Protein depleting pre-existing antibodies for viral gene therapy

用于病毒基因治疗的蛋白质消耗预先存在的抗体

• 批准号: 10696476
• 负责人: Douglas M McCarty
• 金额: $ 30.65万
• 依托单位: NEUROGT, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696476
• 关键词: Address; Adverse event; Animal Model; Animals; Antibodies; Applications Grants; Biodistribution; Blocking Antibodies; Blood specimen; Cells; Clinical Chemistry; Clinical Trials; Codon Nucleotides; Development; Disease; Dose; Dose Limiting; Eligibility Determination; Enzymes; Face; Galium; Gene Delivery; Genetic Diseases; Goals; Growth; Hematology; High Prevalence; Histopathology; Human; Immune response; Immunoglobulin G; Individual; Infusion procedures; Injections; Life; Modeling; Mus; Mutation; Oryctolagus cuniculus; Patients; Phase; Population; Primates; Procedures; Production; Proteins; Recombinant adeno-associated virus (rAAV); Regimen; Safety; Sheep; Small Business Innovation Research Grant; Streptococcus; Temperature; Testing; Therapeutic; Therapy Clinical Trials; Time; Tissue Sample; Toxic effect; Toxicology; Translations; Viral; Viral Antibodies; Viral Genes; Viral Vector; adeno-associated viral vector; cell growth; clinical application; clinically relevant; commercialization; efficacy evaluation; gene replacement therapy; gene therapy; manufacturing scale-up; mouse model; phase 1 study; phase 2 study; preclinical study; protein expression; protein purification; safety testing; tool; transduction efficiency; vector

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.

项目概要： 这是一项快速 SBIR 拨款提案。作为使用腺相关的有效基因治疗（GT）产品 病毒（AAV）载体进入临床应用，翻译面临高流行率的严峻挑战 αAA) 人体抗体 (Abs)。目前，只有 αAAV-Ab 呈阴性的个体才有资格接受 AAV GT 治疗。该 SBIR 项目的目标是开发一种能够有效消除 Abs走向临床应用和商业化，以制造可能挽救生命的AAV GT 产品可供所有需要给药和再次给药的患者使用。 为了解决现有 αAAV-Ab 的挑战，我们开发了一种新的有效 Ab 消耗蛋白 产品抗体切割器 (AbC)，基于已证实的链球菌 IgG 降解酶 (IdeS)。 IdeS 特异性切割人类、灵长类动物、绵羊和兔子（但不包括小鼠）来源的 IgG。大量研究 证明 IdeS 在动物和人类中可有效瞬时降解 IgG，且未检测到剂量 限制毒性。我们的初步研究表明，IV AbC 输注可有效消除 AbC，从而导致 瞬时清除预先存在的 αAAV9-Abs，并允许在兔化的 αAAV9-Abs 中进行有效转导- IV scAAV9-hSGSH 递送后呈阳性 MPS IIIA 小鼠。我们相信 IV AbC 管理提供了 克服预先存在的 αAAV-Ab 的好工具，用于翻译 rAAV GT 来治疗人类疾病。 该提案旨在进一步开发和建立系统性 rAAV9 的最佳 AbC Ab 耗竭方案 基因传递。在第一阶段研究中，我们将确定最佳的 AbC 产品。一旦经过验证，在第二阶段， 最佳 Ab-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 瞬时 Ab 耗竭的功效和治疗潜力。在第二阶段，我们还将优化 AbC 生产程序用于扩大生产以实现临床应用和商业化（目标 ＃4）。值得注意的是，II 期研究将导致 IND 和随后的临床试验，以弥合 AbC MPS 患者全身 scAAV9-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 Ab 耗尽可能会提供答案 应对现有抗体对使用 AAV 和其他病毒载体的基因治疗产品带来的挑战 一般的。