Production of radiometal-based radiopharmaceuticals at a clinical scale via droplet-scale radiochemistry

通过液滴规模放射化学在临床规模生产基于放射性金属的放射性药物

• 批准号: 10697509
• 负责人: Jason Jones
• 金额: $ 27.58万
• 依托单位: DROPLETPHARM INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10697509
• 关键词: 90Y; Address; Amendment; Capital; Cells; Clinical; Clinical Research; Clinical Trials; Coffee; Collection; Complex; Cost Sharing; Cyclic GMP; Dedications; Development; Diagnostic Imaging; Discipline of Nuclear Medicine; Dose; Ensure; Environment; Equipment; FDA approved; FOLH1 gene; Fluorides; Future; Half-Life; Image; Individual; Infrastructure; Investments; Isotopes; Label; Laboratories; Manufacturer; Marketing; Medicine; Metals; Methods; Microfluidics; Monitor; Output; Patients; Phase; Play; Positron-Emission Tomography; Price; Production; Protocols documentation; Radioactivity; Radiochemistry; Radioisotopes; Radiopharmaceuticals; Reaction; Reagent; Research; Resources; Role; Running; Schedule; Side; Site; Small Business Technology Transfer Research; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tracer; Translations; Trastuzumab; Validation; clinical translation; clinically relevant; commercial prototype; commercialization; cost; design; drug development; imaging agent; interest; manufacture; manufacturing facility; manufacturing run; novel; pre-clinical; preclinical development; preclinical study; radiotracer; research and development; theranostics

PROJECT SUMMARY Despite the enormous value of radiopharmaceuticals for imaging and therapy in clinical nuclear medicine, and for research and drug development, the production of these compounds remains very expensive because of the need for complex, capital-intensive equipment and infrastructure (i.e., hot cells, stack monitor, radiosynthesizer, and a suite of QC testing equipment) at each site. For the most widely used PET radiopharmaceutical, [18F]FDG, multiple patients can be scheduled on the same day, enabling the batch production costs to be divided among many individual doses. However, for most other PET tracers, such cost-sharing opportunities are rare or non-existent, meaning that each production run is effectively dedicated to a single patient, resulting in a high cost per patient dose. These challenges discourage manufacturers from investing in the production of valuable but less-used radiopharmaceuticals, which severely limits their availability. Additionally, the high price of many radiopharmaceuticals discourages their use in research (e.g. pre-clinical), and hampers the development and validation of novel radiopharmaceuticals. In addition to limited demand, some radiopharmaceuticals are constrained by supply-side issues (e.g. limited output of Ga-68 generators) that inherently limits the number of patient doses that can be made in a single batch. Instead of relying on cost reductions through increased demand for radiopharmaceuticals and increase size of batches produced, which will be impossible for many cases, our strategy is to lower the batch production cost itself. New microfluidic methods of PET tracer manufacture have emerged in recent years with the potential to revolutionize tracer production via dramatic reductions in cost and complexity. The droplet-based approach developed by the van Dam laboratory at UCLA enables the production of numerous 18F-radiopharmaceuticals with ~100x reagent reduction, 2-3x reduction in synthesis and purification time, and high molar activity, all in a system the size of a coffee cup. Droplet reactions were scaled to clinically-relevant amounts (one to many patient doses) by using an upstream radioisotope concentrator. DropletPharm, Inc. is commercializing a benchtop radiopharmacy platform based on this technology that will enable a transformation to low-cost production of a broad range of radiopharmaceuticals. Though most of the prior development of droplet radiochemistry has focused on 18F-radiopharmaceuticals, there is intense interest in radiometal isotopes for imaging and therapy, with a large number of Ga-68 compounds in pre-clinical development, clinical trials and a few with FDA-approval for routine use. In this Phase I STTR project, we aim to expand the applications of DropletPharm’s droplet radiochemistry approach beyond F-18 radiotracers by building a metal-free droplet reactor and establishing the feasibility of radiometal labeling. We will develop radioisotope concentration methods for Ga-68, Cu-64, and Zr-89 (Aim 1), develop droplet labeling methods for example radiotracers (Aim 2), and demonstrate production of [68Ga]Ga-PSMA-11 in a cGMP setting (Aim 3).

项目摘要 尽管放射性药物在临床核医学中用于成像和治疗的巨大价值， 对于研究和药物开发，这些化合物的生产仍然非常昂贵，因为 对复杂的、资本密集型设备和基础设施的需求（即，热室，堆栈监控器， 无线电合成器和一套QC检测设备）。对于应用最广泛的PET 放射性药物，[18F]FDG，可以在同一天安排多名患者， 生产成本将在许多单独的剂量中分摊。然而，对于大多数其他PET示踪剂， 成本分摊的机会很少或根本不存在，这意味着每次生产实际上都致力于 单个患者，导致每个患者剂量的高成本。这些挑战阻碍了制造商 投资于生产有价值但使用较少的放射性药物，这严重限制了它们的生产。 空房的此外，许多放射性药物的高价格阻碍了它们在研究中的使用（例如， 临床前），并且阻碍了新型放射性药物的开发和验证。除了有限的 由于需求，一些放射性药物受到供应方问题的限制（例如，Ga-68的产量有限 发生器），其固有地限制了可以在单个批次中制备的患者剂量的数量。 与其依赖于通过增加对放射性药物的需求来降低成本， 批量生产，这将是不可能的，在许多情况下，我们的策略是降低批量生产成本 本身近年来出现了PET示踪剂制造的新的微流体方法，其具有潜在的 通过显著降低成本和复杂性来革新示踪剂生产。基于液滴的方法 由加州大学洛杉矶分校的货车达姆实验室开发的18F-放射性药物 试剂减少约100倍，合成和纯化时间减少2- 3倍，以及高摩尔活性，所有这些都在一个 咖啡杯大小的系统。将液滴反应按比例缩放至临床相关量（一对多 患者剂量）。 DropletPharm，Inc.正在商业化一个基于这项技术的台式放射性药物平台， 能够转变为低成本生产广泛的放射性药物。尽管大多数 液滴放射化学的先前发展集中于18F-放射性药物， 在用于成像和治疗的放射性金属同位素中，大量Ga-68化合物在临床前 开发，临床试验和一些FDA批准的常规使用。在第一阶段STTR项目中，我们的目标是 将DropletPharm的液滴放射化学方法的应用扩展到F-18放射性示踪剂之外， 建立一个无金属液滴反应器和建立放射性金属标记的可行性。我们将开发 Ga-68、Cu-64和Zr-89的放射性同位素浓缩方法（目标1），开发用于 示例性放射性示踪剂（目标2），并证明在cGMP环境中产生[68 Ga]Ga-PSMA-11（目标3）。