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A Preclinical Assessment of 89Zr-atezolizumab Identifies a Requirement for Carrier Added Formulations Not Observed with 89Zr-C4.

ABSTRACT: 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 ?Ci/?g) 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.

SUBMITTER: Moroz A

PROVIDER: S-EPMC6430562 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A Preclinical Assessment of 89Zr-atezolizumab Identifies a Requirement for Carrier Added Formulations Not Observed with 89Zr-C4.

Moroz Anna A Lee Chia-Yin CY Wang Yung-Hua YH Hsiao Jeffrey C JC Sevillano Natalia N Truillet Charles C Craik Charles S CS Fong Lawrence L Wang Cheng-I CI Evans Michael J MJ

Bioconjugate chemistry 20180924 10

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 an ...[more]

PMID: 30227708

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Project description:BackgroundProgrammed cell death 1 ligand 1(PD-L1) is overexpressed in many tumors. The radionuclide-labeled anti-PD-L1 monoclonal antibody can be used for imaging and therapy of PD-L1 overexpressing cancer. Here, we described 131I-labeled Atezolizumab (131I-Atezolizumab, targeting PD-L1) as a therapeutic agent for colorectal cancer with PD-L1 overexpression.Methods131I-Atezolizumab was prepared by the Iodogen method. The expression levels of PD-L1 in different human colorectal cells were determined by flow cytometry, western blot and cell binding assay. The immunoreactivity of 131I-Atezolizumab to PD-L1 high-expressing cells was determined by immunoreactive fraction. The killing abilities of different concentrations of 131I-Atezolizumab on cells with high and low expression of PD-L1 were detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Cerenkov luminescence imaging (CLI) and radioimmunotherapy (RIT) of 131I-Atezolizumab were performed on two human colorectal cancer models. The distribution and tumor targeting of 131I-Atezolizumab were evaluated by imaging. Tumor volume and survival time were used as indicators to evaluate the anti-tumor effect of 131I-Atezolizumab.ResultsThe expression level of PD-L1 in vitro determined by the cell binding assay was related to the data of flow cytometry and western blot. 131I-Atezolizumab can specifically bind to PD-L1 high-expressing cells in vitro to reflect the expression level of PD-L1. Immunoreactive fraction of PD-L1 high-expressing RKO cells with 131I-Atezolizumab was 52.2%. The killing ability of 131I-Atezolizumab on PD-L1 high-expressing cells was higher than that of low-expressing cells. CLI proved that the specific uptake level of tumors depends on the expression level of PD-L1. Effect of 131I-Atezolizumab RIT showed an activity-dependent tumor suppressor effect on RKO tumor-bearing mice with high PD-L1 expression. 131I-Atezolizumab (37 MBq) can improve the median survival time of mice (34 days), compared to untreated mice (27 days) (P = 0.027). Although a single activity(37 MBq) of 131I-Atezolizumab also inhibited the tumors of HCT8 tumor-bearing mice with low PD-L1 expression (P < 0.05), it could not prolong the survival of mice(P = 0.29).Conclusion131I-Atezolizumab can be used as a CLI agent for screening PD-L1 expression levels. It may be used as a radioimmunotherapy drug target for PD- L1 overexpressing tumors.

Dataset Information

A Preclinical Assessment of 89Zr-atezolizumab Identifies a Requirement for Carrier Added Formulations Not Observed with 89Zr-C4.

Publications

A Preclinical Assessment of <sup>89</sup>Zr-atezolizumab Identifies a Requirement for Carrier Added Formulations Not Observed with <sup>89</sup>Zr-C4.

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