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

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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.