cGMP manufacturing of PBI-220, a broad spectrum immunoadhesin therapeutic against

描述（由申请人提供）：该申请的重点是制造我们的领先生物防御对策PBI-220，这是一种治疗由A类病原体炭疽芽孢杆菌引起的吸入性炭疽病症状的患者的治疗剂。我们正在开发PBI-220，使用动物规则，用于被动免疫治疗，以补充环丙沙星在治疗这种感染期间的使用。PBI-220是一种免疫粘附素，是CMG 2（保护性抗原（PA）受体）和IgG-Fc结构域的融合体。PBI-220通过阻断PA功能并且还可以触发Fc效应器功能的诱饵受体机制抑制吸入性炭疽。 PBI-220是在重组烟草植物中产生的针对炭疽的广谱治疗剂。我们的总体目标是将PBI-220作为一种稳定的冻干产品供应给国家战略储备，作为治疗传统、强化和先进炭疽菌株引起的疾病的对策。这些菌株可能表现出抗生素耐药性和PA变体，可以逃避单克隆抗体治疗。我们在该资助申请下的近期目标是使用cGMP生产PBI-220，用于临床前研究和1期试验，并证明商业规模生产PBI-220的可行性。我们还将推进荷兰皮带白色兔中炭疽和PBI-220的研究，并继续进行安全性评估、稳定性测试和产品优化，因为我们证明重组烟草生产平台广泛适用于生物制药。 我们将通过建立生产、设施、质量保证（QA）和质量控制（QC）部门，使用cGMP生产PBI-220。工作人员将在全面实施的质量体系（QS）下工作，该体系目前处于部分运行状态，将通过书面程序（SOP）描述从烟草种子部署到产品运输的所有生产步骤。生产目标包括定义精制步骤，从温室生长的重组烟草过渡到田间生长的PBI-220生产，将批量纯化从1克规模扩大到70克规模，实施封闭的纯化单元操作以防止外源因子的进入，确定冻干产品配方和生产周期，并释放纯化的PBI-220用于临床前研究和1期试验。我们还将在荷兰皮带兔中研究炭疽病理学和PBI-220和左氧氟沙星单独和联合给药的药代动力学。 通过QS、QA、QC和设施将实现cGMP生产。我们将通过输入保证（例如原材料）、监测（例如过程中和放行检测）、变更控制和使用SOP的纠正措施、批生产记录、内部稽查和报告，将质量设计纳入生产。QC将分析临床前样品并根据GLP进行放行检测。将使用SDS-PAGE和免疫印迹、等电聚焦、UV光谱、结合试验、分子排阻和肽图谱液相色谱法评价产品鉴别、规格、效价、纯度和稳定性。 说明：该应用的重点是我们的领先生物防御对策PBI-220的可扩展cGMP制造，PBI-220是一种免疫粘附素疗法，用于由A类病原体炭疽芽孢杆菌引起的吸入性炭疽症状患者。我们正在开发PBI-220作为一种被动免疫疗法，以补充在感染治疗期间使用批准的抗生素，如环丙沙星。我们将为正在进行的临床前研究和1期试验生产PBI-220，并证明重组烟草生产平台的商业可行性，从而根据动物规则推进生物许可申请（BLA）批准（21 CFR 601.90（子部分H），这将允许PBI-220被供应到战略国家储备，作为对传统，加强和先进的炭疽菌株。

DESCRIPTION (provided by applicant): This application focuses on manufacturing our lead biodefense countermeasure, PBI-220, a therapeutic for patients symptomatic for inhalational anthrax caused by Bacillus anthracis, a Category A pathogen. We are developing PBI-220, using the Animal Rule, for passive immunotherapy to complement the use of Ciprofloxacin during treatment of this infection. PBI-220 is an immunoadhesin, a fusion of CMG2 (the Protective Antigen (PA) receptor) and IgG-Fc domains. PBI-220 suppresses inhalational anthrax via a decoy- receptor mechanism that interdicts PA function and may also trigger Fc effector functions. PBI-220 is a broad spectrum therapeutic against anthrax produced in recombinant tobacco plants. Our overall goal is to supply PBI-220, as a stable freeze-dried product, to the Strategic National Stockpile as a countermeasure for the treatment of disease caused by traditional, enhanced and advanced anthrax strains. These strains may display antibiotic resistance and PA variants that can evade monoclonal antibody therapeutics. Our immediate aims under this grant application are to manufacture PBI-220 using cGMP, for preclinical studies and a Phase 1 trial, and to demonstrate the feasibility of commercial scale PBI-220 manufacturing. We will also advance the study of anthrax and PBI-220 in Dutch Belted White rabbits and continue safety evaluation, stability testing and product optimization as we demonstrate that the recombinant tobacco production platform is broadly applicable to biopharmaceutical manufacturing. We will manufacture PBI-220 using cGMP by establishing Manufacturing, Facilities, Quality Assurance (QA) and Quality Control (QC) departments. Personnel will operate under a fully implemented Quality System (QS), now in partial operation, which will describe, through written procedures (SOP), all production steps from the deployment of tobacco seeds to the shipping of product. Manufacturing goals include defining a polishing step, transitioning to field-grown from greenhouse-grown recombinant tobacco for PBI-220 production, scaling batch purification from the 1 gram to the 70 gram scale, implementing closed purification unit operations to prevent entry of adventitious agents, defining a freeze-dried product formulation and production cycle and releasing purified PBI-220 for pre-clinical studies and a Phase 1 trial. We will also study anthrax pathology and the pharmacokinetics of PBI-220 and Levofloxacin, each alone and in combination, in Dutch Belted rabbits. Through the QS, QA, QC and Facilities will enable cGMP manufacturing. We will design quality into manufacturing through input assurance (e.g. raw materials), monitoring (e.g. in process and release testing), change control and corrective actions using SOPs, batch production records, internal audits and reports. QC will analyze pre-clinical samples and conduct release testing under GLP. Product identity, strength, potency, purity and stability will be evaluated using SDS-PAGE and immunoblotting, isoelectric focusing, UV spectroscopy, binding assays, size exclusion and peptide mapping liquid chromatography. NARRATIVE: This application focuses on the scalable cGMP manufacturing of our lead biodefense countermeasure, PBI-220, an immunoadhesin therapy for patients symptomatic for inhalational anthrax caused by Bacillus anthracis, a Category A pathogen. We are developing PBI-220 as a passive immunotherapy to complement the use of approved antibiotics such as Ciprofloxacin during treatment of the infection. We will manufacture PBI-220 for ongoing preclinical studies and a Phase 1 trial and demonstrate the commercial feasibility of the recombinant tobacco production platform, thus advancing towards Biologic License Application (BLA) approval, under the Animal Rule (21 CFR 601.90 (Subpart H), which will allow PBI-220 to be supplied to the Strategic National Stockpile as a countermeasure against traditional, enhanced and advanced anthrax strains.