Elaine M Jagoda, Olga Vasalatiy, Falguni Basuli, Ana Christina L Opina, Mark R Williams, Karen Wong, Kelly C Lane, Steve Adler, Anita Thein Ton, Lawrence P Szajek, Biying Xu, Donna Butcher, Elijah F Edmondson, Rolf E Swenson, John Greiner, James Gulley, Janet Eary, Peter L Choyke
{"title":"Immuno-PET Imaging of the Programmed Cell Death-1 Ligand (PD-L1) Using a Zirconium-89 Labeled Therapeutic Antibody, Avelumab.","authors":"Elaine M Jagoda, Olga Vasalatiy, Falguni Basuli, Ana Christina L Opina, Mark R Williams, Karen Wong, Kelly C Lane, Steve Adler, Anita Thein Ton, Lawrence P Szajek, Biying Xu, Donna Butcher, Elijah F Edmondson, Rolf E Swenson, John Greiner, James Gulley, Janet Eary, Peter L Choyke","doi":"10.1177/1536012119829986","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>The goal is to evaluate avelumab, an anti-PD-L1 monoclonal immunoglobulin G antibody labeled with zirconium-89 in human PD-L1-expressing cancer cells and mouse xenografts for clinical translation.</p><p><strong>Methods: </strong>[<sup>89</sup>Zr]Zr-DFO-PD-L1 monoclonal antibody (mAb) was synthesized using avelumab conjugated to desferrioxamine. In vitro binding studies and biodistribution studies were performed with PD-L1+MDA-MB231 cells and MDA-MB231 xenograft mouse models, respectively. Biodistributions were determined at 1, 2, 3, 5, and 7 days post coinjection of [<sup>89</sup>Zr]Zr-DFO-PD-L1 mAb without or with unlabeled avelumab (10, 20, 40, and 400 µg).</p><p><strong>Results: </strong>[<sup>89</sup>Zr]Zr-DFO-PD-L1 mAb exhibited high affinity (K<sub>d</sub> ∼ 0.3 nM) and detected moderate PD-L1 expression levels in MDA-MB231 cells. The spleen and lymph nodes exhibited the highest [<sup>89</sup>Zr]Zr-DFO-PD-L1 mAb uptakes in all time points, while MDA-MB231 tumor uptakes were lower but highly retained. In the unlabeled avelumab dose escalation studies, spleen tissue-muscle ratios decreased in a dose-dependent manner indicating specific [<sup>89</sup>Zr]Zr-DFO-PD-L1 mAb binding to PD-L1. In contrast, lymph node and tumor tissue-muscle ratios increased 4- to 5-fold at 20 and 40 µg avelumab doses.</p><p><strong>Conclusions: </strong>[<sup>89</sup>Zr]Zr-DFO-PD-L1 mAb exhibited specific and high affinity for PD-L1 in vitro and had target tissue uptakes correlating with PD-L1 expression levels in vivo. [<sup>89</sup>Zr]Zr-DFO-PD-L1 mAb uptake in PD-L1+tumors increased with escalating doses of avelumab.</p>","PeriodicalId":18855,"journal":{"name":"Molecular Imaging","volume":null,"pages":null},"PeriodicalIF":2.2000,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1536012119829986","citationCount":"55","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Imaging","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/1536012119829986","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
引用次数: 55
Abstract
Objective: The goal is to evaluate avelumab, an anti-PD-L1 monoclonal immunoglobulin G antibody labeled with zirconium-89 in human PD-L1-expressing cancer cells and mouse xenografts for clinical translation.
Methods: [89Zr]Zr-DFO-PD-L1 monoclonal antibody (mAb) was synthesized using avelumab conjugated to desferrioxamine. In vitro binding studies and biodistribution studies were performed with PD-L1+MDA-MB231 cells and MDA-MB231 xenograft mouse models, respectively. Biodistributions were determined at 1, 2, 3, 5, and 7 days post coinjection of [89Zr]Zr-DFO-PD-L1 mAb without or with unlabeled avelumab (10, 20, 40, and 400 µg).
Results: [89Zr]Zr-DFO-PD-L1 mAb exhibited high affinity (Kd ∼ 0.3 nM) and detected moderate PD-L1 expression levels in MDA-MB231 cells. The spleen and lymph nodes exhibited the highest [89Zr]Zr-DFO-PD-L1 mAb uptakes in all time points, while MDA-MB231 tumor uptakes were lower but highly retained. In the unlabeled avelumab dose escalation studies, spleen tissue-muscle ratios decreased in a dose-dependent manner indicating specific [89Zr]Zr-DFO-PD-L1 mAb binding to PD-L1. In contrast, lymph node and tumor tissue-muscle ratios increased 4- to 5-fold at 20 and 40 µg avelumab doses.
Conclusions: [89Zr]Zr-DFO-PD-L1 mAb exhibited specific and high affinity for PD-L1 in vitro and had target tissue uptakes correlating with PD-L1 expression levels in vivo. [89Zr]Zr-DFO-PD-L1 mAb uptake in PD-L1+tumors increased with escalating doses of avelumab.
Molecular ImagingBiochemistry, Genetics and Molecular Biology-Biotechnology
自引率
3.60%
发文量
21
期刊介绍:
Molecular Imaging is a peer-reviewed, open access journal highlighting the breadth of molecular imaging research from basic science to preclinical studies to human applications. This serves both the scientific and clinical communities by disseminating novel results and concepts relevant to the biological study of normal and disease processes in both basic and translational studies ranging from mice to humans.