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

• 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
• 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

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）：摘要目前对于复发性、转移性、雄激素非依赖性前列腺癌还没有有效的治疗方法，最有效的治疗方法是早期和适当的干预。血液 PSA 筛查和直肠指检可以检测前列腺癌的早期预警信号，但目前还没有有效的组织特异性方法来定位转移性疾病。人前列腺特异性膜抗原 (PSMA) 是一种完整的跨膜蛋白，与前列腺上皮、前列腺肿瘤细胞和其他肿瘤类型的新血管系统相关。 PSMA 是一种由 750 个氨基酸组成的 II 型糖蛋白，通常在正常人前列腺上皮中少量表达，但在前列腺癌（包括转移性疾病）中表达上调。 PSMA 的胞外部分与 NAALDase（N-乙酰化α-连接酸性二肽酶）高度同源，NAALDase 参与神经元信号肽的失活。 PSMA 的酶促方面是一种独特的外肽酶，对聚 γ-谷氨酸叶酸具有反应性，能够顺序去除聚 γ-谷氨酰末端。由于几乎所有前列腺癌，尤其是低分化癌、转移性癌和激素难治性癌均表达 PSMA，因此它是前列腺成像和治疗的一个非常有吸引力的靶点。据报道，一系列 PSMA 抑制剂可作为开发针对 PSMA 酶活性的药物的平台。 在成功完成的 1 期 SBIR 奖项 (1R43EB004253) 中，Molecular Insight 开发了新型放射性标记抑制剂，可与 PSMA 相互作用，并可能为前列腺癌的检测、治疗和管理提供特定靶向。来自体外 PSMA 细胞结合测定和正常大鼠体内分布研究的两种最活跃的化合物在大鼠中进行了急性毒性测试，并提交了探索性 IND 来评估它们作为人类转移性前列腺癌显像剂的作用。将 7 名确诊为转移性前列腺癌的患者与两种类似的 I-123 标记化合物进行了比较。在先前鉴定的前列腺转移以及先前未知的疾病的定位中，观察到两种化合物异常的肿瘤积累。根据 FDA 的要求，探索性 IND 必须结束，并将结果提交给该机构，然后再进行更复杂的传统测试。随后，申办者必须完成传统 IND 所需的所有安全评估和 CMC 开发，以进行人体功效测试。 Iodine-123 的物理半衰期较短（13 小时），因此每项研究都需要进行 GMP 生产，并且由于辐射防护保障措施，初步研究仅进行少量，因此需要扩大生产规模以生产多个剂量。此外，随着药物在临床开发路径上的进展，药品成分链的上游也会受到更多的审查。 SBIR 2 期应用的最终目标是启动关键成分药物前体的 GMP 活动，执行 CMC 优化并扩大最终药物产品的规模，启动代谢物研究并完成启动传统 IND 所需的临床前安全测试。 公共健康相关性：血清前列腺特异性抗原 (PSA) 的测定是潜在前列腺癌的有效早期筛查，每年收入估计超过 3.5 亿美元。尽管目前血液中PSA水平的筛查方法对于早期检测很有价值，但细针活检的确认并不能对整个前列腺进行代表性评估或确定淋巴结受累。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前列腺癌患者治疗的重要补充。针对该蛋白胞外域的新型前列腺特异性膜抗原（PSMA）代表了一种用于诊断、管理或治疗前列腺癌的潜在新药物，并在未满足临床需求的领域体现了重大的商业机会。目前还没有针对复发性、转移性、雄激素非依赖性前列腺癌的有效疗法或组织特异性方法来空间定位疾病。 在成功完成的 1 期 SBIR 奖项 (1R43EB004253) 中，Molecular Insight 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靶向。在一项探索性 IND 中，已将 7 名患者与两种 I-123 标记的化合物进行了比较，两种化合物都表现出异常的肿瘤积累和快速的全身消除。先导化合物将接受常规临床试验所需的额外安全性评估，并进行剂量发现、人体安全性和功效测试。 SBIR 2 期应用的最终目标是启动药物前体的 GMP 活动，进行 CMC 优化并扩大最终药物产品的规模，并完成启动传统临床试验所需的临床前安全测试。