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Bioconjug Chem. 2018 Oct 17;29(10):3476-3482. doi: 10.1021/acs.bioconjchem.8b00632. Epub 2018 Sep 24.

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

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Skolkovo Institute of Science and Technology , Skolkovo Innovation Center, 3 Nobel Street , Moscow 143026 , Russia.
Department of Radiology and Biomedical Imaging , University of California, San Francisco , 505 Parnassus Avenue , San Francisco , California 94143 , United States.
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR) , 8A Biomedical Grove Immunos No. 03-06 , Biopolis, 138648 , Singapore.
Department of Pharmaceutical Chemistry , University of California, San Francisco , 505 Parnassus Avenue , San Francisco , California 94143 , United States.
Imagerie Moleculaire In Vivo, INSERM, CEA, Université Paris Sud, CNRS, Université Paris Saclay, CEA-Service Hospitalier Frederic Joliot , Orsay 94100 , France.


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.

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