Development of a Commercial-Ready Kit for CTT1403, a Novel PSMA-Targeted Radiotherapy

开发 CTT1403（一种新型 PSMA 靶向放射疗法）的商业化试剂盒

基本信息

批准号：
10491276
负责人：
Hunter Nicole Bomba
金额：
$ 100万
依托单位：
CANCER TARGETED TECHNOLOGY, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10491276
关键词：
Affinity Albumins American Animal Model Antigen Targeting Automation Benchmarking Binding Binding Sites Biological Availability Biological Markers Blood Blood Circulation Blood Circulation Time Brachytherapy Cancer Etiology Cancer Patient Castration Cessation of life Characteristics Chemicals Chlorides Clinic Clinical Clinical Trials Companions Custom Development Diagnostic Imaging Disease Progression Disease Resistance Distal Dose Dose-Limiting Enrollment External Beam Radiation Therapy FDA approved FOLH1 gene Formulation Funding Grant Half-Life Human Resources In Situ Kidney Label Lesion Malignant Neoplasms Malignant neoplasm of prostate Manuals Marketing Measures Metastatic to Methods Modeling Neoplasm Metastasis Organ Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Population Positron-Emission Tomography Privatization Process Prodrugs Radiation Radiation Tolerance Radiation therapy Radiolabeled Radionuclide therapy Radiopharmaceuticals Radium Reagent Regimen Renal clearance function Reproducibility Safety Scanning Shipping Site Small Business Innovation Research Grant Speed Targeted Radiotherapy Technology Testing Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Uses Time Tissues Translating Treatment Efficacy Tumor Markers United States Visceral Work base bone bone cell bone imaging bone metabolism cancer diagnosis cancer imaging cancer site castration resistant prostate cancer clinical research site cohort commercialization cost cost effective design fluorodeoxyglucose imaging agent improved innovation manufacturing process men molecular imaging neoplastic cell novel novel therapeutics peptidomimetics phase I trial phosphoramidate radiotracer refractory cancer scaffold side effect soft tissue standard of care success targeted agent targeted delivery targeted radiotherapeutic targeted treatment tumor uptake

项目摘要

PROJECT ABSTRACT Prostate-Specific Membrane Antigen (PSMA) is an ideal tumor biomarker with specific expression on >90% of all prostate cancers that increases with disease progression. Cancer Targeted Technology (CTT) has developed an innovative phosphoramidate-based peptidomimetic that binds irreversibly to PSMA, leading to >90% internalization and selective accumulation in tumor cells. With previous SBIR grant support, CTT developed and evaluated an 18F-labeled PET diagnostic imaging agent, CTT1057. In a Phase 1 clinical trial, CTT1057 demonstrated significant uptake in PSMA-avid bone and visceral lesions in prostate cancer (PCa) patients with far greater accuracy than standard of care scans. CTT1057 was subsequently licensed to Advanced Accelerator Applications/Novartis. CTT then modified the novel scaffold to develop a specific and potent companion therapeutic, CTT1403, radiolabeled with 177Lu. CTT1403, unlike other PSMA-targeting agents in development, not only binds irreversibly to PSMA but also incorporates an albumin-binding motif to dramatically slow blood clearance, resulting in unprecedented tumor uptake of >80% that translates to a significant survival advantage in animal models. Manually radiomanufactured CTT1403 is currently in a 40-patient Phase 1 trial in men with castration resistant PCa and to date has demonstrated an excellent safety profile, extended blood circulation time, extended tumor exposure and low uptake in kidney and other dose limiting normal organs. With excellent drug characteristics and a high likelihood of efficacy, the development of a reliable, robust and efficient CTT1403 manufacturing and distribution strategy is critical for subsequent clinical trials with very large patient cohorts. Automated, kit-based radiomanufacture has proven rapid, robust, and reproducible for benchmark agents like 18F-FDG. Development of a novel CTT1403 manufacturing process that facilitates automation will expand access to CTT1403 for radiopharmacies across the United States, increasing availability for pivotal clinical trials and potential for subsequent market and commercialization success. In this SBIR Direct to Phase II grant, we will develop a novel, simplified method for CTT1403 synthesis by developing a new drug precursor, CTT2001, for direct (1-step) 177Lu radiolabeling to be converted to a kit format for use in an automated synthesizer. This process and automation will reduce cost of goods, manufacturing time, and increase distribution efficiency. AIM 1: Demonstrate feasibility of a PSMA-targeted 1-step radiolabeling process. CTT will manufacture the CTT2001 precursor, develop a simple and efficient CTT1403 radiolabeling process, and assess whether the PSMA-targeting function remains intact. AIM 2: Develop an automated kit formulation for CTT1403 synthesis, on the Trasis synthesizer, will include a custom designed, disposable cassette and a custom kit of pre-measured reagents for simple and robust 177Lu labeling. CTT1403 release testing will also be fully developed to rapidly facilitate transition of the kit to large-scale manufacture and clinical use upon completion of this project.

