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

描述(申请人提供)：此申请专注于制造我们的铅生物防御对策，PBI-220，一种治疗由A类病原体炭疽芽孢杆菌引起的吸入性炭疽症状的患者。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CMG2(保护性抗原(PA)受体)和Ig G-Fc结构域的融合。PBI-220通过诱骗受体机制抑制吸入性炭疽，该机制阻断PA功能，也可能触发FC效应器功能。 PBI-220是一种广谱治疗方法，用于治疗重组烟草中产生的炭疽病。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，作为治疗由传统、强化和先进的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变种，可以逃避单抗治疗。根据这项赠款申请，我们的直接目标是使用cGMP制造PBI-220，用于临床前研究和第一阶段试验，并证明商业规模生产PBI-220的可行性。我们还将推进炭疽和PBI-220在荷兰腰带白兔身上的研究，并继续进行安全性评估、稳定性测试和产品优化，以证明该重组烟草生产平台广泛适用于生物制药制造。 我们将通过建立制造、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)下操作，该体系现已部分运行，该体系将通过书面程序(SOP)描述从烟草种子部署到产品运输的所有生产步骤。制造目标包括确定抛光步骤、从温室种植的重组烟草过渡到用于生产PBI-220的田间种植、将批量纯化从1克扩大到70克、实施封闭的净化单元操作以防止外来因素进入、确定冻干产品配方和生产周期以及释放用于临床前研究和第一阶段试验的纯化的PBI-220。我们还将研究炭疽病的病理学和PBI-220和左氧氟沙星在荷兰带兔身上的药代动力学。 通过QS，QA、QC和设施将使cGMP生产成为可能。我们将通过输入保证(例如，原材料)、监控(例如，在过程和放行测试中)、变更控制和使用SOP、批量生产记录、内部审计和报告的纠正措施，将质量设计到制造中。QC将分析临床前样本，并根据GLP进行释放测试。产品的同一性、强度、效价、纯度和稳定性将通过SDS-PAGE和免疫印迹、等电聚焦、紫外光谱、结合分析、大小排除和肽图高效液相色谱进行评估。 说明：本申请专注于我们领先生物防御对策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的患者。我们正在开发PBI-220作为被动免疫疗法，以补充在感染治疗期间使用经批准的抗生素，如环丙沙星。我们将生产用于正在进行的临床前研究和第一阶段试验的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(21 CFR 601.90(H分部))推动生物许可证申请(BLA)的批准，这将允许向国家战略储备供应PBI-220，以对抗传统的、增强的和先进的炭疽菌株。

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.