Imaging, Biodistribution, and Dosimetry of Radionuclide-Labeled PD-L1 Antibody in an Immunocompetent Mouse Model of Breast Cancer.
Imaging, Biodistribution, and Dosimetry of Radionuclide-Labeled PD-L1 Antibody in an Immunocompetent Mouse Model of Breast Cancer.
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DOI：
10.1158/0008-5472.can-15-2141
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发表时间：
2016-01-15
期刊：
影响因子：
11.2
通讯作者：
Sgouros G
中科院分区：
文献类型：
--
作者：
Josefsson A;Nedrow JR;Park S;Banerjee SR;Rittenbach A;Jammes F;Tsui B;Sgouros G
程序性细胞死亡配体1(PD-L1)参与免疫检查点系统，参与预防自身免疫。PD-L1表达于肿瘤细胞、肿瘤相关巨噬细胞以及肿瘤微环境中的其他细胞。抗PD-L1抗体对多种癌症具有活性，联合抗PD-L1治疗和外照射可提高治疗效果。PD-L1表达状态是判断预后和治疗反应的重要指标，但精确捕捉肿瘤微环境中PD-L1表达动态的方法仍然有限。在这项研究中，我们开发了一种与放射性同位素铟-111(111In)偶联的小鼠抗PD-L1抗体，用于在免疫未受损的乳腺癌小鼠模型中进行成像和生物分布研究。注射后72小时，111In-DTPA-抗PD-L1抗体在肿瘤及脾、肝、胸腺、心脏和肺组织中的分布达到高峰。联合注射标记抗体和100倍未标记抗体在24小时内显著减少了脾摄取，表明过量的未标记抗体有效地阻断了脾中的PD-L1部位，从而将111In-DTPA-抗PD-L1的浓度转移到血流中，并潜在地增加了肿瘤的摄取。111In-DTPA-抗PD-L1在144小时从所有脏器中清除。此外，剂量学计算显示，放射性核素标记的抗PD-L1抗体产生了可耐受的计划骨髓剂量，进一步支持其用于放射性药物治疗。综上所述，这些研究证明了使用抗PD-L1抗体进行放射性核素成像和放射免疫治疗的可行性，并突出了优化和监测免疫检查点抑制治疗效果的新机会。
The programmed cell death ligand 1 (PD-L1) participates in an immune checkpoint system involved in preventing autoimmunity. PD-L1 is expressed on tumor cells, tumor-associated macrophages, and other cells in the tumor microenvironment. Anti-PD-L1 antibodies are active against a variety of cancers, and combined anti-PD-L1 therapy with external beam radiotherapy has been shown to increase therapeutic efficacy. PD-L1 expression status is an important indicator of prognosis and therapy responsiveness, but methods to precisely capture the dynamics of PD-L1 expression in the tumor microenvironment are still limited. In this study, we developed a murine anti-PD-L1 antibody conjugated to the radioactive isotope Indium-111 (111In) for imaging and biodistribution studies in an immune-intact mouse model of breast cancer. The distribution of 111In-DTPA-anti-PD-L1 in tumors as well as the spleen, liver, thymus, heart, and lungs peaked 72 hours after injection. Co-injection of labeled and 100-fold unlabeled antibody significantly reduced spleen uptake at 24 hours, indicating that an excess of unlabeled antibody effectively blocked PD-L1 sites in the spleen, thus shifting the concentration of 111In-DTPA-anti-PD-L1 into the blood stream and potentially increasing tumor uptake. Clearance of 111In-DTPA-anti-PD-L1 from all organs occurred at 144 hours. Moreover, dosimetry calculations revealed that radionuclide-labeled anti-PD-L1 antibody yielded tolerable projected marrow doses, further supporting its use for radiopharmaceutical therapy. Taken together, these studies demonstrate the feasibility of using anti-PD-L1 antibody for radionuclide imaging and radioimmunotherapy, and highlight a new opportunity to optimize and monitor the efficacy of immune checkpoint inhibition therapy.