Novel Radiotracer for ImmunoPET Imaging of PD-1 Checkpoint Expression on Tumor Infiltrating Lymphocytes

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• 作者：Arutselvan Natarajan ; Aaron T. Mayer ; Lingyun Xu ; Robert E. Reeves ; Jacob Gano ; Sanjiv S. Gambhir
• 刊名：Bioconjugate Chemistry
• 出版年：2015
• 出版时间：October 21, 2015
• 年：2015
• 卷：26
• 期：10
• 页码：2062-2069
• 全文大小：344K
• ISSN：1520-4812

文摘

Immune checkpoint signaling through the programmed death 1 (PD-1) axis to its ligand (PD-L1) significantly dampens anti-tumor immune responses. Cancer patients treated with checkpoint inhibitors that block this suppressive signaling have exhibited objective response rates of 20鈥?0% for advanced solid tumors, lymphomas, and malignant melanomas. This represents a tremendous advance in cancer treatment. Unfortunately, all patients do not respond to immune checkpoint blockade. Recent findings suggest that patients with tumor infiltrating lymphocytes (TILs) expressing PD-1 may be most likely to respond to 伪PD-1/PD-L1 checkpoint inhibitors. There is a compelling need for diagnostic and prognostic imaging tools to assess the PD-1 status of TILs in vivo. Here we have developed a novel immunoPET tracer to image PD-1 expressing TILs in a transgenic mouse model bearing melanoma. A ⁶⁴Cu labeled anti-mouse antibody (IgG) PD-1 immuno positron emission tomography (PET) tracer was developed to detect PD-1 expressing murine TILs. Quality control of the tracer showed &gt;95% purity by HPLC and &gt;70% immunoreactivity in an in vitro cell binding assay. ImmunoPET scans were performed over 1鈥?8 h on Foxp3+.LuciDTR4 mice bearing B16鈥揊10 melanoma tumors. Mice receiving anti-PD-1 tracer (200 卤 10 渭Ci/10鈥?2 渭g/200 渭L) revealed high tracer uptake in lymphoid organs and tumors. BLI images of FoxP3⁺ CD4⁺ Tregs known to express PD-1 confirmed lymphocyte infiltration of tumors at the time of PET imaging. Biodistribution measurements performed at 48 h revealed a high (11脳) tumor to muscle uptake ratio of the PET tracer (p < 0.05). PD-1 tumors exhibited 7.4 卤 0.7%ID/g tracer uptake and showed a 2脳 fold signal decrease when binding was blocked by unlabeled antibody. To the best of our knowledge this data is the first report to image PD-1 expression in living subjects with PET. This radiotracer has the potential to assess the prognostic value of PD-1 in preclinical models of immunotherapy and may ultimately aid in predicting response to therapies targeting immune checkpoints.