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

描述(申请人提供)：目前还没有对复发、转移性、雄激素非依赖性前列腺癌的有效治疗方法，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发现前列腺癌的早期预警信号，但还没有一种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类型肿瘤的新生血管有关。PSMA是一种由750个氨基酸组成的II型糖蛋白，在正常人前列腺上皮细胞中有少量表达，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-连结酸性二肽酶)高度同源，NAALDase参与神经元信号肽的失活。PSMA的酶方面是一种独特的外肽酶，与聚γ-谷氨酸叶酸反应，能够顺序地去除聚γ-谷氨酰末端。由于PSMA几乎在所有前列腺癌中都有表达，尤其是低分化、转移性和激素不敏感的前列腺癌，它是前列腺癌成像和治疗的一个非常有吸引力的靶点。已经报道了一系列PSMA抑制剂，它们可以作为开发针对PSMA酶活性的试剂的平台。在成功完成的第一阶段SBIR奖(1R43EB004253)中，分子洞察公司开发了与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。来自体外PSMA细胞结合实验和正常大鼠体内分布研究的两个最有效的化合物，在大鼠身上进行了急性毒性测试，并在IND文件中进行了探索性评估，以评估它们作为人类转移性前列腺癌显像剂的作用。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。在先前发现的前列腺癌转移以及先前未知疾病的定位中，这两种化合物都观察到了异常的肿瘤聚集。根据FDA的要求，在进行更详细的传统测试之前，必须关闭探索性IND，并将结果提交给该机构。随后，赞助商必须完成常规IND进行人体功效测试所需的所有安全评估和CMC开发。碘-123的物理半衰期很短(13小时)，因此每次研究都需要生产GMP，而且由于辐射防护保障措施，只进行少量的初步研究，因此需要扩大生产以生产多剂量。此外，随着药物在临床开发过程中的进展，药物产品的组份链上也会进行更多的检查。这一第二阶段SBIR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所需的临床前安全性测试。 公共卫生相关性：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，估计每年收入超过3.5亿美元。虽然目前血液中PSA水平的筛查方法对早期发现很有价值，但细针活检的确认并不能给出整个前列腺的代表性评估或确定淋巴转移。一种可靠的非侵入性诊断和监测原发和转移肿瘤的方法将是前列腺癌患者治疗的重要补充。针对前列腺癌胞外区域的新型前列腺特异性膜抗原(PSMA)代表了一种潜在的新型药物，用于前列腺癌的诊断、治疗或治疗，并在一个尚未得到满足的临床需求领域体现了重要的商业机会。目前还没有有效的治疗复发、转移性、雄激素非依赖性前列腺癌的方法，也没有一种组织特异性的方法来定位疾病。在成功完成的第一阶段SBIR奖(1R43EB004253)中，分子洞察公司开发了与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。在一项探索性IND中，7名患者与两种I-123标记化合物进行了比较，两种化合物都显示出异常的肿瘤聚集和快速全身消除。这种先导化合物将被纳入常规临床试验所需的额外安全评估，并进行剂量发现、人体安全性和有效性测试。这一第二阶段SBIR应用的最终目标是启动针对药物前体的GMP活动，对最终药物产品进行CMC优化和放大，并完成启动传统临床试验所需的临床前安全性测试。

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.