Development of a Molecular Targeting Agent for PSMA to Diagnose Metastatic Prosta

开发 PSMA 分子靶向剂来诊断转移性前列腺

基本信息

批准号：
8073631
负责人：
JAMES F KRONAUGE
金额：
$ 32.74万
依托单位：
MOLECULAR INSIGHT PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8073631
关键词：
Acute Acute Toxicity Tests Amino Acids Animals Antigen Targeting Area Award Binding Biological Assay Blood Cancer Patient Canis familiaris Carcinoma Cells Chemicals Clinical Clinical Trials Clinical trial protocol document Contracts Detection Development Diagnosis Diagnostic Dipeptidases Disease Documentation Dose Drug Formulations Drug Kinetics Early Diagnosis Enzymes Epithelium Equilibrium Evaluation Excipients Excretory function Exhibits Exopeptidase Extracellular Domain Fine-needle biopsy Folate Free Radical Scavengers GMP lots Glutamate Carboxypeptidase II Glycoproteins Goals Half-Life High Pressure Liquid Chromatography Hormones Hour Human Human Cell Line Image In Vitro Intervention Iodine LNCaP Label Laboratories Lead Link Lymph Node Involvement Malignant neoplasm of prostate Manufacturer Name Membrane Membrane Proteins Metabolic Metastatic Prostate Cancer Methods Modeling Molecular Molecular Target Monitor Names Neoplasm Metastasis Neurons Pathway interactions Patients Peptide Signal Sequences Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Primary Neoplasm Process Prodrugs Production Prostate Prostate-Specific Antigen Prostatic Epithelium Proteins Radiation Protection Radioactive Radioisotopes Radiolabeled Radiopharmaceuticals Rattus Reference Standards Refractory Regulatory Affairs Relapse Reporting Resources Running Safety Screening procedure Selection Criteria Series Serum Small Business Innovation Research Grant System Testing Tissues Toxic effect Urine Validation abstracting androgen independent prostate cancer cancer imaging design detector digital effective therapy efficacy testing extracellular human data human glutamate carboxypeptidase II in vivo inhibitor/antagonist insight liquid chromatography mass spectrometry man neoplastic cell neovasculature novel pre-clinical preclinical safety preclinical toxicity process optimization public health relevance radiochemical radiotracer rectal research clinical testing safety study safety testing scale up tumor uptake

Acute Acute Toxicity Tests Amino Acids Animals Antigen Targeting Area Award Binding Biological Assay Blood Cancer Patient Canis familiaris Carcinoma Cells Chemicals Clinical Clinical Trials Clinical trial protocol document Contracts Detection Development Diagnosis Diagnostic Dipeptidases Disease Documentation Dose Drug Formulations Drug Kinetics Early Diagnosis Enzymes Epithelium Equilibrium Evaluation Excipients Excretory function Exhibits Exopeptidase Extracellular Domain Fine-needle biopsy Folate Free Radical Scavengers GMP lots Glutamate Carboxypeptidase II Glycoproteins Goals Half-Life High Pressure Liquid Chromatography Hormones Hour Human Human Cell Line Image In Vitro Intervention Iodine LNCaP Label Laboratories Lead Link Lymph Node Involvement Malignant neoplasm of prostate Manufacturer Name Membrane Membrane Proteins Metabolic Metastatic Prostate Cancer Methods Modeling Molecular Molecular Target Monitor Names Neoplasm Metastasis Neurons Pathway interactions Patients Peptide Signal Sequences Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Primary Neoplasm Process Prodrugs Production Prostate Prostate-Specific Antigen Prostatic Epithelium Proteins Radiation Protection Radioactive Radioisotopes Radiolabeled Radiopharmaceuticals Rattus Reference Standards Refractory Regulatory Affairs Relapse Reporting Resources Running Safety Screening procedure Selection Criteria Series Serum Small Business Innovation Research Grant System Testing Tissues Toxic effect Urine Validation abstracting androgen independent prostate cancer cancer imaging design detector digital effective therapy efficacy testing extracellular human data human glutamate carboxypeptidase II in vivo inhibitor/antagonist insight liquid chromatography mass spectrometry man neoplastic cell neovasculature novel pre-clinical preclinical safety preclinical toxicity process optimization public health relevance radiochemical radiotracer rectal research clinical testing safety study safety testing scale up tumor uptake

