Small Molecule PSMA-Targeted Alpha Therapy

小分子 PSMA 靶向阿尔法疗法

• 批准号: 10411890
• 负责人: MARTIN G POMPER
• 金额: $ 36.22万
• 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/10411890
• 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 尽管治疗去势抵抗性前列腺癌（CRPC）的新靶向药物不断增加， 这种疾病仍然是不可治愈的，几乎一半的男性患有这种形式的PC在两年内发生骨转移。 转移性骨疾病的一年生存率约为40%。靶向前列腺特异性膜 用于前列腺和其他癌症的成像和放射性核素治疗（RT）的小分子PSMA 使核医学领域重新焕发生机诺华最近收购了我们开发的[177 Lu]R2， [177 Lu]PSMA-617，两种β粒子发射体177 Lu标记的PSMA靶向RT，正在多中心临床 审判在欧洲，已经进行了使用α粒子发射剂[225 Ac]PSMA-617的初步试验， 已经显示出实质性的治疗效果，即使在对相应的177 Lu产生耐药性的患者中也是如此。 标记化合物。然而，对靶向α粒子RT（达特）的这些令人鼓舞的反应通常发生在 立即消融唾液腺和泪腺的费用，长期毒性未知。因此，委员会认为， 尽管广泛的努力，翻译RT PC是在一个关键阶段，尚未确定一种代理， 在不影响生活质量的情况下提供持久的反应。我们在这方面所采取的方法 竞争性更新是将我们的基本工作集中在211 At上，它每次衰变都会发射一个α粒子， 低剂量药代动力学临床试验。我们假设211 At将提供一个中间体， 毒性最低但效果较差的177 Lu和更强大但具有潜在破坏性的225 Ac， 每次衰变产生四个α粒子，难以在体内控制，并促进上述毒性。我们的目标 通过结合高线性能量转移（LET）肿瘤， 通过有益药代动力学和剂量的分子设计，211 At的细胞杀伤作用和更好的毒性控制 战略布局我们的铅211 At标记化合物[211 At]VK-02-90-Lu的初步体内数据表明， 通过免疫组织化学证实，脱靶毒性低于相关的225 Ac标记加合物， 生存特征。目前的计划旨在提供实验原理和数据， IND使能治疗研究。