Small Molecule PSMA-Targeted Alpha Therapy

小分子 PSMA 靶向阿尔法疗法

基本信息

批准号：
8671057
负责人：
MARTIN G POMPER
金额：
$ 46.5万
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 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8671057
关键词：
Acetates Address Affinity Alpha Particles Androgens Animal Model Animals Antibodies Antigen Targeting Area Autoradiography Binding Biochemical Biodistribution Biological Biological Assay Bone Diseases Bone Tissue Cell Nucleus Clinic Clinical Clinical Research DNA Deposition Development Disease Disease Resistance Dose Drug Kinetics Electrons Enzyme Inhibitor Drugs Enzyme Inhibitors Evaluation Experimental Models Funding Glutamate Carboxypeptidase II Goals Helium Hormones Human Image Isotopes J591 Monoclonal Antibody Kidney Knowledge Label Lead Left Ligand Binding Liver Microsomes Malignant Neoplasms Malignant neoplasm of prostate Medical Metastatic Neoplasm to the Bone Micrometastasis Molecular Molecular Weight Mus Normal tissue morphology Nuclear Organ Parents Patients Phase Phase III Clinical Trials Placebo Control Production Publishing Radiation therapy Radioactivity Radiolabeled Radiopharmaceuticals Recurrence Relative Biological Effectiveness Resistance Route Solid Neoplasm Survival Rate Targeted Radiotherapy Testing Time Tissues Toxic effect Translations abiraterone analog antibody conjugate antigen binding base bone cell killing design dosimetry effective therapy in vitro Assay in vivo killings meetings men mouse model neoplastic cell neovasculature particle programs public health relevance radiotracer residence scaffold small molecule soft tissue stability testing success tumor

项目摘要

DESCRIPTION (provided by applicant): Despite the expanding arsenal of new targeted agents to treat castrate-resistant prostate cancer (CRPC), the disease remains incurable, with nearly half of men with this form of prostate cancer (PCa) developing bone metastases at two years. Metastatic bone disease carries a one year survival rate on the order of 40%. New targeted therapies vary widely in mechanism, from those that inhibit androgen production, such as the CYP enzyme inhibitor abiraterone acetate, to those that focus on metastatic bone deposits, such as the ?-particle emitter, 223RaCl2. The recent Phase III, placebo-controlled ALSYMPCA trial, which studied 223RaCl2 in men with CRPC and symptomatic bone metastases, demonstrated such a clear survival benefit that the trial was discontinued early. Nevertheless, 223RaCl2 only increased median overall survival from 11.2 to 14 months. Here, we intend to build on this initial clinical success with ?-emitter therapy by generating targeted compounds that emit ?-particles specific for both bone-localized and soft tissue-localized tumors. Alpha particles are helium nuclei that have a short but highly lethal range and have proved much more effective than ?-particle emitters in the context of molecularly targeted radiotherapy for cancer. A goal of developing ? - emitters is to minimize damage to adjacent, surrounding tissue, which is currently unattainable by standard external beam therapy. They have been employed clinically for treatment of PCa previously, but as antibody conjugates, which tend to have limited access to solid tumors. Here we will extend our program in the development of low molecular weight radiopharmaceuticals for PCa that target the prostate-specific membrane antigen (PSMA) to molecular radiotherapeutics - specifically for the synthesis and optimization of compounds for ?-emitter therapy. We have shown in clinical studies that our agents are capable of targeting both bone and soft tissue. Because PSMA is internalized upon ligand binding, fluorescent versions of our compounds localize to the perinuclear area, near the primary target for radiation therapy - cellular DNA. Preliminary dosimetry studies suggest effective treatment can be achieved with acceptable levels of radioactivity deposited to normal tissues, including kidney. We believe that treatment of metastatic CRPC is an unmet medical need for which molecular radiotherapy - particularly with targeted ?-emitters - is ideally suited. We will take a graded approach across three aims that can be summarized as: (1) synthesis of PSMA binding agents that incorporate the ?-emitter, 211At; (2) biological characterization of compounds meeting affinity and stability criteria; and, (3) radiotherapy of suitable leads in relevant mouse models of PCa and comparison of relative biological effectiveness of the top lead, and its 131I-labeled analog, to the emerging clinical PSMA-targeted radiotherapeutic, the humanized anti-PSMA antibody, 177Lu-J591. The goal is to have a lead compound at the end of this funding period ready to progress through the necessary steps for translation to patients with CRPC and biochemical-only recurrence.

描述（由申请人提供）：尽管用于治疗去势抵抗性前列腺癌 (CRPC) 的新靶向药物不断增加，但该疾病仍然无法治愈，近一半患有这种形式前列腺癌 (PCa) 的男性在两岁时发生骨转移。年。转移性骨病的一年生存率约为 40%。新的靶向疗法在机制上差异很大，从抑制雄激素产生的疗法（例如 CYP 酶抑制剂醋酸阿比特龙）到专注于转移性骨沉积物的疗法（例如 β 粒子发射器 223RaCl2）。最近的 III 期安慰剂对照 ALSYMPCA 试验研究了 223RaCl2 对患有 CRPC 和有症状骨转移的男性患者的疗效，结果证明该试验具有明显的生存益处，因此该试验提前终止。然而，223RaCl2 仅将中位总生存期从 11.2 个月增加到 14 个月。在这里，我们打算通过生成针对骨局部和软组织局部肿瘤发射特异性 β 粒子的靶向化合物，在 β 发射器治疗的初步临床成功的基础上再接再厉。 α粒子是氦原子核，其射程短但高度致命，并且已被证明在癌症分子靶向放射治疗中比α粒子发射器更有效。发展目标？ - 发射器的目的是尽量减少对邻近周围组织的损害，这是目前标准外部光束疗法无法实现的。它们之前已在临床上用于治疗前列腺癌，但作为抗体偶联物，其进入实体瘤的机会往往有限。在这里，我们将把针对前列腺特异性膜抗原 (PSMA) 的低分子量放射性药物开发用于 PCa 的计划扩展到分子放射治疗 - 特别是用于 β 发射体治疗的化合物的合成和优化。我们的临床研究表明，我们的药物能够靶向骨骼和软组织。由于 PSMA 在配体结合后内化，因此我们的化合物的荧光版本定位于核周区域，靠近放射治疗的主要目标 - 细胞 DNA。初步剂量测定研究表明，通过沉积到包括肾脏在内的正常组织的可接受水平的放射性，可以实现有效的治疗。我们相信，转移性 CRPC 的治疗是一项未得到满足的医疗需求，而分子放射治疗（尤其是靶向 β 发射体）非常适合。我们将针对三个目标采取分级方法，可概括为：（1）合成包含 β-发射体 211At 的 PSMA 结合剂； (2) 满足亲和力和稳定性标准的化合物的生物学表征； (3) 在 PCa 相关小鼠模型中对合适的导线进行放射治疗，并比较顶级导线及其 131I 标记类似物与新兴临床 PSMA 靶向放射治疗药物（人源化抗 PSMA 抗体 177Lu）的相对生物有效性-J591。我们的目标是在本次资助期结束时开发出一种先导化合物，准备好通过必要的步骤将其转化为 CRPC 和仅生化复发的患者。