Development of a PSMA-Targeted Small-Molecule Drug Conjugate for Prostate Cancer

开发针对前列腺癌的 PSMA 靶向小分子药物偶联物

• 批准号: 9555871
• 负责人: Beatrice Langton-Webster
• 金额: $ 30万
• 依托单位: CANCER TARGETED TECHNOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9555871
• 关键词: Adverse effects; Affinity; Albumins; American; Amines; Animals; Antibodies; Antigen Targeting; Binding; Biodistribution; Biological Markers; Biological Models; Blood; Blood Circulation; Buffers; Cancer Etiology; Castration; Cell Line; Cells; Cessation of life; Characteristics; Clinical Trials; Companions; Complement; Complex; Development; Diagnostic; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Effectiveness; Elements; Endosomes; Enzyme Inhibitor Drugs; Enzymes; Exhibits; Exposure to; FOLH1 gene; Foundations; Future; Half-Life; Human; Image; In Vitro; Kinetics; Label; Ligands; Lysosomes; Malignant Neoplasms; Malignant neoplasm of prostate; Monitor; Mus; New Agents; Normal tissue morphology; Nude Mice; Organ; PC3 cell line; Patients; Performance; Pharmaceutical Preparations; Phase; Physiological; Plasma; Positioning Attribute; Positron-Emission Tomography; Property; Prostate Cancer therapy; Radiation therapy; Radioactivity; Resistance; Scheme; Solid Neoplasm; Specificity; Structure of base of prostate; System; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Tracer; Translating; Tumor Markers; Tumor Volume; Urea; Work; base; cancer diagnosis; castration resistant prostate cancer; chemotherapy; clinically relevant; cost; cytotoxicity; design; imaging agent; implantation; in vivo; inhibitor/antagonist; innovation; men; mouse model; neoplastic cell; neovasculature; novel; phosphoramidate; prostate cancer cell; scaffold; small molecule; small molecule inhibitor; success; targeted agent; targeted delivery; targeted imaging; targeted treatment; treatment choice; tumor; tumor xenograft; uptake

PROJECT SUMMARY/ABSTRACT Prostate-Specific Membrane Antigen (PSMA) is an 'ideal biomarker' for tumor targeting as it exhibits restricted expression on prostate tumor cells and the neovasculature of a number of other solid tumors. Cancer Targeted Technology has developed unique phosphoramidate-based PSMA inhibitor scaffolds that irreversibly bind to the enzyme target and selectively penetrate prostate tumor cells through the internalization of the PSMA enzyme-inhibitor complex, accumulating in endosomes and lysosomes. We recently demonstrated that the addition of an albumin-binding motif to our PSMA-targeted agents dramatically slows clearance in mice, resulting in tumor uptake of nearly 50% injected dose/g. Furthermore, CTT has licensed a novel pH-triggered linker system (Phos-Am) that is stable under physiological conditions, but can be tuned to rapidly release amine-containing drugs at endosomal/lysosomal pH. Together, these advances support the development of a PSMA-targeted drug-conjugate that can be trafficked to and selectively liberated within PSMA(+) tumor cells. The objective of this Phase-I application is to design and prove the effectiveness of a PSMA-targeted Small Molecule Drug Conjugate (SMDC): CTT1700. CTT1700 will incorporate these crucial components: phosphoramidate-based PSMA-targeting molecule, albumin binder, Phos-Am linker system, and Monomethyl Auristatin E (MMAE) as the conjugated drug payload. We expect that CTT1700 will exhibit the following key in vitro and in vivo performance characteristics: specificity for and rapid internalization by PSMA(+) prostate tumor cells, stability in plasma, rapid subcellular drug release, appropriate biodistribution and circulation half- life and potent anti-tumor activity. Our aims for this Phase-I application are as follows: Aim #1: Determine the stability and in vitro performance of CTT1700. We will prepare CTT1700 and assess its stability and drug release kinetics in buffer (pH = 4.5-7.4), as well as in mouse and human plasma. Concentration-dependent in vitro cytotoxicity and specificity will be assessed with PSMA(+) and PSMA(-) cells lines. Aim #2: Determine the in vivo efficacy of CTT1700. We will determine the biodistribution of CTT1700 and its released drug, MMAE, in blood and key organs. In vivo performance will be evaluated using a PSMA(+) tumor xenograft mouse model dosed once per week for 6 weeks and monitoring tumor volume for 10 weeks. This innovative work harnesses the ideal performance properties of a cell-penetrating irreversible small- molecule PSMA inhibitor that possesses the desirable pharmacokinetics of antibodies without the additional manufacturing costs associated with antibodies. Further, CTT1700 should have considerable significance for prostate cancer therapy by reducing chemotherapy-associated toxic side effects to non-target tissues. It is expected that CTT1700 will represent a breakthrough in targeted chemotherapy for prostate cancer and other tumors that are characterized by PSMA expression.

项目总结/摘要 前列腺特异性膜抗原（PSMA）是肿瘤靶向的“理想生物标志物”，因为它表现出 在前列腺肿瘤细胞和许多其他实体瘤的新生血管中的表达受限。癌 Targeted Technology开发了独特的基于氨基磷酸酯的PSMA抑制剂支架， 结合到酶靶点，并通过内化的蛋白质选择性地穿透前列腺肿瘤细胞。 PSMA酶-抑制剂复合物，在内体和溶酶体中积累。我们最近证明， 向我们的PSMA靶向剂中加入白蛋白结合基序显著减缓了小鼠中的清除， 导致肿瘤摄取接近50%注射剂量/g。此外，CTT已批准了一种新型的pH触发 连接体系统（Phos-Am），在生理条件下稳定，但可调节以快速释放 总之，这些进展支持了一种新的含胺药物的开发， PSMA靶向药物-偶联物，可运输至PSMA（+）肿瘤细胞并在其中选择性释放。 本阶段的目标-I应用程序是设计和证明的有效性PSMA为目标的 小分子药物偶联物（SMDC）：CTT 1700。CTT 1700将包含这些关键组件： 基于氨基磷酸酯的PSMA靶向分子、白蛋白结合剂、Phos-Am接头系统和单甲基 奥瑞他汀E（MMAE）作为缀合的药物有效负载。我们预计CTT 1700将展示以下关键， 体外和体内性能特征：对PSMA（+）前列腺的特异性和快速内化 肿瘤细胞，血浆中的稳定性，快速的亚细胞药物释放，适当的生物分布和循环半- 有效的抗肿瘤活性。我们的第一阶段申请目标如下： 目的#1：确定CTT 1700的稳定性和体外性能。我们将准备CTT 1700， 评估其在缓冲液（pH = 4.5-7.4）以及小鼠和人血浆中的稳定性和药物释放动力学。 将使用PSMA（+）和PSMA（-）细胞评估浓度依赖性体外细胞毒性和特异性 线目的#2：确定CTT 1700的体内功效。我们将确定CTT 1700的生物分布 及其释放的药物MMAE在血液和关键器官中的作用。将使用PSMA（+）评价体内性能 肿瘤异种移植小鼠模型，每周给药一次，持续6周，并监测肿瘤体积，持续10周。 这项创新工作利用了细胞穿透不可逆小分子的理想性能， 分子PSMA抑制剂，其具有抗体的所需药代动力学，而没有额外的抗肿瘤活性。 与抗体相关的制造成本。此外，CTT 1700应该具有相当大的意义， 通过减少对非靶组织的化疗相关毒副作用来治疗前列腺癌。是 预计CTT 1700将代表前列腺癌和其他癌症靶向化疗的突破， 这些肿瘤的特征在于PSMA表达。