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）：尽管新的靶向药物的武器库不断扩大，以治疗耐castrate的前列腺癌（CRPC），但该疾病仍然无法治愈，两年来患有这种形式的前列腺癌（PCA）的男性近一半。转移性骨病的生存率为40％。新的靶向疗法的机制差异很大，从抑制雄激素产生的疗法（例如CYP酶抑制剂阿比里特酮）到专注于转移性骨沉积物的人，例如？ - 颗粒发射极，223racl2。最近的III期安慰剂对照ALSYMPCA试验研究了CRPC男性和有症状的骨转移的男性的223racl2，表现出了如此明显的生存益处，以至于该试验早期停用。然而，223RACL2仅将中位总生存率从11.2增加到14个月。在这里，我们打算通过产生靶向的化合物来基于这种最初的临床成功疗法，这些化合物对骨位定位和软组织 - 定位肿瘤的特异性粒子。 α颗粒是氦核，在癌症分子靶向放疗的背景下，证明比粒子发射器更有效。发展的目标？ - 发射器将最大程度地减少对邻近的周围组织的损害，目前无法通过标准的外束治疗无法实现。它们以前曾在临床上接受过临床治疗，但作为抗体偶联物，这些抗体偶联物往往使用实体瘤。在这里，我们将把针对PCA的低分子量放射性药物开发，该程序将靶向前列腺特异性膜抗原（PSMA）的PCA扩展到分子放射性疗法药 - 专门用于合成和优化？ - emitter治疗。我们在临床研究中表明，我们的药物能够靶向骨骼和软组织。由于PSMA是在配体结合时内部化的，因此我们化合物的荧光版本位于核周区域，靠近放射治疗的主要靶标 - 细胞DNA。初步剂量测定研究表明，可以通过沉积在包括肾脏在内的正常组织中的可接受的放射性水平来实现有效的治疗。我们认为，转移性CRPC的治疗是对哪种分子放射疗法（尤其是针对目标？发射器）的未满足的医学需求。我们将在三个目标中采用分级方法，可以概括为：（1）合成包含？ - emitter，211AT的PSMA结合剂；（2）符合亲和力和稳定标准的化合物的生物学特征；（3）在PCA的相关小鼠模型中合适的铅的放射疗法，以及最高铅的相对生物学有效性及其131i标记的类似物的比较，与新兴的临床PSMA靶向放射线疗法，人为人型的抗PSMA抗体，177LU-J591。目的是在此资金期结束时拥有铅化合物，随时可以通过将CRPC和仅生物化学复发的患者翻译成的必要步骤进行。