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项目摘要

DESCRIPTION (provided by applicant): Abstract There is presently no effective therapy for relapsing, metastatic, androgen-independent prostate cancer and the most effective treatment occurs with early and appropriate intervention. Blood PSA screening and digital rectal exams can detect early warning signs of prostate cancer but an effective tissue-specific method for spatial localization of metastatic disease is not available. Human prostate specific membrane antigen (PSMA) is an integral trans-membrane protein, associated with the prostate epithelium, prostatic tumor cells and the neovasculature of other tumor types. PSMA is a 750 amino acid type II glycoprotein which is typically expressed to a small extent in normal human prostate epithelium but is up-regulated in prostate cancer, including metastatic disease. The extracellular portion of PSMA is highly homologous to the enzyme NAALDase (N-acetylated a-linked acidic dipeptidase) which is involved in the deactivation of neuronal signaling peptides. The enzymatic aspect of PSMA is a unique exopeptidase with reactivity toward poly-gamma-glutamated folates, capable of sequentially removing the poly-gamma-glutamyl termini. Since PSMA is expressed by virtually all prostate cancers and especially poorly differentiated, metastatic and hormone-refractory carcinomas, it is a very attractive target for prostate imaging and therapy. A range of PSMA inhibitors have been reported that may serve as platforms for the development of agents targeted to PSMA enzymatic activity. In a successfully completed phase 1 SBIR award (1R43EB004253), Molecular Insight has developed novel radiolabeled inhibitors that interact with PSMA and may provide specific targeting for the detection, treatment and management of prostate cancer. Two of the most active compounds, from in vitro PSMA cell binding assays and normal rat in vivo distribution studies, were tested for acute toxicity in rats and an exploratory IND filed to evaluate them as metastatic prostate cancer imaging agent in humans. Seven patients with confirmed metastatic prostate cancer were compared with two similar I-123 labeled compounds. Exceptional tumor accumulation was observed by both compounds in previously identified prostate metastasis along with localization of previously unknown disease. As required by the FDA, the exploratory IND must be closed and the results presented to the agency before proceeding to more elaborate traditional testing. Subsequently, the sponsor must fulfill all the safety assessments and CMC developments required for a conventional IND to proceed to human efficacy testing. The short physical half life of the Iodine-123 (13 hours) necessitates GMP production for each study and preliminary studies are only performed of small quantities due to radiation protection safeguards, consequently scale up production is required to produce multiple doses. Additionally as an agent progresses down the clinical development pathway more scrutiny is applied further up the chain of components for the drug product. The ultimate goal of this phase 2 SBIR application is to initiate the GMP campaign for the critical component drug precursor, perform CMC optimization and scale up of the final drug product, initiate metabolite studies and complete the preclinical safety testing require to initiate a conventional IND. PUBLIC HEALTH RELEVANCE: Determination of serum prostate specific antigen (PSA) is an effective early screen for potential prostate cancer with revenues estimated at over $350 million annually. Although the current screening method of PSA levels in the blood is valuable for early detection, the confirmation by fine needle biopsy does not give a representative evaluation of the entire prostate or determine lymph node involvement. A reliable method for non-invasive diagnosis and monitoring of primary and metastatic tumors would be an important addition to the management of prostate cancer victims. New Prostrate Specific Membrane Antigen (PSMA) targeted to the extracellular domain of this protein represents a potential new class of drugs for the diagnosis, management or treatment of prostate cancer and embody a significant commercial opportunity in an area of unmet clinical need. There is presently no effective therapy for relapsing, metastatic, androgen-independent prostate cancer or a tissue specific method to spatially locate disease. In a successfully completed phase 1 SBIR award (1R43EB004253), Molecular Insight has developed novel inhibitors that interact with PSMA and may provide specific targeting for the detection, treatment and management of prostate cancer. Seven patients have been compared with two I-123 labeled compounds in an exploratory IND and both compounds exhibit exceptional tumor accumulation and rapid whole body elimination. The lead compound will be entered into additional safety assessments required for a conventional clinical trial and proceed to dose finding, human safety and efficacy testing. The ultimate goal of this phase 2 SBIR application is to initiate the GMP campaign for the drug precursor, perform CMC optimization and scale up of the final drug product and complete the preclinical safety testing require to initiate a traditional clinical trial.

