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，特异性表达在> 90％上随着疾病进展的增加的所有前列腺癌。癌症靶向技术（CTT）已开发一种创新的基于磷化酰胺的肽瘤，可与PSMA不可逆地结合，导致90％肿瘤细胞中的内在化和选择性积累。在先前的SBIR赠款支持下，CTT开发了评估了18F标记的PET诊断成像剂CTT1057。在第1阶段临床试验中，CTT1057 在前列腺癌（PCA）患者中，表现出明显摄取的PSMA-avid骨和内脏病变与护理标准扫描相比，准确性要高得多。随后，CTT1057获得了高级加速器的许可申请/诺华。 CTT然后修改了新颖的脚手架以发展特定而有力的伴侣治疗性，CTT1403，用177LU标记。 CTT1403，与其他正在开发的PSMA靶向剂不同，不仅可以不可逆转地与PSMA结合，而且还结合了白蛋白结合基序，以极大的慢血液清除率，导致前所未有的肿瘤吸收> 80％，这转化为显着的生存优势在动物模型中。手动放射器的CTT1403目前正在接受40名患者1阶段试验抗cast割的PCA和迄今为止显示出极好的安全性，延长血液循环时间，肿瘤暴露延长，肾脏和其他限制正常器官的摄取量低。出色药物特征和高功效的可能性，可靠，健壮和有效的CTT1403的发展制造和分销策略对于随后的患者队列非常大的临床试验至关重要。自动化，基于套件的放射制造已被证明是快速，健壮和可重现的基准代理 18f-fdg。开发新型的CTT1403制造过程，以促进自动化到CTT1403用于整个美国的放射性药物，增加了关键临床试验的可用性随后的市场和商业化成功的潜力。在此SBIR直接获得第二阶段赠款中，我们将通过开发新的药物前体CTT2001来开发一种新颖的，简化的CTT1403合成方法直接（1步）177LU放射性标记将转换为套件格式，以用于自动合成器。这过程和自动化将降低商品成本，制造时间并提高分配效率。目的 1：证明靶向PSMA的1步放射性标记过程的可行性。 CTT将制造 CTT2001前体，开发一个简单有效的CTT1403放射性标记过程，并评估是否是否靶向PSMA的函数仍然完好无损。 AIM 2：为CTT1403开发自动化套件公式在Trasis合成器上的合成将包括一个定制设计的，一次性盒和定制套件预测的试剂可用于简单且坚固的177LU标签。 CTT1403发布测试也将完全开发该项目完成后，迅速促进套件过渡到大规模制造和临床使用。