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PET Imaging of Tumor PD-L1 Expression with a Highly Specific Nonblocking Single-Domain Antibody.
The Journal of Nuclear Medicine ( IF 9.3 ) Pub Date : 2019-06-28 , DOI: 10.2967/jnumed.119.226712
Gaochao Lv 1 , Xiaorong Sun 2 , Ling Qiu 3 , Yan Sun 4 , Ke Li 1 , Qingzhu Liu 1 , Qi Zhao 5 , Songbing Qin 6 , Jianguo Lin 3
Affiliation  

Although immunotherapy through programmed death 1/programmed death ligand 1 (PD-1/PD-L1) checkpoint blockade has shown impressive clinical outcomes, not all patients respond to it. Recent studies have demonstrated that the expression level of PD-L1 in tumors is one of the factors that correlate with PD-1/PD-L1 checkpoint blockade therapy. Herein, a 68Ga-labeled single-domain antibody tracer, 68Ga-NOTA-Nb109, was designed and developed for specific and noninvasive imaging of PD-L1 expression in a melanoma-bearing mouse model. Methods: The single-domain antibody Nb109 was labeled with the radionuclide 68Ga through a NOTA chelator. An in vitro binding assay was performed to assess the affinity and binding epitope of Nb109 to PD-L1. The clinical application value of 68Ga-NOTA-Nb109 was evaluated by a stability assay; by biodistribution and pharmacokinetics studies; and by PET imaging, autoradiography, and immunohistochemical staining studies on tumor-bearing models with differences in PD-L1 expression. Results: 68Ga-NOTA-Nb109 was obtained with a radiochemical yield of more than 95% and radiochemical purity of more than 98% in 10 min. It showed a highly specific affinity for PD-L1, with an equilibrium dissociation constant of 2.9 × 10-9 M. A competitive binding assay indicated Nb109 to have a binding epitope different from that of PD-1 and PD-L1 antibody. All biodistribution, PET imaging, autoradiography, and immunohistochemical staining studies revealed that 68Ga-NOTA-Nb109 specifically accumulated in A375-hPD-L1 tumor, with a maximum uptake of 5.0% ± 0.35% injected dose/g at 1 h. Conclusion: 68Ga-NOTA-Nb109 holds great potential for noninvasive PET imaging of the PD-L1 status in tumors and for timely evaluation of the effect of immune checkpoint targeting treatment.

中文翻译:

使用高度特异性的非阻断单域抗体对肿瘤 PD-L1 表达进行 PET 成像。

尽管通过程序性死亡 1/程序性死亡配体 1 (PD-1/PD-L1) 检查点阻断的免疫疗法已显示出令人印象深刻的临床结果,但并非所有患者都对其有反应。最近的研究表明,PD-L1在肿瘤中的表达水平是与PD-1/PD-L1检查点阻断治疗相关的因素之一。在此,设计和开发了一种 68Ga 标记的单域抗体示踪剂 68Ga-NOTA-Nb109,用于在黑色素瘤小鼠模型中对 PD-L1 表达进行特异性和无创成像。方法:单域抗体Nb109通过NOTA螯合剂用放射性核素68Ga标记。进行体外结合测定以评估 Nb109 对 PD-L1 的亲和力和结合表位。通过稳定性试验评价68Ga-NOTA-Nb109的临床应用价值;通过生物分布和药代动力学研究;通过 PET 成像、放射自显影和免疫组织化学染色对 PD-L1 表达差异的荷瘤模型进行研究。结果:10 min内得到68Ga-NOTA-Nb109,放化学收率达95%以上,放化学纯度达98%以上。它对 PD-L1 显示出高度特异性的亲和力,平衡解离常数为 2.9 × 10-9 M。竞争结合试验表明 Nb109 具有与 PD-1 和 PD-L1 抗体不同的结合表位。所有生物分布、PET 成像、放射自显影和免疫组织化学染色研究表明,68Ga-NOTA-Nb109 在 A375-hPD-L1 肿瘤中特异性积累,1 小时时最大摄取量为 5.0% ± 0.35% 注射剂量/g。结论:
更新日期:2020-01-02
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