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，在>90%的前列腺癌细胞上特异性表达。 所有的前列腺癌都会随着疾病的进展而增加。癌症靶向技术（CTT） 一种创新的基于氨基磷酸酯的肽模拟物，与PSMA不可逆地结合，导致>90% 在肿瘤细胞中内化和选择性积累。在以前的SBIR赠款支持下，CTT开发并 评价了18F标记的PET诊断成像剂CTT 1057。在1期临床试验中，CTT 1057 在前列腺癌（PCa）患者的PSMA-avid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。CTT 1057随后被授权给Advanced Accelerator 应用/诺华。然后，CTT修改了新的支架，以开发一种特异性和有效的伴侣 治疗用CTT 1403，用177 Lu放射性标记。CTT 1403与其他正在开发的PSMA靶向药物不同， 不仅与PSMA不可逆地结合，而且还结合了白蛋白结合基序， 清除，导致前所未有的肿瘤吸收>80%，这意味着显著的生存优势 在动物模型中。手动放射制造的CTT 1403目前在40例患者中进行了1期试验， 去势抵抗性PCa，迄今已证明具有良好的安全性，延长血液循环， 时间、延长的肿瘤暴露以及肾脏和其他剂量限制性正常器官中的低摄取。以优异 药物特性和疗效的高可能性，开发一种可靠，强大和有效的CTT 1403 生产和分销策略对于后续的大型患者队列临床试验至关重要。 基于试剂盒的自动化放射性制造已被证明是快速、稳健和可重复的， 18F-FDG。开发一种新的CTT 1403制造工艺，促进自动化将扩大访问 到CTT 1403在美国各地的放射性药物，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。在这个SBIR直接到第二阶段赠款，我们将 通过开发新的药物前体CTT 2001，开发一种新的简化的CTT 1403合成方法， 直接（1步）177 Lu放射性标记转化为试剂盒形式，用于自动合成仪。这 流程和自动化将降低商品成本、制造时间，并提高配送效率。目的 1：证明PSMA靶向一步放射性标记工艺的可行性。CTT将生产 CTT 2001前体，开发一种简单有效的CTT 1403放射性标记工艺，并评估 PSMA靶向功能保持完整。目的2：开发CTT 1403的自动化试剂盒配方 在Trasis合成仪上进行的合成将包括定制设计的一次性卡匣和定制的 用于简单和稳健的177 Lu标记的预测量试剂。CTT 1403发布测试也将得到充分开发 以在本项目完成后迅速促进试剂盒向大规模生产和临床使用的过渡。

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.