Small Molecule PSMA-Targeted Alpha Therapy

小分子 PSMA 靶向阿尔法疗法

基本信息

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
项目类别：
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

项目摘要

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。靶向前列腺特异性膜的转移性骨病的一年生存率约为 40%。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) 诺华最近收购了我们开发的[177Lu]R2，并重振了核医学领域。 [177Lu]PSMA-617，两种β粒子发射体177Lu标记的PSMA靶向RT，处于多中心临床在欧洲，已经进行了使用 α 粒子发射剂 [225Ac]PSMA-617 的初步试验。已显示出显着的治疗效果，即使是对相应的 177Lu- 产生耐药性的患者然而，这些对靶向 α 粒子 RT (TAT) 的令人鼓舞的反应常常出现在立即消融唾液腺和泪腺的费用，长期毒性未知。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在不影响生活质量的情况下提供持久的反应。竞争性的更新是将我们专注于 211At 的基础工作扩展至我们勇敢地说 211At 将提供介于两者之间的中间体。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，这些粒子在体内难以控制并促进上述毒性。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了很多信息。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，具有相似的效果当前的程序旨在提供实验原理和数据。支持 IND 的治疗研究。