Development and validation of a quality control system for pharmaceutical development and production of targeted alpha therapies

使用放射性药物的下一代癌症治疗有可能改变癌症治疗方法。特别是靶向α治疗（达特）是一种非常有前途的新兴癌症治疗方法，其中α辐射靶向癌细胞，选择性地杀死局部肿瘤和非局部癌症（包括转移性癌症和白血病）。它利用α发射体的异常高的能量沉积，结合高的所谓线性能量转移（LET），直接产生双链DNA断裂。达特的初步实验研究证明了通过PSMA靶向去势抵抗性前列腺癌的这种治疗的功效。患者具有广泛的转移，但在用Ac-225标记的PSMA-617进行放射性药物治疗后，患者进入缓解期[Kratochwil等人，J.Nucl.Med. 57（2016）1941]。本项目提供了利用以前STFC后续资助项目的成就（ST/T003162/1），将开发的设备从关键功能测试阶段带到基于该设备的放射性药物α治疗开发的质量控制（QC）系统的开发和验证阶段，微流体α粒子传感器（MAS）。在本项目中，这将嵌入到流体QC系统中，该系统用于同位素生产和随后的放射性药物QC。技术的关键功能（传感器和流体）最近已经证明了分析和实验（ST/T003162/1）作为概念验证，最高可达TRL 3（分析和实验关键功能或特征概念验证）。总体目标是：（O.1）与行业合作伙伴一起为α治疗开发和生产开发概念验证QC流程（LabLogic），符合放射性药物行业的要求;（O.2）确定满足这些要求所需的进一步技术规格;（O.3）测试一系列实施方案，以满足这些要求，直至原则上开发出完整的装置，同时考虑到质量控制所需的进步;和（O.4）在受控实验室环境中（TRL 4：实验室环境中的技术基本验证，EXACT，南安普顿）和与已建立的医用同位素生产商（TRL 5：相关环境中的技术基本验证，TRIUMF，加拿大）对组合技术及其用于放射性药物质量控制的潜力进行验证。作为该项目（O.5）的一个关键目标，将加强与TRIUMF和LabLogic的合作伙伴关系，并利用这些合作伙伴关系来推进该设备和相关QC流程的IP开发和市场开发，并为未来达特开发产生新的英国能力。

Next-generation cancer treatments using radiopharmaceuticals have the potential to transform cancer treatment methodology. Targeted Alpha Therapy (TAT), in particular, is an extremely promising, emerging cancer treatment, in which alpha radiation is targeted to cancerous cells, selectively killing both localised tumours and delocalised cancers (including metastatic cancers and leukaemia). It utilises the exceptionally high energy deposition of the alpha emitters, combined with the high so-called Linear Energy Transfer (LET), directly generating double-stranded DNA breakages. An initial experimental investigation of TAT demonstrated the power of such a treatment through PSMA targeting of a castration-resistant prostate cancer. The patient had wide-spread metastases, but after radiopharmaceutical treatment with Ac-225 labelled PSMA-617, the patient entered remission [Kratochwil, et al., J.Nucl.Med. 57(2016)1941].The present project offers to capitalise on the achievements of a previous STFC Follow-on-Funding project (ST/T003162/1), taking a developed device from the stage of critical functionality tests to the development and validation of a quality control (QC) system for radiopharmaceutical alpha therapy development based on the device, a microfluidic alpha-particle sensor (MAS). In the present project, this will be embedded in a fluidic QC system developed for utilisation in both isotope production and subsequent radiopharmaceutical QC. The critical functions of the technology (sensor and fluidic) have recently been demonstrated analytically and experimentally (ST/T003162/1) as proof-of-concept up to a current level of TRL 3 (analytical and experimental critical function or characteristic proof-of-concept).The overarching objectives are: (O.1) to develop proof-of-concept QC processes for alpha treatment development and production, with an industry partner (LabLogic), in line with the requirements of the radiopharmaceutical industry; (O.2) to determine further technology specifications required to meet these requirements; (O.3) to test a range of implementation options to meet these requirements to a stage where a complete device - in principle - has been developed, taking into account the advancements required for QC; and (O.4) to carry out a validation of the combined technology and its potential for radiopharmaceutical QC in a controlled laboratory environment (TRL 4: technology basic validation in a laboratory environment, EXACT, Southampton) and with an established medical isotope producer (TRL 5: technology basic validation in a relevant environment, TRIUMF, Canada). As a key objective of the project (O.5), the partnerships with TRIUMF and LabLogic will be strengthened and utilised to advance both IP development and market development for the device and associated QC processes, as well as to generate new UK capacity for future TAT developments.