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

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，90%的前列腺特异性表达于 所有随着疾病进展而增加的前列腺癌。癌症靶向技术(CTT)已经发展起来 一种创新的以磷酰胺为基础的肽模拟物，它与PSMA不可逆结合，导致&gt；90% 肿瘤细胞的内化和选择性蓄积。在之前的SBIR赠款支持下，CTT开发了 评价了一种18F标记的PET诊断显像剂CTT1057。在一期临床试验中，CTT1057 前列腺癌(PCa)患者的PSMA阳性骨和内脏病变中显示出显著的摄取 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。CTT随后对这种新型支架进行了修饰，以开发出一种特定而有效的伴侣 治疗性，CTT1403，放射性标记177Lu。CTT1403与其他正在开发的PSMA靶向剂不同， 不仅与PSMA不可逆转地结合，而且还结合了一个白蛋白结合基序来显著降低血液速度 清除，导致前所未有的肿瘤摄取&gt；80%，这转化为显著的生存优势 在动物模型中。人工放射制造的CTT1403目前正处于一项有40名患者参加的1期试验，患者患有 抗阉割的PCA和到目前为止已经显示出极好的安全性，延长了血液循环 时间长，肿瘤暴露时间长，肾脏和其他限制正常器官的剂量摄取率低。以出色的表现 药物的特点和极高的疗效可能性，开发出可靠、稳健、高效的CTT1403 制造和分销策略对于后续具有非常大的患者队列的临床试验至关重要。 自动化的、基于套件的放射制造已被证明是快速、可靠和可重复性的，适用于基准代理，如 18F-FDG。开发一种促进自动化的新型CTT1403制造工艺将扩大访问范围 到CTT1403用于全美的放射性药物，增加关键临床试验和 后续市场和商业化成功的潜力。在这项SBIR直接到第二阶段的拨款中，我们将 通过开发一种新的药物前体CTT2001来开发一种新的、简化的CTT1403合成方法 直接(1步)177Lu放射性标记将转换为试剂盒格式，用于自动合成器。这 流程和自动化将降低货物成本、制造时间，并提高配送效率。目标 1：论证以PSMA为靶点的1步放射性标记过程的可行性。CTT将生产 CTT2001前体，开发一种简单有效的CTT1403放射性标记方法，并评估 PSMA靶向功能保持不变。目标2：为CTT1403开发自动化试剂盒配方 在Trasis合成器上进行的合成将包括一个定制设计的一次性盒式磁带和一个定制套件 用于简单和可靠的177Lu标记的预先测量的试剂。CTT1403版本测试也将得到全面开发 以促进该试剂盒在该项目完成后迅速过渡到大规模生产和临床使用。

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.