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Peptide-based PET quantifies target engagement of PD-L1 therapeutics
Dhiraj Kumar, … , Martin G. Pomper, Sridhar Nimmagadda
Dhiraj Kumar, … , Martin G. Pomper, Sridhar Nimmagadda
Published February 1, 2019; First published November 20, 2018
Citation Information: J Clin Invest. 2019;129(2):616-630. https://doi.org/10.1172/JCI122216.
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Categories: Research Article Oncology Therapeutics

Peptide-based PET quantifies target engagement of PD-L1 therapeutics

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Abstract

Immune checkpoint therapies have shown tremendous promise in cancer therapy. However, tools to assess their target engagement, and hence the ability to predict their efficacy, have been lacking. Here, we show that target engagement and tumor-residence kinetics of antibody therapeutics targeting programmed death ligand-1 (PD-L1) can be quantified noninvasively. In computational docking studies, we observed that PD-L1–targeted monoclonal antibodies (atezolizumab, avelumab, and durvalumab) and a high-affinity PD-L1–binding peptide, WL12, have common interaction sites on PD-L1. Using the peptide radiotracer [64Cu]WL12 in vivo, we employed positron emission tomography (PET) imaging and biodistribution studies in multiple xenograft models and demonstrated that variable PD-L1 expression and its saturation by atezolizumab, avelumab, and durvalumab can be quantified independently of biophysical properties and pharmacokinetics of antibodies. Next, we used [64Cu]WL12 to evaluate the impact of time and dose on the unoccupied fraction of tumor PD-L1 during treatment. These quantitative measures enabled, by mathematical modeling, prediction of antibody doses needed to achieve therapeutically effective occupancy (defined as >90%). Thus, we show that peptide-based PET is a promising tool for optimizing dose and therapeutic regimens employing PD-L1 checkpoint antibodies, and can be used for improving therapeutic efficacy.

Authors

Dhiraj Kumar, Ala Lisok, Elyes Dahmane, Matthew McCoy, Sagar Shelake, Samit Chatterjee, Viola Allaj, Polina Sysa-Shah, Bryan Wharram, Wojciech G. Lesniak, Ellen Tully, Edward Gabrielson, Elizabeth M. Jaffee, John T. Poirier, Charles M. Rudin, Jogarao V.S. Gobburu, Martin G. Pomper, Sridhar Nimmagadda

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Figure 1

WL12 binding interface on PD-L1 overlaps with PD-1 and PD-L1 therapeutics.

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WL12 binding interface on PD-L1 overlaps with PD-1 and PD-L1 therapeutic...
(A) WL12 binding mode to PD-L1 (green and cyan) overlaps those of PD-1 (purple and cyan), AtzMab (red and cyan), AveMab (orange and cyan), and DurMab (blue and cyan). Noninteracting residues are shown in gray. The variety of contacts encompassing the shared binding region (cyan) illustrate the diverse binding mechanisms of different therapeutic antibodies.
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ISSN: 0021-9738 (print), 1558-8238 (online)

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