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. Zr-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 forZr-atezolizumab could be improved and to make direct comparisons to Zr-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 activityZr-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, Zr-atezolizumab uptake was generally higher in normal mouse tissues compared toZr-C4 and lower in H1975, a tumor model with modest PD-L1 expression. Also unexpectedly, reducing the specific activity at least 15-fold suppressed Zr-atezo uptake in normal mouse tissues but increased tumor uptake to levels observed with high specific activityZr-C4. In summary, these data reveal that low specific activity Zr-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 likeZr-C4 PET may be simpler to implement clinically to measure the broad dynamic range of PD-L1 expression known to manifest among tumors.

Quantitative PET imaging of PD-L1 expression in xenograft and syngeneic tumour models using a site-specifically labelled PD-L1 antibody

“…In addition, choosing a dose that saturates the antigen sink in lymphoid tissue completely might tip the balance in another individual and potentially block tumour target. Indeed, it has been suggested that low specific activity 89 Zr-DFO-6E11 may be needed to accurately determine tumour PD-L1 expression levels [21].…”

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

“…A 89 Zr-labeled mAb against mouse PD-L1 was used to show increased tracer uptake in a syngeneic head and neck tumor model after fractionated radiotherapy (Kikuchi et al 2017). Other research teams have also successfully employed mAbs for imaging of PD-L1 using different radionuclides, including 89 Zr, 111 In, 64 Cu and 131 I (Hettich et al 2016;Chatterjee et al 2016;Josefsson et al 2016;Nedrow et al 2017aNedrow et al , 2017bLesniak et al 2016;Li et al 2018;Moroz et al 2018;Truillet et al 2018;Pang et al 2018).…”

Quantifying PD-L1 Expression to Monitor Immune Checkpoint Therapy: Opportunities and Challenges

“…A diverse selection of mouse (mPD-L1) [126,127,137] or human PD-L1 reactive (hPD-L1) [122,123,128,129,136,[138][139][140][141][142] mAbs have been investigated for their potential to detect PD-L1 levels in vivo. Most of those studies were conducted in immune compromised mice with human tumor xenografts, or in immunocompetent mice with syngeneic tumors.…”