Small Molecule PSMA-Targeted Alpha Therapy

小分子 PSMA 靶向阿尔法疗法

• 批准号: 9886363
• 负责人: MARTIN G POMPER
• 金额: $ 31.93万
• 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/9886363
• 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.

项目概要 尽管治疗去势抵抗性前列腺癌（CRPC）的新靶向药物不断增多，但 这种疾病仍然无法治愈，近一半患有这种 PC 的男性在两年内会发生骨转移。 转移性骨病的一年生存率约为 40%。靶向前列腺特异性膜 抗原 (PSMA) 与小分子，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。诺华最近收购了我们开发的[177Lu]R2，并且 [177Lu]PSMA-617，两种β粒子发射体177Lu标记的PSMA靶向RT，处于多中心临床 试验。在欧洲，已经进行了使用α粒子发射剂[225Ac]PSMA-617的初步试验， 即使在对相应 177Lu- 产生耐药性的患者中，也显示出显着的治疗效果 标记的化合物。然而，这些对靶向 α 粒子 RT (TAT) 的令人鼓舞的反应往往是在 立即消融唾液腺和泪腺的费用，长期毒性未知。因此， 尽管做出了广泛的努力，PC 的转化 RT 仍处于关键阶段，尚未确定一种药物可以 提供持久的反应而不影响生活质量。我们在这方面将采取的方法 竞争性的更新是将我们专注于 211At 的基础工作扩展至 低剂量、药代动力学临床试验。我们假设 211At 将提供介于 毒性最小但效果较差的 177Lu 和毒性更强但具有潜在破坏性的 225Ac，其排放总量 每次衰变有四个 α 粒子，这在体内难以控制并促进上述毒性。我们的目标 就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剂 通过分子设计实现有益的药代动力学和剂量，杀死 211At 细胞并更好地控制毒性 策略。我们的先导 211At 标记化合物 [211At]VK-02-90-Lu 的初步体内数据表明很多 经免疫组织化学证实，与相关 225Ac 标记的加合物相比，脱靶毒性较低，具有相似的效果 生存特征。当前的计划旨在提供实验原理和数据 支持 IND 的治疗研究。