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

Author

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

Subjects
Cancer treatment -- Usage, Mass spectrometry -- Usage, Positron emission tomography -- Usage, Death, Diagnostic imaging, Monoclonal antibodies, Cancer, Peptides, Occupancy, Tumors, Tomography, Antibodies, Therapeutics, Health care industry
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 [[sup.64]Cu]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 [[sup.64]Cu]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., Introduction The success of cancer drug therapy depends on a number of factors within the tumor including drug access, completeness of drug-target engagement, and targeting cancer cell heterogeneity. Target engagement [...]

Published
2019
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15. Abstract 2467: Association of specificity protein 1 and survivin expression in medulloblastoma: Identifying effective therapeutic targets

Author

Sankpal, Umesh T., primary, Eslin, Don, additional, Bowman, W. Paul, additional, Murray, Jeffrey C., additional, Sanchez, Irene, additional, Jones, Michelle, additional, Shelake, Sagar, additional, Hernandez, Yazmin, additional, Wadwani, Anmol, additional, Patel, Hassaan, additional, Dudhia, Ashni, additional, and Basha, Riyaz M., additional

Published
2016
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16. Abstract 4818: Tolfenamic acid and curcumin treatment induces pancreatic cancer cell growth inhibition via suppressing Sp1 expression, NF-kB translocation to nucleus

Author

Basha, Riyaz M., primary, Connelly, Sarah F., additional, Purnachandra, Ganji, additional, Sankpal, Umesh T., additional, Patel, Hassaan, additional, Vishwanatha, Jamboor K., additional, Shelake, Sagar, additional, Tabor-Simecka, Leslie, additional, Shoji, Mamoru, additional, Simecka, Jerry Simecka W., additional, and El-Rayes, Bassel, additional

Published
2016
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17. Small molecule tolfenamic acid and dietary spice curcumin treatment enhances antiproliferative effect in pancreatic cancer cells via suppressing Sp1, disrupting NF-kB translocation to nucleus and cell cycle phase distribution

Author

Basha, Riyaz, primary, Connelly, Sarah F., additional, Sankpal, Umesh T., additional, Nagaraju, Ganji Purnachandra, additional, Patel, Hassaan, additional, Vishwanatha, Jamboor K., additional, Shelake, Sagar, additional, Tabor-Simecka, Leslie, additional, Shoji, Mamoru, additional, Simecka, Jerry W., additional, and El-Rayes, Bassel, additional

Published
2016
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18. Combination of 13 cis ‐retinoic acid and tolfenamic acid induces apoptosis and effectively inhibits high‐risk neuroblastoma cell proliferation

Author

Shelake, Sagar, primary, Eslin, Don, additional, Sutphin, Robert M., additional, Sankpal, Umesh T., additional, Wadwani, Anmol, additional, Kenyon, Laura E., additional, Tabor‐Simecka, Leslie, additional, Bowman, W. Paul, additional, Vishwanatha, Jamboor K., additional, and Basha, Riyaz, additional

Published
2015
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