RADIOLABELED ANTIBODIES TARGETING LAT1 FOR IMAGING AND THERAPY OF PROSTATE CANCER

 描述(申请人提供)：L型氨基酸转运体-1(LAT1，SLC7A5)是前列腺癌成像和治疗的优秀靶点，因为它在许多原发癌和转移性前列腺癌中上调，并与总生存率呈显著负相关。目前的LAT1成像范例使用放射性标记氨基酸，这些氨基酸比正常组织在更大程度上被输送到肿瘤细胞中。然而，这些基于底物的方法在脑外肿瘤中成像LAT1的成功有限。LAT1可以调节其底物的流入和流出，导致肿瘤显影较差的肿瘤相对较低和短暂的摄取。与目前可用的L运输底物相比，抗LAT1抗体的特异性将为LAT1蛋白密度提供更准确的测量，后者对LAT1不是完全有选择性的。这种增加的选择性很重要，因为LAT1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估对LAT1具有选择性的放射性标记抗体结构，作为正电子发射断层扫描(PET)和治疗药物，以克服目前可用的示踪剂的实质性限制。这些新药物的开发对于充分发挥基于LAT1的成像和治疗策略的潜力至关重要。这项工作的长期目标是开发针对LAT1的临床适用的成像和治疗药物，这些药物具有最佳的生物学特性，是前列腺癌侵袭性的可靠标志，预测针对LAT1的治疗反应，并可用于放射免疫治疗(RIT)。在我们以前工作的基础上，我们的目标是研究抗LAT1免疫PET试剂[89Zr]DFO-Ab2在相关前列腺癌模型中的肿瘤摄取。接下来，我们将比较这些新试剂与放射性标记氨基酸[18F]FET和[18F]FACBC的吸收情况。最后，我们将开发一种治疗策略，通过免疫PET显示LAT1水平，然后用90Y标记的抗LAT1抗体构建治疗，90Y是一种治疗性放射性核素。除了提供临床上相关的免疫PET和RIT试剂外，这项工作还将带来功能强大且具有良好特性的新工具，用于研究LAT1在癌症生物学中的作用，这是目前可用的放射性标记氨基酸无法实现的。因此，通过这项提议开发的免疫PET和RIT试剂具有很高的创新性，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LAT1在癌症生物学中的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。

 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.