Development of Tumor Proliferation PET Tracer FLT using a Low Cost Single Dose Automatic Production and Quality Control Biomarker Generator System

使用低成本单剂量自动生产和质量控制生物标志物生成系统开发肿瘤增殖 PET 示踪剂 FLT

• 批准号: 9291438
• 负责人: Thomas Bruckbauer
• 金额: $ 71.18万
• 依托单位: ABT MOLECULAR IMAGING, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-14 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291438
• 关键词: Aluminum Oxide; Anions; Biochemical; Biological Markers; Capital; Cation Exchange Resins; Chemistry; Clinical Trials; Cyclotrons; Data; Development; Diagnosis; Diagnostic; Disease; Dose; Endotoxins; Ensure; European; Excision; FLT3 gene; Funding; Goals; Healthcare; High Pressure Liquid Chromatography; Hydrolysis; Image; Institution; International; Investments; Japan; Label; Lead; Letters; Malignant Neoplasms; Manuals; Measures; Metabolic; Methods; Monitor; National Cancer Institute; Patients; Persons; Pharmacopoeias; Phase; Population; Positron-Emission Tomography; Production; Quality Control; Radiation; Radio; Radioisotopes; Research Personnel; Residual state; Risk; Running; Site; Small Business Innovation Research Grant; Solid; Solvents; System; Technology; Testing; Tracer; Treatment Efficacy; United States National Institutes of Health; Vascular Endothelial Growth Factor Receptor-1; Western Europe; Work; animal imaging; base; cancer diagnosis; cancer imaging; cancer therapy; commercialization; cost; detector; evaporation; in vivo; meetings; molecular imaging; novel; patient population; prototype; public health relevance; research and development; tool; tumor; uptake

 DESCRIPTION (provided by applicant): Worldwide, a person dies from cancer every 5 seconds. Positron emission tomography (PET) is an effective tool that is critical in diagnosing cancer and monitoring treatment efficacy. PET imaging relies on use of short-lived radioisotopes. Commercial distribution of the most commonly used radio tracer, [18F]FDG, has resulted in 80% patient population coverage in the U.S, Western Europe and Japan. However, the "emerging world" (~85% of the world's population) still does not have ready access to [18F]FDG. ABT Molecular Imaging, Inc. (ABT) is focused on increasing PET access in the U.S. and worldwide. The firm's proprietary "Dose on Demand(tm)" Biomarker Generator (BG) greatly simplifies production of [18F]FDG. It also reduces the investment required by healthcare institutions to introduce PET diagnostics into new regions. The need for PET- related advances remains, however. The [18F]FDG biomarker is not the only one required for successful diagnosis/treatment monitoring of cancers. [18F]FLT has been shown to provide complementary information [18F]FDG regarding tumor proliferation in a range of cancers constituting 72% of all existing cases (see Comm. Plan Section A), yet it costs $3000-$4000/dose where available. [18F]FLT has shown so much promise that the National Cancer Institute has an established IND (11/2004) for [18F]FLT to actively encourage investigators to cross-file on (there are more than 350 clinical trials). The Fast Track SBIR project proposed here will provide the funding needed to develop and validate ABT's ability to automatically synthesize and perform automatic QC testing on [18F]FLT simplifying site IND submissions with ABT support. The envisioned ABT system will generate [18F]FLT for ~$250/dose using disposable dose-synthesis cards that can be used in-between [18F]FDG doses. The challenges to integrating [18F]FLT are (1) producing enough F-18 to account for the synthesis yield of [18F]FLT, (2) automating synthesis, and (3) automating QC tests of [18F]FLT on the BG system. For this Fast Track, ABT's PI, Dr. Khachaturian, will lead an expert R&D team of 12 in pursuing 3 Phase I and 3 Phase II Aims: (Aim 1) Validate the feasibility of increasing the amount of [18F] produced by the cyclotron from 1 to 1.7 [mCi/min]; (Aim 2) produce one unit dose of [18F]FLT (2.0-3.6 [mL], 2.5-5 [mCi]) with both US and EU precursors; and (Aim 3) pass the US and EU pharmacopeia quality controls tests. Phase I verification will fully validate proof of concept, such that Phase II development ca focus on ensuring consistent [18F]FLT yield and quality for manufacturing. The Phase II Aims are: (Aim 4) F-18 yield shall be >1.7 [mCi/min] at 3s for n = 4 targets and 20 runs/target; (Aim 5) 24 consecutive unit doses of [18F]FLT can be synthesized with both labeling precursors; and (Aim 6) 24 consecutive unit [18F]FLT doses will pass the US and EU pharmacopeia requirements. Phase III support will come from ABT's current investors and will enable the distribution of [18F]FLT, contingent upon receiving the NIH Fast Track support and meeting the Phase I and II R&D goals.

 描述(申请人提供)：在世界范围内，每5秒就有一人死于癌症。正电子发射断层扫描(PET)是诊断癌症和监测治疗效果的一种有效工具。PET成像依赖于使用寿命较短的放射性同位素。最常用的放射性示踪剂[18F]FDG的商业分发已经在美国、西欧和日本覆盖了80%的患者人口。然而，“新兴世界”(约占世界人口的85%)仍然无法随时使用[18F]FDG。ABT分子成像公司(ABT)专注于在美国和世界范围内增加PET的使用。该公司专有的“按需剂量(Tm)”生物标记发生器(BG)极大地简化了[18F]FDG的生产。它还减少了医疗机构将PET诊断引入新地区所需的投资。然而，对PET相关进展的需求仍然存在。[18F]FDG生物标记物并不是癌症成功诊断/治疗监测所必需的唯一标记物。[18F]FLT已被证明提供了关于占所有现有病例72%的一系列癌症中肿瘤增殖的补充信息[18F]FDG(见Comm。计划A部分)，但如果有的话，每剂的价格是3000-4000美元。[18F]Flt已经显示出如此大的希望，以至于国家癌症研究所为[18F]Flt设立了IND(11/2004)，以积极鼓励研究人员交叉归档(有350多项临床试验)。这里建议的快速跟踪SBIR项目将提供所需的资金，以开发和验证ABT的自动合成能力，并在[18F]FLT上执行自动QC测试，通过ABT支持简化现场IND提交。设想的ABT系统将使用可在[18F]FDG剂量之间使用的一次性剂量合成卡，以~250美元/剂量的价格生成[18F]FLT。整合[18F]Flt的挑战是(1)产生足够的F-18来说明[18F]Flt的合成产率，(2)自动化合成，以及(3)在BG系统上自动化[18F]Flt的质量控制测试。对于这一快速通道，ABT的Pi，Khachaturian博士将领导一个12人的专家研发团队，以实现3个第一阶段和3个第二阶段的目标：(目标1)验证将回旋加速器产生的[18F]量从1增加到1.7[mci/min]的可行性；(目标2)用美国和欧盟的前体生产一单位剂量的[18F]Flt(2.0-3.6[毫升]，2.5-5[mCI])；以及(目标3)通过美国和欧盟药典的质量控制测试。第一阶段验证将充分验证概念的证明，以便第二阶段的开发可以集中于确保制造的一致的[18F]Flt产量和质量。第二阶段的目标是：(目标4)对于n=4个目标和20次/目标，F-18的产量在3s时应为1.7[mci/min]；(目标5) 两种标记前体均可合成24个连续单位剂量的[18F]Flt；(目标6)24个连续单位剂量的[18F]Flt将通过美国和欧盟药典的要求。第三阶段的支持将来自ABT的现有投资者，并将在获得NIH快速通道支持和满足第一阶段和第二阶段研发目标的情况下，实现[18F]FLT的分销。