Ab-depleting protein product, antibody cleaver (AbC), based on the demonstrated IgG degrading enzymes of Streptococci (IdeS). IdeS specifically cleaves IgG of humans, primate, sheep and rabbit (but not mouse) origin. Numerous studies demonstrate effective transient IgG degradation by IdeS in animals and humans, with no detectable dose limiting toxicity. Our preliminary studies showed effective Ab depletion by an IV AbC infusion, leading to the transient clearance of pre-existing αAAV9-Abs and allowing effective transduction in rabbitized αAAV9-Abs- positive MPS IIIA mice after an IV scAAV9-hSGSH delivery. We believe that IV AbC administration offers a great tool to overcome the pre-existing αAAV-Abs for the translation of rAAV GT to treat diseases in humans. This proposal is to further develop and establish an optimal AbC Ab-depletion regimen for systemic rAAV9 gene delivery. In Phase I studies, we will identify optimal AbC product. Once validated, in Phase II, the optimal Ab-C product will be evaluated in pre-clinical studies in animal models (Aim #2, 3), to assess the efficacy and therapeutic potential of transient Ab-depletion by AbC. In Phase II, we will also optimize the AbC production procedures for scale-up manufacture towards clinical application and commercialization (Aim #4). Notably, The Phase II studies will lead to an IND and subsequent clinical trials to bridge the AbC administration with systemic scAAV9-hSGSH gene replacement therapy clinical trials in patients with MPS IIIA, for which an IND were recently submitted. More importantly, the AbC Ab depletion may offer the answer to the challenge posed by pre-existing Abs to gene therapy products using AAV and other viral vectors in general.