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

基本信息

批准号：
8076969
负责人：
KEITH WYCOFF
金额：
$ 157.85万
依托单位：
PLANET BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
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/8076969
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

项目摘要

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主要生物防御对策 PBI-220，这是一种针对由炭疽杆菌（A 类病原体）引起的吸入性炭疽症状患者的治疗剂。我们正在开发 PBI-220，使用动物规则，用于被动免疫疗法，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 IgG-Fc 结构域的融合体。 PBI-220 通过诱饵受体机制抑制吸入性炭疽，该机制会阻止 PA 功能，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病的广谱治疗剂。我们的总体目标是向国家战略储备供应 PBI-220 作为一种稳定的冻干产品，作为治疗由传统、增强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 变异，可以逃避单克隆抗体治疗。我们在此拨款申请中的直接目标是使用 cGMP 生产 PBI-220，用于临床前研究和一期试验，并证明商业规模 PBI-220 生产的可行性。我们还将推进荷兰带白兔炭疽和PBI-220的研究，并继续进行安全性评价、稳定性测试和产品优化，证明重组烟草生产平台广泛适用于生物制药生产。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。人员将在全面实施的质量体系（QS）下运作，该体系目前已部分运行，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。制造目标包括确定精制步骤、从温室种植的重组烟草过渡到田间种植的 PBI-220 生产、将批量纯化从 1 克规模扩大到 70 克规模、实施封闭式纯化单元操作以防止外来物质进入，定义冻干产品配方和生产周期，并发布纯化的 PBI-220 用于临床前研究和一期试验。我们还将在荷兰带兔中研究炭疽病理学以及 PBI-220 和左氧氟沙星（单独使用或联合使用）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）、监控（例如过程和发布测试）、变更控制和使用标准操作程序（SOP）、批量生产记录、内部审核和报告的纠正措施来设计制造质量。 QC 将分析临床前样品并根据 GLP 进行放行测试。将使用 SDS-PAGE 和免疫印迹、等电聚焦、紫外光谱、结合测定、尺寸排阻和肽图谱液相色谱来评估产品特性、强度、效力、纯度和稳定性。叙述：本应用重点关注我们领先的生物防御对策 PBI-220 的可扩展 cGMP 生产，PBI-220 是一种免疫粘附素疗法，用于治疗由炭疽杆菌（一种 A 类病原体）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，以补充在治疗感染期间使用已批准的抗生素（例如环丙沙星）。我们将生产 PBI-220 用于正在进行的临床前研究和一期试验，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 子部分））推进生物许可证申请 (BLA) 批准，这将使 PBI-220 能够供应给国家战略储备，作为对抗传统、增强和先进炭疽菌株的对策。