当前位置：
X-MOL 学术
›
Bioconjugate Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
A Preclinical Assessment of 89Zr-atezolizumab Identifies a Requirement for Carrier Added Formulations Not Observed with 89Zr-C4
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-09-18 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00632 Anna Moroz 1, 2 , Chia-Yin Lee 3 , Yung-hua Wang 2 , Jeffrey C. Hsiao 2 , Natalia Sevillano 4 , Charles Truillet 5 , Charles S. Craik 4 , Lawrence Fong , Cheng-I Wang 3 , Michael J. Evans 2, 4
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-09-18 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00632 Anna Moroz 1, 2 , Chia-Yin Lee 3 , Yung-hua Wang 2 , Jeffrey C. Hsiao 2 , Natalia Sevillano 4 , Charles Truillet 5 , Charles S. Craik 4 , Lawrence Fong , Cheng-I Wang 3 , Michael J. Evans 2, 4
Affiliation
|
The swell of experimental imaging technologies to noninvasively measure immune checkpoint protein expression presents the opportunity for rigorous comparative studies toward identifying a gold standard. 89Zr-atezolizumab is currently in man, and early data show tumor targeting but also abundant uptake in several normal tissues. Therefore, we conducted a reverse translational study both to understand if tumor to normal tissue ratios for 89Zr-atezolizumab could be improved and to make direct comparisons to 89Zr-C4, a radiotracer that we showed can detect a large dynamic range of tumor-associated PD-L1 expression. PET/CT and biodistribution studies in tumor bearing immunocompetent and nu/nu mice revealed that high specific activity 89Zr-atezolizumab (∼2 μCi/μg) binds to PD-L1 on tumors but also results in very high uptake in many normal mouse tissues, as expected. Unexpectedly, 89Zr-atezolizumab uptake was generally higher in normal mouse tissues compared to 89Zr-C4 and lower in H1975, a tumor model with modest PD-L1 expression. Also unexpectedly, reducing the specific activity at least 15-fold suppressed 89Zr-atezo uptake in normal mouse tissues but increased tumor uptake to levels observed with high specific activity 89Zr-C4. In summary, these data reveal that low specific activity 89Zr-atezo may be necessary for accurately measuring PD-L1 in the tumor microenvironment, assuming a threshold can be identified that preferentially suppresses binding in normal tissues without reducing binding to tumors with abundant expression. Alternatively, high specific activity approaches like 89Zr-C4 PET may be simpler to implement clinically to measure the broad dynamic range of PD-L1 expression known to manifest among tumors.
中文翻译：
对89 Zr-atezolizumab的临床前评估确定了对用89 Zr-C4未观察到的载体添加制剂的要求
无创测量免疫检查点蛋白表达的实验成像技术的兴起为确定金标准进行了严格的比较研究提供了机会。89 Zr-atezolizumab目前在人体中，早期数据显示靶向肿瘤，但在几种正常组织中也有大量摄取。因此，我们进行了反向翻译研究，以了解是否可以改善89 Zr-atezolizumab的肿瘤与正常组织的比率，并与89 Zr-C4（我们显示的放射性示踪剂可以检测到较大的肿瘤动态范围）进行直接比较。相关的PD-L1表达。在具有荷瘤免疫能力和nu / nu小鼠体内的PET / CT和生物分布研究表明，高比活性89Zr-atezolizumab（〜2μCi/μg）与肿瘤上的PD-L1结合，但也可以像预期的那样在许多正常小鼠组织中引起很高的摄取。出乎意料的是，正常小鼠组织中89 Zr-atezolizumab的摄取通常比89 Zr-C4高，而在H1975（PD-L1表达适中的肿瘤模型）中则更低。同样出乎意料的是，将比活性降低至少15倍抑制了正常小鼠组织中89 Zr-苯偶氮的摄取，但是却将肿瘤摄取增加到了高比活性89 Zr-C4所观察到的水平。总之，这些数据表明较低的比活度89Zr-atezo对于准确测量肿瘤微环境中的PD-L1可能是必需的，前提是可以确定一个阈值，该阈值优先抑制正常组织中的结合而不降低与表达丰富的肿瘤的结合。或者，高比活度方法（如89 Zr-C4 PET）在临床上更容易实施，以测量已知在肿瘤中表现出来的PD-L1表达的广泛动态范围。
更新日期：2018-09-18
中文翻译：
对89 Zr-atezolizumab的临床前评估确定了对用89 Zr-C4未观察到的载体添加制剂的要求
无创测量免疫检查点蛋白表达的实验成像技术的兴起为确定金标准进行了严格的比较研究提供了机会。89 Zr-atezolizumab目前在人体中，早期数据显示靶向肿瘤，但在几种正常组织中也有大量摄取。因此，我们进行了反向翻译研究，以了解是否可以改善89 Zr-atezolizumab的肿瘤与正常组织的比率，并与89 Zr-C4（我们显示的放射性示踪剂可以检测到较大的肿瘤动态范围）进行直接比较。相关的PD-L1表达。在具有荷瘤免疫能力和nu / nu小鼠体内的PET / CT和生物分布研究表明，高比活性89Zr-atezolizumab（〜2μCi/μg）与肿瘤上的PD-L1结合，但也可以像预期的那样在许多正常小鼠组织中引起很高的摄取。出乎意料的是，正常小鼠组织中89 Zr-atezolizumab的摄取通常比89 Zr-C4高，而在H1975（PD-L1表达适中的肿瘤模型）中则更低。同样出乎意料的是，将比活性降低至少15倍抑制了正常小鼠组织中89 Zr-苯偶氮的摄取，但是却将肿瘤摄取增加到了高比活性89 Zr-C4所观察到的水平。总之，这些数据表明较低的比活度89Zr-atezo对于准确测量肿瘤微环境中的PD-L1可能是必需的，前提是可以确定一个阈值，该阈值优先抑制正常组织中的结合而不降低与表达丰富的肿瘤的结合。或者，高比活度方法（如89 Zr-C4 PET）在临床上更容易实施，以测量已知在肿瘤中表现出来的PD-L1表达的广泛动态范围。
京公网安备 11010802027423号