Macro-to-micro (M2µ) Activity Apportionment for αRPT

αRPT 的宏观到微观 (M2µ) 活动分配

• 批准号: 10713712
• 负责人: Robert Francois Hobbs
• 金额: $ 49.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713712
• 关键词: Alpha Particle Emitter; Alpha Particles; Anatomy; Animals; Antibodies; Bone Marrow; Clinical; Clinical Trials; Combined Modality Therapy; Data; Dose; Dose Limiting; Drug Kinetics; ERBB2 gene; FDA approved; FOLH1 gene; Family suidae; Fractionation; Goals; Human; Image; Kidney; Lacrimal gland structure; Link; Literature; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Medicine; Metastatic Neoplasm to the Bone; Methodology; Methods; Microscopic; Miniature Swine; Modality; Modeling; Mus; Organ; Organ Model; Patients; Peptides; Pre-Clinical Model; Process; Publishing; Radiobiology; Radioisotopes; Radiopharmaceuticals; Reporting; Risk; Salivary Glands; Small Intestines; Standardization; Testing; Therapeutic; Therapeutic Uses; Time; Toxic effect; Translating; Translations; Uncertainty; United States National Institutes of Health; Work; absorption; cancer therapy; clinical practice; clinically relevant; design; dosimetry; interest; mouse model; particle; particle therapy; porcine model; pre-clinical; predicting response; programs; response; single photon emission computed tomography; small molecule; spatiotemporal; targeted delivery; targeted treatment; translation to humans; treatment planning

Recent advances in the targeted delivery of radionuclides and the increased availability of -emitters appropriate for clinical use have led to patient trials of multiple α-emitter radiopharmaceutical therapeutics (RPTs). One of these, Xofigo (223RaCl2) was FDA-approved and is in routine clinical practice, with many others likely to follow. One of the stated goals (pillars) of the NIH is a greater level of personalization in medicine. In the realm of radiopharmaceutical therapy (RPT) this translates directly as a need for more accurate personalized dosimetry in order to enable fractionation and administered activity tailored to each patient. However, current dosimetry paradigms are poorly suited to RPT. This reality is reflected by the discrepancies between clinical (or experimental) toxicity and expected toxicity calculated using standard organ-level (or voxel-level) dosimetry, including most notably: (a) hematotoxicity in 223Ra therapy of bone metastases, (b) renal and salivary gland toxicity in pre-clinical models and patients. The objective of this work is to create a dosimetric methodology more suited to αRPT, namely the Macro to micro (M2) methodology, which requires sub-organ activity apportionment factors for organs at risk. This will be accomplished via the following Aims: 1. In murine models, measure αRPT activity concentration in selected whole organs and in relevant organ sub-regions; generate apportionment factor histograms. The translation to human assumes that the link between macroscopic and microscopic spatiotemporal relationship for a given agent measured in a pre-clinical model will apply to the human as the distribution of the agent to the different microscopic compartments should remain the same. We will test and quantify the validity of this assumption and refine the human apportionment factors by introducing a third species, the mini-pig In Aim 2. We will assess apportionment factor transferability, by obtaining corresponding apportionment factor histograms for a porcine model. In Aim 3. We will demonstrate that M2µ predicts toxicity in the porcine model. 4. Apply the M2µ methodology to clinical trial data to quantify the potential benefit of personalized M2µ dosimetry and/or derive dose–response relationships. Successful completion of the proposal will reconcile experimental and clinical results not currently understood and provide a robust standardized dosimetry for personalized dosimetry-based treatment planning of αRPT. Such standardization will enable the dosimetry to be normalized to EQD2, thus enabling rational combinations with other RPTs or external beam therapy as well as relevant absorbed dose reporting. Here we plan to expand this approach to encompass the wide range of RPT/organ combinations that have either been shown to be or are potentially dose-limiting and that require the Macro to micro (M2) methodology to properly correlate dosimetry with toxicity thresholds and provide a deliverable that will allow end-users to convert macroscopically-measured activity to standardized dosimetry at the organ and (clinically relevant) sub-organ-level for a wide range of RPTs and correspondingly relevant organs.

放射性核素定向输送和 α 发射体可用性增加的最新进展 临床应用导致了多种 α 发射体放射性药物治疗 (RPT) 的患者试验。之一 其中，Xofigo (223RaCl2) 已获得 FDA 批准，并已进入常规临床实践，许多其他产品可能会跟进。 NIH 的既定目标（支柱）之一是提高医疗个性化水平。在领域 放射性药物治疗 (RPT) 这直接意味着需要更准确的个性化剂量测定 以便能够针对每位患者进行分段和管理活动。然而，目前的剂量测定 范式不太适合 RPT。这一现实反映在临床（或 实验）毒性和使用标准器官水平（或体素水平）剂量测定计算的预期毒性， 其中最值得注意的是：(a) 223Ra 骨转移治疗中的血液毒性，(b) 肾和唾液腺 临床前模型和患者的毒性。这项工作的目的是创建一种更有效的剂量测定方法 适合αRPT，即宏观到微观（M2）方法，需要子器官活动分配 危险器官的因素。这将通过以下目标来实现： 1. 在小鼠模型中，测量 αRPT 选定的整个器官和相关器官分区的活动浓度；生成分配因子 直方图。对人类的翻译假设宏观和微观之间的联系 在临床前模型中测量的给定药物的时空关系将适用于人类 药剂在不同微观室中的分布应保持相同。我们将测试并 量化这一假设的有效性，并通过引入第三个物种来完善人类分配因素， 目标 2 中的迷你猪。我们将评估分配因子的可转移性，通过获得相应的 猪模型的分配因子直方图。在目标 3 中，我们将证明 M2μ 可以预测毒性 猪模型。 4. 将 M2μ 方法应用于临床试验数据，以量化潜在益处 个性化 M2μ 剂量测定和/或得出剂量-反应关系。提案顺利完成 将协调目前尚未理解的实验和临床结果，并提供稳健的标准化 剂量测定用于基于剂量测定的个性化 αRPT 治疗计划。这种标准化将使 剂量测定将标准化为 EQD2，从而能够与其他 RPT 或外部束进行合理组合 治疗以及相关吸收剂量报告。在这里，我们计划扩展这种方法以涵盖 广泛的 RPT/器官组合已被证明具有或潜在的剂量限制性 需要宏观到微观 (M2) 方法将剂量测定与毒性阈值正确关联起来 提供可交付成果，允许最终用户将宏观测量的活动转换为标准化的活动 器官和（临床相关）亚器官水平的剂量测定，适用于各种 RPT 和相应的 有关机关。