Protein depleting pre-existing antibodies for viral gene therapy

项目总结： 这是一个快速通道的SBIR赠款提案。作为有效的基因治疗(GT)产品使用腺相关 病毒(AAV)载体进入临床应用，翻译面临高流行的严峻挑战 人的α(AA)抗体(Ab)。目前，只有α抗体阴性的个人才有资格获得AAVGT 治疗。这个SBIR项目的目标是开发一种能够有效地耗尽 ABS走向临床应用和商业化，以制造潜在的救命AAV GT 产品可供所有需要给药和重新给药的患者使用。 为了应对现有α抗体的挑战，我们开发了一种新的有效的抗体耗竭蛋白 产品，抗体裂解器(ABC)，基于已证明的链球菌(IDES)的抗体降解酶(IDES)。 IDES特异性地切割人、灵长类动物、绵羊和兔子(但不包括小鼠)的免疫球蛋白。无数的研究 显示IDES在动物和人类中有效的瞬时免疫球蛋白降解，没有检测到的剂量 限制毒性。我们的初步研究表明，静脉注射ABC有效地消耗了抗体，导致 瞬时清除预先存在的αAAV9-抗体并允许在兔化的αAAV9-Abs中有效转导 静脉注射scAAV9-hSGSH后MPS IIIA阳性小鼠。我们相信，IV ABC政府提供了一个 很好的工具，以克服先前存在的rAAVGT的翻译αAAV抗体，以治疗人类的疾病。 这项建议是为了进一步开发和建立系统性rAAV9的最佳ABC抗体耗竭方案 基因传递。在第一阶段的研究中，我们将确定最优的ABC产品。一旦经过验证，在第二阶段， 最佳的单抗-C产品将在动物模型的临床前研究中进行评估(目标2，3)，以评估 ABC一过性抗体耗竭的疗效和治疗潜力在第二阶段，我们还将优化 面向临床应用和商业化的放大生产ABC生产程序(目标 #4)。值得注意的是，第二阶段研究将导致IND和随后的临床试验，以弥合ABC 系统性scAAV9-hSGSH基因替代治疗多发性硬化的临床研究 IIIA，最近提交了IND。更重要的是，ABC抗体耗尽可能提供了答案 针对现有抗体对使用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.