RADIOLABELED ANTIBODIES TARGETING LAT1 FOR IMAGING AND THERAPY OF PROSTATE CANCER

针对 LAT1 的放射性标记抗体用于前列腺癌的成像和治疗

• 批准号: 9765182
• 负责人: Suzanne Elizabeth Lapi
• 金额: $ 32.62万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765182
• 关键词: 90Y; Address; Amino Acid Transport System L; Amino Acid Transporter; Amino Acids; Animal Model; Animals; Antibodies; Basic Science; Binding; Biodistribution; Biological; Biological Assay; Brain; Cancer Biology; Cancer Model; Clinical; Clinical Research; Development; Extracellular Domain; FRAP1 gene; Goals; Human; Image; Imagery; ImmunoPET; Immunohistochemistry; Immunotherapeutic agent; Immunotherapy; In Vitro; Label; Lead; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Metabolism; Metastatic Prostate Cancer; Methods; Monoclonal Antibodies; Neutral Amino Acid Transport Systems; New Agents; Normal tissue morphology; Outcome; Patient-Focused Outcomes; Patients; Play; Positron-Emission Tomography; Pre-Clinical Model; Predictive Value; Property; Prostate Cancer therapy; Prostatic Neoplasms; Proteins; Proteomics; Radio; Radioimmunoconjugate; Radioimmunotherapy; Radioisotopes; Radiolabeled; Research Personnel; Role; SLC43A1 gene; Signal Transduction; Specificity; System; Technology; Therapeutic; Therapeutic Agents; Toxic effect; Tracer; Translations; Western Blotting; Work; Xenograft procedure; base; cancer genomics; clinical application; clinically relevant; density; dosimetry; high risk; human model; imaging agent; imaging approach; imaging biomarker; imaging properties; improved; improved outcome; in vivo; in vivo imaging; innovation; metabolomics; molecular imaging; neoplastic cell; novel; pre-clinical; predicting response; prognostic value; prostate cancer model; public health relevance; success; targeted agent; targeted treatment; theranostics; tool; treatment strategy; tumor; tumor growth; uptake

 DESCRIPTION (provided by applicant): The L-type amino acid transporter-1 (LAT1, SLC7A5) is an outstanding target for both imaging and therapy of prostate cancer because it is upregulated in many primary and metastatic prostate cancers and is strongly negatively correlated with overall survival. The current paradigm for imaging LAT1 uses radiolabeled amino acids that are transported into tumor cells to a greater extent than normal tissues. However, these substrate-based approaches for imaging LAT1 in tumors outside of the brain have met with limited success. LAT1 can mediate both influx and efflux of its substrates, leading to relatively low and transient uptake in tumors with poor tumor visualization. The specificity of anti-LAT1 antibodies will provide a more accurate measure of LAT1 protein density than the currently available system L transport substrates, which are not entirely selective for LAT1. This increased selectivity is important because LAT1 is the transporter that provides the greatest prognostic and predictive values. The overall goal of this project is to develop and evaluate radiolabeled antibody constructs selective for LAT1 as positron emission tomography (PET) and therapeutic agents that overcome the substantial limitations of currently available tracers. The development of these new agents is essential to realizing the full potential of LAT1-based imaging and treatment strategies. The long-term goal of this work is to develop clinically applicable imaging and therapeutic agents targeting LAT1 that possess optimal biological properties, are robust markers of prostate tumor aggressiveness, predict response to therapies targeting LAT1, and can be used for radio immunotherapy (RIT). Building on our previous work, we aim to investigate the tumor uptake of the anti-LAT1 immunoPET agent [89Zr] DFO-Ab2 in relevant prostate cancer models. Next, we will compare the uptake of these novel agents to the radiolabeled amino acids [18F] FET and [18F] FACBC. Finally, we will develop a theranostic strategy to visualize LAT1 levels through immunoPET followed by therapy with the anti-LAT1 antibody constructs labeled with 90Y, a therapeutic radionuclide. In addition to providing clinically relevant immunoPET and RIT agents, this work will lead to powerful and well characterized new tools for investigating the role of LAT1 in cancer biology that cannot be performed with currently available radiolabeled amino acids. Thus, the immunoPET and RIT agents developed through this proposal are highly innovative, have great potential for clinical impact, and can help investigators around the world answer clinical and basic research questions regarding the role of LAT1 in cancer biology that cannot be currently addressed with existing technologies.

 描述（由申请人提供）：L型氨基酸转运蛋白-1（LAT 1，SLC 7A 5）是前列腺癌成像和治疗的突出靶点，因为它在许多原发性和转移性前列腺癌中上调，并且与总生存期呈强烈负相关。目前用于成像LAT 1的范例使用比正常组织更大程度地转运到肿瘤细胞中的放射性标记的氨基酸。然而，这些用于在脑外肿瘤中成像LAT 1的基于底物的方法取得了有限的成功。LAT 1可以介导其底物的流入和流出，导致肿瘤可视化较差的肿瘤中相对较低和短暂的摄取。抗LAT 1抗体的特异性将提供比目前可用的系统L转运底物更准确的LAT 1蛋白密度测量，所述系统L转运底物对LAT 1不是完全选择性的。这种增加的选择性是重要的，因为LAT 1是提供最大预后和预测价值的转运蛋白。该项目的总体目标是开发和评价选择性LAT 1的放射性标记抗体构建体作为正电子发射断层扫描（PET）和治疗剂，克服目前可用示踪剂的实质性限制。这些新药物的开发对于实现基于LAT 1的成像和治疗策略的全部潜力至关重要。这项工作的长期目标是开发临床适用的成像和治疗剂靶向LAT 1，具有最佳的生物学特性，是前列腺肿瘤侵袭性的强大标志物，预测对靶向LAT 1治疗的反应，并可用于放射免疫治疗（RIT）。基于我们以前的工作，我们的目标是研究抗LAT 1免疫PET剂[89 Zr] DFO-Ab 2在相关前列腺癌模型中的肿瘤摄取。接下来，我们将比较这些新型药物与放射性标记的氨基酸[18 F] FET和[18 F] FACBC的摄取。最后，我们将开发一种治疗诊断策略，通过免疫PET观察LAT 1水平，然后用90 Y（一种治疗性放射性核素）标记的抗LAT 1抗体结构进行治疗。除了提供临床相关的immunoPET和RIT试剂外，这项工作还将产生强大且表征良好的新工具，用于研究LAT 1在癌症生物学中的作用，而这种作用无法用目前可用的放射性标记氨基酸进行。因此，通过该提案开发的免疫PET和RIT试剂具有高度创新性，具有巨大的临床影响潜力，可以帮助世界各地的研究人员回答有关LAT 1在癌症生物学中作用的临床和基础研究问题，这些问题目前无法用现有技术解决。