Small Molecule PSMA-Targeted Alpha Therapy

小分子 PSMA 靶向阿尔法疗法

• 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
• 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

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的前列腺癌（PCa）的男性在两年内发生骨转移。转移性骨疾病的一年生存率约为40%。新的靶向治疗在机制上有很大的不同，从抑制雄激素产生的治疗，如β-内酰胺酶抑制剂醋酸阿比特龙，到关注转移性骨沉积的治疗，如β-内酰胺酶抑制剂醋酸阿比特龙。粒子发射器，223 RaCl 2。最近的III期，安慰剂对照的ALSYMPCA试验，研究了223 RaCl 2在CRPC和症状性骨转移男性中的作用，证明了如此明显的生存益处，以至于该试验提前终止。然而，223 RaCl 2仅将中位总生存期从11.2个月增加到14个月。在这里，我们打算建立在这一初步的临床成功与？通过产生靶向化合物的发射体疗法，对骨局部和软组织局部肿瘤都具有特异性的颗粒。α粒子是氦核，射程短但致命性高，已被证明比？在癌症的分子靶向放射治疗的背景下的粒子发射器。发展的目标？- 发射器的目的是最小化对邻近周围组织的损伤，这是目前标准外部射束治疗无法达到的。它们先前已在临床上用于治疗PCa，但作为抗体缀合物，其往往对实体瘤具有有限的可及性。在这里，我们将扩展我们的计划，在低分子量放射性药物的发展，前列腺癌的目标是前列腺特异性膜抗原（PSMA）的分子放射治疗-特别是化合物的合成和优化？放射治疗我们在临床研究中表明，我们的药物能够靶向骨和软组织。由于PSMA在配体结合后被内化，因此我们的化合物的荧光形式定位于核周区域，靠近放射治疗的主要靶点-细胞DNA。初步剂量测定研究表明，沉积到正常组织（包括肾脏）的放射性水平可接受，可实现有效治疗。我们认为，转移性CRPC的治疗是一个未满足的医疗需求，分子放射治疗-特别是靶向？-发射器-非常适合。我们将在三个目标上采取分级方法，这些目标可以概括为：（1）合成掺入？发射极，211 At;（2）满足亲和性和稳定性标准的化合物的生物学表征;和（3）在PCa的相关小鼠模型中对合适的先导物进行放射治疗，并比较顶先导物及其131 I标记的类似物与新兴的临床靶向PSMA的放射性物质、人源化抗PSMA抗体177 Lu-J591的相对生物学有效性。我们的目标是在本资助期结束时有一种先导化合物，准备通过必要的步骤进展，以转化为CRPC和仅生化复发的患者。