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 尽管治疗去势抵抗前列腺癌(CRPC)的新靶向药物的阵列不断扩大，但 疾病仍然无法治愈，近一半患有这种形式的PC的男性在两年内出现骨转移。 转移性骨病的一年存活率约为40%。靶向前列腺特异性膜 小分子抗原(PSMA)用于前列腺癌和其他癌症的成像和放射性核素治疗(RT) 重振了核医学领域。诺华公司最近收购了我们开发的[177 Lu]R2，以及 [177Lu]β粒子发射体177Lu标记的两个pSMA靶向RT在多中心临床 审判。在欧洲，已经进行了使用α粒子发射剂[225Ac]PSMA-617的初步试验 显示出显著的治疗效果，即使在对相应的177Lu产生抗药性的患者- 标有化合物的。然而，这些对靶向α粒子RT(TAT)的鼓舞人心的反应通常来自于 立即切除唾液腺和泪腺的费用，长期毒性尚不清楚。因此， 尽管进行了广泛的努力，PC的翻译RT仍处于关键阶段，尚未确定 在不影响生活质量的情况下提供持久的响应。我们在这方面将采取的方法 竞争性更新是将我们专注于211At的基本工作扩展到每个衰变释放一个α粒子 低剂量、药动学临床试验。我们假设211At将提供一个介于 毒性最小，但效率较低的177Lu和功率更大但具有潜在破坏性的225Ac，它总共释放出 每腐烂四个α粒子，这些粒子在体内很难控制，并促进上述毒性。我们的目标 是通过结合高线性能量转移(LET)肿瘤来获得具有最佳治疗指数的药物 通过有益的药代动力学和剂量的分子设计更好地控制毒性对211 At的细胞杀伤作用 战略。我们的铅-211At标记化合物[211At]VK-02-90-Lu的初步体内数据表明 免疫组织化学证实，与相关的225Ac标记的加合物相比，靶外毒性更低，具有类似的 生存特征。目前的计划旨在提供实验原理和数据，以 支持IND的治疗性研究。