Small Molecule PSMA-Targeted Alpha Therapy

小分子 PSMA 靶向阿尔法疗法

• 批准号: 10092113
• 负责人: MARTIN G POMPER
• 金额: $ 38.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092113
• 关键词: Ablation; Alpha Particle Emitter; Alpha Particles; Antigen Targeting; Beta Particle; Biodistribution; Biological; Blood; Bone Diseases; Catabolism; Characteristics; Chemistry; Clinical Trials; Cohort Studies; Data; Discipline of Nuclear Medicine; Disease; Dose; Drug Kinetics; Europe; Evaluation; FOLH1 gene; Frequencies; Gallium; Goals; Human; Image; Immunohistochemistry; Knowledge; Label; Lacrimal gland structure; Lead; Linear Energy Transfer; Lutetium; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolism; Metastatic Neoplasm to the Bone; Molecular; Multi-Institutional Clinical Trial; Mus; Patients; Pharmaceutical Chemistry; Phase; Phase I Clinical Trials; Positioning Attribute; Positron-Emission Tomography; Procedures; Prostate; Quality of life; Radiation therapy; Radioactivity; Radiochemistry; Radiolabeled; Radiometry; Radionuclide therapy; Recommendation; Regimen; Resistance; Salivary Glands; Specimen; Structure; Survival Rate; Testing; Therapeutic Clinical Trial; Therapeutic Index; Therapeutic Studies; Tissues; Toxic effect; Urine; Work; Xenograft procedure; adduct; analog; base; castration resistant prostate cancer; cell killing; clinical investigation; design; dosimetry; experience; human imaging; human subject; imaging agent; imaging study; in vivo; lipophilicity; meetings; men; molecular imaging; neoplastic cell; programs; radiotracer; resistance mechanism; response; small molecule; targeted agent; targeted treatment; treatment effect; tumor

Project Summary Despite the expanding array of new targeted agents to treat castration-resistant prostate cancer (CRPC), the disease remains incurable with nearly half of men with this form of PC developing bone metastases at two years. Metastatic bone disease carries a one-year survival rate of ~40%. Targeting the prostate-specific membrane antigen (PSMA) with small molecules for imaging and radionuclide therapy (RT) of prostate and other cancers has revitalized the field of nuclear medicine. Novartis has recently acquired [177Lu]R2, developed by us, and [177Lu]PSMA-617, two PSMA-targeted RT labeled with the β-particle emitter 177Lu that are in multi-center clinical trials. In Europe, there have been preliminary trials using the α-particle emitting agent [225Ac]PSMA-617 that have shown substantial treatment effects, even in patients that became resistant to the corresponding 177Lu- labeled compound. However, these encouraging responses to targeted α-particle RT (TAT) often came at the expense of immediate ablation of the salivary and lacrimal glands, with long-term toxicities unknown. Accordingly, despite widespread efforts, translational RT for PC is at a crucial stage, having yet to identify an agent that provides durable responses without compromising quality of life. The approach that we shall take in this competing renewal is to extend our basic work focusing on 211At, which emits a single α-particle per decay, to a low-dose, pharmacokinetic clinical trial. We hypothesize that 211At will provide an intermediate between the minimally toxic, but less effective 177Lu and the more powerful but potentially damaging 225Ac, which emits a total of four α-particles per decay that are difficult to control in vivo and promote the aforementioned toxicity. Our goal is to have an agent with an optimal therapeutic index by combining the high linear energy transfer (LET) tumor cell kill of 211At with greater control of toxicity through molecular design for salutary pharmacokinetics and dosing strategies. Preliminary in vivo data with our lead 211At-labeled compound, [211At]VK-02-90-Lu, indicates much lower off-target toxicity than for a related 225Ac-labeled adduct, confirmed by immunohistochemistry, with similar survival characteristics. The current program is intended to provide the experimental rationale and data for an IND-enabling therapeutic study.

项目摘要 尽管新的靶向药物不断扩大，以治疗耐castration的前列腺癌（CRPC），但仍在 疾病仍然无法治愈，其中几乎一半的男性在两年内开发了骨转移。 转移性骨病的生存率约为40％。靶向前列腺特异性膜 抗原（PSMA），带有小分子用于成像和前列腺和其他癌症的放射性疗法（RT） 振兴了核医学领域。诺华最近收购了我们开发的[177lu] R2， [177LU] PSMA-617，两个标记为β粒子发射极177LU的PSMA靶向RT，在多中心临床中 试验。在欧洲，已经使用α粒子发射剂[225AC] PSMA-617进行了初步试验 已经显示出实质的治疗效果，即使在对相应177lu-抗性的患者中 标记化合物。但是，这些对靶向α粒子RT（TAT）的鼓励反应通常是在 立即消融唾液和富富基础的费用，长期毒性未知。根据 尽管宽度努力，但PC的翻译RT仍处于关键阶段，还没有确定一个代理商 提供持久的回应，而不会折衷生活质量。我们将采取的方法 竞争的更新是将我们的基本工作扩展到211AT上，该工作每衰减发出单个α粒子， 低剂量的药代动力学临床试验。我们假设211AT将在 最小的有毒，但有效的177LU效率较小，功率更强大但有可能破坏的225AC，这散发出了总数 在每个衰减的四个α粒子中，很难在体内控制并促进Priore提及。我们的目标 通过组合高线性能量转移（LET）肿瘤，具有具有最佳治疗指数的代理 通过分子设计对毒性和剂量的分子设计，对211AT的细胞杀死211AT的杀伤 策略。带有铅211AT标记化合物的初步体内数据，[211AT] VK-02-90-LU，指示很多 通过免疫组织化学证实，脱离目标的毒性低于相关的225AC标记加合物的毒性。 生存特征。当前的程序旨在为一个实验原理和数据提供 辅助治疗研究。