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

PBI-220 的 cGMP 生产，一种广谱免疫粘附素治疗药物

• 批准号: 8262149
• 负责人: KEITH WYCOFF
• 金额: $ 116.61万
• 依托单位: PLANET BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-03 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262149
• 关键词: Affinity; Anthrax disease; Antibiotic Resistance; Antibiotics; Antibody Formation; Antigen Receptors; Antigens; Applications Grants; Bacillus anthracis; Bacillus anthracis spore; Binding; Biological Assay; Biological Models; Biological Products; Blood capillaries; California; Categories; Chimera organism; Ciprofloxacin; Complement; Cyclic GMP; Development; Disease; Drug Formulations; Drug Interactions; Drug Kinetics; Engineering; Evaluation; Exclusion; Extracellular Domain; Fc domain; Fluoroquinolones; Freeze Drying; Funding; Funding Mechanisms; Goals; Grant; Half-Life; Histopathology; Housing; Human; Human Resources; IgG1; Immune; Immunoblotting; Immunoglobulin G; In Vitro; Infection; Isoelectric Focusing; Lead; Levaquin; Licensing; Liquid Chromatography; Marketing; Mediating; Monitor; Monoclonal Antibodies; Morphogenesis; New Zealand; Oryctolagus cuniculus; Passive Immunotherapy; Pathology; Patients; Peptide Mapping; Pharmaceutical Preparations; Phase I Clinical Trials; Plants; Polishes; Preparation; Procedures; Process; Production; Proteins; Quality Control; Readiness; Recombinants; Records; Reporting; Research; Safety; Sampling; Seeds; Shipping; Ships; Spectrum Analysis; System; Technology; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Time; Tobacco; Toxicity Tests; Variant; Writing; animal rule; anthrax toxin; base; biodefense; capillary; cost; design; in vivo; manufacturing facility; manufacturing process development; operation; pathogen; pre-clinical; preclinical study; prevent; quality assurance; receptor; reconstitution; scale up; stability testing

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.

描述（由申请人提供）：本申请的重点是制造我们的铅生物粘度相反测量，PBI-220，这是一种针对由炭疽芽孢杆菌引起的吸入性炭疽病的患者的治疗性，一种是一种病原体。我们正在使用动物规则开发PBI-220，用于被动免疫疗法，以补充这种感染治疗过程中环丙沙星的使用。 PBI-220是一种免疫粘附素，是CMG2（保护性抗原（PA）受体）和IgG-FC结构域的融合。 PBI-220通过诱导PA功能的诱饵受体机制抑制吸入炭疽，也可能触发FC效应器功能。 PBI-220是一种针对重组烟草植物产生的炭疽的广泛谱系治疗。我们的总体目标是将PBI-220作为一种稳定的冻干产品提供给战略性的国家储存，以作为由传统，增强和先进的炭疽菌菌株引起的疾病治疗的对策。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疗法。我们在此赠款申请下的直接目标是使用CGMP制造PBI-220，用于临床前研究和1阶段试验，并证明商业规模PBI-220制造的可行性。我们还将推进对荷兰皮带的白兔子的炭疽和PBI-220的研究，并继续安全评估，稳定性测试和产品优化，因为我们证明了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）部门来制造PBI-220。人员将根据目前处于部分操作的完全实施的质量系统（QS）进行操作，该系统将通过书面程序（SOP）来描述从部署烟草种子到产品运输的所有生产步骤。制造目标包括定义抛光步骤，转变为从温室成长的重组烟草进行PBI-220生产的野外烟草，将批量纯化从1克到70克量表进行扩展，从而实现了封闭的纯化单元操作，以防止进入不定的剂，以进行冻结的产品配方和生产周期和纯化的PBBI-220，以防止固定剂进行纯化。我们还将在荷兰腰带的兔子中研究植物病理学和PBI-220和左氧氟沙星的药代动力学。 通过QS，QA，QC和设施将实现CGMP制造。我们将通过输入保证（例如原材料），监视（例如，在过程和发布测试中），使用SOP，批处理生产记录，内部审核和报告来设计质量。 QC将分析临床前样品并在GLP下进行释放测试。将使用SDS-PAGE和免疫印迹，等电聚焦，UV光谱，结合测定，尺寸排除和肽映射液相色谱法对产品身份，强度，效力，纯度和稳定性进行评估。 叙述：该应用集中于我们铅生物诱体对策的可扩展CGMP生产PBI-220，一种针对由炭疽芽孢杆菌引起的吸入性炭疽病的患者的免疫粘附治疗，一种是一种病原体。我们正在开发PBI-220作为一种被动免疫疗法，以补充批准的抗生素（例如环丙沙星）在治疗感染期间。我们将制造PBI-220用于正在进行的临床前研究和1阶段试验，并证明了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）（第H）（小节H）促进了生物许可申请（BLA）批准，这将允许PBI-220促进策略股票和反对策略库存，并以战略性的股票代表。