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In Vivo Imaging of the Programmed Death Ligand 1 by 18F PET
The Journal of Nuclear Medicine ( IF 9.1 ) Pub Date : 2017-11-01 , DOI: 10.2967/jnumed.117.191718
Dinko E. González Trotter , Xiangjun Meng , Paul McQuade , Daniel Rubins , Michael Klimas , Zhizhen Zeng , Brett M. Connolly , Patricia J. Miller , Stacey S. O’Malley , Shu-An Lin , Krista L. Getty , Laurence Fayadat-Dilman , Linda Liang , Elisabet Wahlberg , Olof Widmark , Caroline Ekblad , Fredrik Y. Frejd , Eric D. Hostetler , Jeffrey L. Evelhoch

Programmed death ligand 1 (PD-L1) is an immune regulatory ligand that binds to the T-cell immune check point programmed death 1. Tumor expression of PD-L1 is correlated with immune suppression and poor prognosis. It is also correlated with therapeutic efficacy of programmed death 1 and PD-L1 inhibitors. In vivo imaging may enable real-time follow-up of changing PD-L1 expression and heterogeneity evaluation of PD-L1 expression across tumors in the same subject. We have radiolabeled the PD-L1–binding Affibody molecule NOTA-ZPD-L1_1 with 18F and evaluated its in vitro and in vivo binding affinity, targeting, and specificity. Methods: The affinity of the PD-L1–binding Affibody ligand ZPD-L1_1 was evaluated by surface plasmon resonance. Labeling was accomplished by maleimide coupling of NOTA to a unique cysteine residue and chelation of 18F-AlF. In vivo studies were performed in PD-L1–positive, PD-L1–negative, and mixed tumor-bearing severe combined immunodeficiency mice. Tracer was injected via the tail vein, and dynamic PET scans were acquired for 90 min, followed by γ-counting biodistribution. Immunohistochemical staining with an antibody specific for anti–PD-L1 (22C3) was used to evaluate the tumor distribution of PD-L1. Immunohistochemistry results were then compared with ex vivo autoradiographic images obtained from adjacent tissue sections. Results: NOTA-ZPD-L1_1 was labeled, with a radiochemical yield of 15.1% ± 5.6%, radiochemical purity of 96.7% ± 2.0%, and specific activity of 14.6 ± 6.5 GBq/μmol. Surface plasmon resonance showed a NOTA-conjugated ligand binding affinity of 1 nM. PET imaging demonstrated rapid uptake of tracer in the PD-L1–positive tumor, whereas the PD-L1–negative control tumor showed little tracer retention. Tracer clearance from most organs and blood was quick, with biodistribution showing prominent kidney retention, low liver uptake, and a significant difference between PD-L1–positive (percentage injected dose per gram [%ID/g] = 2.56 ± 0.33) and –negative (%ID/g = 0.32 ± 0.05) tumors (P = 0.0006). Ex vivo autoradiography showed excellent spatial correlation with immunohistochemistry in mixed tumors. Conclusion: Our results show that Affibody ligands can be effective at targeting tumor PD-L1 in vivo, with good specificity and rapid clearance. Future studies will explore methods to reduce kidney activity retention and further increase tumor uptake.



中文翻译:

18 F PET对程序化死亡配体1的体内成像

程序性死亡配体1(PD-L1)是与T细胞免疫检查点程序性死亡1结合的免疫调节配体。PD-L1的肿瘤表达与免疫抑制和不良预后相关。它还与程序性死亡1和PD-L1抑制剂的治疗功效相关。体内成像可以实时追踪变化的PD-L1表达,并在同一受试者的整个肿瘤中评估PD-L1表达的异质性。我们已经用18 F对PD-L1结合的Affibody分子NOTA-Z PD-L1_1进行了放射性标记,并评估了其在体内和体外的结合亲和力,靶向性和特异性。方法: PD-L1结合亲和体配体Z PD-L1_1的亲和力通过表面等离振子共振评价。标记是通过将NOTA的马来酰亚胺偶联至独特的半胱氨酸残基和18 F-AlF的螯合来完成的。在PD-L1阳性,PD-L1阴性和带有荷瘤的严重混合免疫缺陷小鼠中进行了体内研究。通过尾静脉注射示踪剂,并进行90分钟动态PET扫描,然后进行γ计数生物分布。用抗PD-L1(22C3)特异的抗体进行免疫组织化学染色,以评估PD-L1的肿瘤分布。然后将免疫组织化学结果与从相邻组织切片获得的离体放射自显影图像进行比较。结果: NOTA-Z PD-L1_1标记后的放射化学产率为15.1%±5.6%,放射化学纯度为96.7%±2.0%,比活度为14.6±6.5 GBq /μmol。表面等离子体共振显示出NOTA-缀合的配体结合亲和力为1 nM。PET成像显示PD-L1阳性肿瘤中示踪剂的快速摄取,而PD-L1阴性对照肿瘤中示踪剂保留很少。示踪剂从大多数器官和血液中清除的速度很快,生物分布显示出显着的肾脏滞留,低肝摄取,以及PD-L1阳性(每克注射剂量百分数[%ID / g] = 2.56±0.33)之间的显着差异–阴性(%ID / g = 0.32±0.05)肿瘤(P = 0.0006)。离体放射自显影在混合肿瘤中显示出与免疫组织化学极好的空间相关性。结论:我们的结果表明,Affibody配体可以有效靶向体内的PD-L1肿瘤,具有良好的特异性和快速清除率。未来的研究将探索减少肾脏活动保留并进一步增加肿瘤吸收的方法。

更新日期:2017-11-01
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