描述（由申请人提供）：摘要目前尚无有效的治疗，用于复发，转移，雄激素独立的前列腺癌，最有效的治疗方法是在早期和适当的干预下发生的。血液PSA筛查和数字直肠检查可以检测前列腺癌的预警信号，但没有有效的组织特异性方法用于转移性疾病的空间定位。人前列腺特异性膜抗原（PSMA）是一种积分的跨膜蛋白，与前列腺上皮，前列腺肿瘤细胞和其他肿瘤类型的新生血管相关。 PSMA是一种750氨基酸II型糖蛋白，通常在正常的人类前列腺上皮中略有表达，但在前列腺癌（包括转移性疾病）中被上调。 PSMA的细胞外部分与酶（N-乙酰化的A-链式A-链式酸性二肽酶）高度同源，该酶参与神经元信号肽的失活。 PSMA的酶促方面是一种独特的雌激酶，对聚粉红谷氨酸的叶酸具有反应性，能够顺序去除聚-GAMMA-谷氨酸末端。由于PSMA几乎由所有前列腺癌表达，尤其是分化较差的转移性和激素 - 耐药性癌，因此它是前列腺成像和治疗的非常有吸引力的靶标。据报道，一系列的PSMA抑制剂可能是开发针对PSMA酶活性的药物的平台。在成功完成1期SBIR奖（1R43EB004253）中，分子见解开发了与PSMA相互作用的新型放射性标记抑制剂，并可能为前列腺癌的检测，治疗和管理提供特定的靶向。从体外PSMA细胞结合测定和体内分布研究中正常大鼠的两种最活跃的化合物测试了大鼠的急性毒性，以及探索性IND，以评估它们作为人类转移性前列腺癌成像剂。将7例确认的转移性前列腺癌患者与两名标记化合物的I-123类似的I-123患者进行了比较。两种化合物在先前鉴定的前列腺转移以及先前未知疾病的定位中都观察到了特殊的肿瘤积累。根据FDA的要求，必须关闭探索性IND，并在进行更精细的传统测试之前向机构提供的结果。随后，赞助商必须履行常规IND所需的所有安全评估和CMC开发，以进行人体效力测试。碘123（13小时）的物理半寿命短，每项研究和初步研究都需要GMP产生，仅由于辐射保护保护措施而进行少量，因此需要扩大生产来产生多种剂量。此外，随着代理的发展，临床开发途径的进展将进一步应用在药物的组件链上。该阶段2 SBIR应用的最终目标是为关键组件药物前体发起GMP运动，进行CMC优化并扩大最终药物产品，启动代谢物研究并完成临床前安全测试，以启动常规IND。公共卫生相关性：确定血清前列腺特异性抗原（PSA）是潜在前列腺癌的有效早期筛选，每年估计收入超过3.5亿美元。尽管当前血液中PSA水平的筛查方法对于早期检测很有价值，但细针活检确认并未对整个前列腺进行代表性评估或确定淋巴结的参与。对原发性和转移性肿瘤进行非侵入性诊断和监测的可靠方法将是对前列腺癌受害者治疗的重要补充。针对该蛋白质细胞外结构域的新型pros液特异性膜抗原（PSMA）代表了一种潜在的新药物，用于诊断，管理或治疗前列腺癌，并在未满足的临床需求领域体现出重要的商业机会。目前尚无有效的治疗，用于复发，转移性，雄激素独立的前列腺癌或组织特异性方法来定位疾病。在成功完成的1阶段SBIR奖（1R43EB004253）中，分子见解开发了与PSMA相互作用的新型抑制剂，并可能为前列腺癌的检测，治疗和管理提供特定的靶向。将七名患者与探索性IND中的两名I-123标记化合物进行了比较，两种化合物均表现出非凡的肿瘤积累和快速的全身消除。铅化合物将被输入常规临床试验所需的其他安全评估，并继续进行剂量发现，人体安全和有效性测试。该阶段2 SBIR应用的最终目标是启动GMP运动的药物前体，进行CMC优化并扩大最终药物的规模，并完成临床前安全测试，以启动传统的临床试验。