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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：L型氨基酸转运蛋白1（LAT1，SLC7A5）是前列腺癌成像和治疗的杰出靶标，因为它在许多原发性和转移性前列腺癌中都进行了更新，并且与整体生存率密切相关。用于成像LAT1的当前范式使用放射性标记的氨基酸，这些氨基酸比正常组织更大程度地运输到肿瘤细胞中。但是，这些基于底物在大脑以外肿瘤中成像LAT1的基质方法取得了有限的成功。 LAT1可以介导其底物的影响和外排，从而导致肿瘤可视化不良的肿瘤中相对较低和短暂的吸收。抗LAT1抗体的特异性将比当前可用的系统L传输底物提供更准确的LAT1蛋白质密度度量，而LAT1并非完全选择性。这种提高的选择性很重要，因为LAT1是提供最佳预后和预测值的运输蛋白。该项目的总体目的是开发和评估对LAT1的选择性放射性标记的抗体构建体，因为阳性发射断层扫描（PET）和治疗剂克服了当前可用的示踪剂的实质性局限性。这些新代理的发展对于实现基于LAT1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具有最佳生物学特性的LAT1的临床适用成像和治疗剂，是前列腺肿瘤侵袭性的鲁棒标记，预测针对LAT1的疗法的反应，并且可用于无线电免疫治疗（RIT）。在我们先前的工作的基础上，我们旨在研究相关前列腺癌模型中抗LAT1免疫物剂[89ZR] DFO-AB2的肿瘤摄取。接下来，我们将比较这些新型药物的摄取与放射标记的氨基酸[18F] FET和[18F] FACBC。最后，我们将制定一种治疗策略，通过免疫集可视化LAT1水平，然后用抗LAT1抗体构建体进行治疗，该抗体构建体标记为90Y（一种治疗性放射性核素）。除了提供与临床相关的免疫集和RIT药物外，这项工作还将为研究LAT1在癌症生物学中的作用而产生强大而有特征的新工具，而目前可用的放射性标记的氨基酸则无法进行。这是通过该提案开发的免疫情节和RIT代理人具有很高的创新性，具有巨大的临床影响潜力，并且可以帮助世界各地的研究人员回答有关LAT1在癌症生物学中的作用的临床和基础研究问题，目前无法通过现有技术来解决。