项目摘要前列腺特异性膜抗原 (PSMA) 是一种理想的肿瘤生物标志物，在 >90% 的前列腺组织中特异性表达所有随疾病进展而增加的前列腺癌。癌症靶向技术（CTT）已开发一种基于氨基磷酸酯的创新肽模拟物，可与 PSMA 不可逆结合，导致 >90% 肿瘤细胞内化和选择性积累。在之前的 SBIR 拨款支持下，CTT 开发并评估了 18F 标记的 PET 诊断成像剂 CTT1057。在 1 期临床试验中，CTT1057 研究表明，前列腺癌 (PCa) 患者的 PSMA 骨和内脏病变有显着吸收比标准护理扫描的准确性高得多。 CTT1057随后被授权给Advanced Accelerator 应用/诺华。然后，CTT 修改了新型支架，开发出一种特定且有效的伴侣治疗剂，CTT1403，用 177Lu 放射性标记。 CTT1403 与正在开发的其他 PSMA 靶向药物不同，不仅不可逆地与 PSMA 结合，而且还包含白蛋白结合基序，可显着减缓血液流动清除，导致前所未有的肿瘤摄取>80%，转化为显着的生存优势在动物模型中。手动放射性制造的 CTT1403 目前正在进行一项有 40 名患者参与的 1 期临床试验，受试者为患有以下疾病的男性：迄今为止，去势抵抗性 PCa 已表现出出色的安全性，可延长血液循环时间、肿瘤暴露时间延长以及肾脏和其他限制正常器官剂量的低吸收。具有优良的药物特性和高功效可能性，开发可靠、稳健和高效的 CTT1403 制造和分销策略对于后续针对大量患者进行的临床试验至关重要。事实证明，基于套件的自动化无线电制造对于基准代理（例如 18F-FDG。开发一种促进自动化的新型 CTT1403 制造工艺将扩大使用范围美国各地的放射性药物符合 CTT1403，增加了关键临床试验的可用性后续市场和商业化成功的潜力。在这项 SBIR Direct to Phase II 拨款中，我们将通过开发新药物前体 CTT2001，开发一种新颖、简化的 CTT1403 合成方法，用于直接（一步）177Lu 放射性标记转换为试剂盒格式，用于自动合成器。这流程和自动化将降低商品成本、制造时间并提高分销效率。目的 1：展示 PSMA 目标一步放射性标记过程的可行性。 CTT 将制造 CTT2001前体，开发简单高效的CTT1403放射性标记流程，并评估是否 PSMA 靶向功能保持完整。目标 2：开发 CTT1403 的自动化试剂盒配方 Trasis 合成器上的合成将包括定制设计的一次性盒和定制套件预先测量的试剂可实现简单而稳定的 177Lu 标记。 CTT1403发布测试也将全面展开项目完成后，迅速促进该试剂盒向大规模生产和临床使用过渡。