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

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没有有效的治疗，最有效的治疗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，但目前尚无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生血管相关。PSMA是一种750个氨基酸的II型糖蛋白，其通常在正常人前列腺上皮中小程度表达，但在前列腺癌（包括转移性疾病）中上调。PSMA的细胞外部分与参与神经元信号肽失活的酶NAALDase（N-乙酰化α-连接的酸性二肽酶）高度同源。PSMA的酶促方面是一种独特的外肽酶，对聚-γ-谷氨酸化叶酸具有反应性，能够依次去除聚-γ-谷氨酰末端。由于PSMA几乎在所有前列腺癌中表达，尤其是低分化、转移性和难治性癌，因此它是前列腺成像和治疗的非常有吸引力的靶点。已经报道了一系列PSMA抑制剂，其可以用作开发靶向PSMA酶活性的药剂的平台。 在一项成功完成的SBIR 1期奖（1 R43 EB 004253）中，Molecular Insight开发了新型放射性标记抑制剂，可与PSMA相互作用，并可为前列腺癌的检测、治疗和管理提供特异性靶向。来自体外PSMA细胞结合试验和正常大鼠体内分布研究的两种最具活性的化合物在大鼠中进行了急性毒性试验，并提交了探索性IND，以评估它们作为人类转移性前列腺癌成像剂。7例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。在先前鉴别的前列腺转移沿着先前未知疾病的局部化中，两种化合物均观察到异常的肿瘤蓄积。根据FDA的要求，探索性IND必须关闭，并在进行更复杂的传统测试之前将结果提交给FDA。随后，申办者必须完成常规IND进行人体疗效试验所需的所有安全性评估和CMC开发。由于碘-123的物理半衰期较短（13小时），每次研究都需要GMP生产，由于辐射防护措施，仅进行少量初步研究，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途径中的进展，对制剂组分链的上游进行了更多的审查。该2期SBIR申请的最终目标是启动关键组分药物前体的GMP活动，进行CMC优化并扩大最终制剂的规模，启动代谢物研究并完成启动常规IND所需的临床前安全性试验。 公共卫生相关性：血清前列腺特异性抗原（PSA）测定是一种有效的潜在前列腺癌早期筛查方法，每年的收入估计超过3.5亿美元。虽然目前的血液PSA水平筛查方法对早期检测有价值，但细针穿刺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。一种可靠的方法，非侵入性诊断和监测原发性和转移性肿瘤将是一个重要的除了前列腺癌患者的管理。靶向该蛋白质的细胞外结构域的新型前列腺特异性膜抗原（PSMA）代表了用于前列腺癌的诊断、管理或治疗的潜在的新药物类别，并且在未满足的临床需求的领域中体现了显著的商业机会。目前还没有有效的治疗复发性、转移性、雄激素非依赖性前列腺癌的方法或组织特异性方法来空间定位疾病。 在一项成功完成的SBIR 1期奖（1 R43 EB 004253）中，Molecular Insight开发了与PSMA相互作用的新型抑制剂，可为前列腺癌的检测、治疗和管理提供特异性靶向。在探索性IND中，7名患者与两种I-123标记的化合物进行了比较，两种化合物均显示出异常的肿瘤蓄积和快速的全身消除。先导化合物将进入常规临床试验所需的额外安全性评估，并继续进行剂量探索、人体安全性和有效性试验。SBIR第2阶段申请的最终目标是启动药物前体的GMP活动，进行CMC优化和扩大最终制剂的规模，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.