title: A humanized antibody for imaging immune checkpoint ligand PD-L1 expression in tumors.
abstract: Antibodies targeting the PD-1/PD-L1 immune checkpoint lead to tumor regression and improved survival in several cancers. PD-L1 expression in tumors may be predictive of response to checkpoint blockade therapy. Because tissue samples might not always be available to guide therapy, we developed and evaluated a humanized antibody for non-invasive imaging of PD-L1 expression in tumors. Radiolabeled [111In]PD-L1-mAb and near-infrared dye conjugated NIR-PD-L1-mAb imaging agents were developed using the mouse and human cross-reactive PD-L1 antibody MPDL3280A. We tested specificity of [111In]PD-L1-mAb and NIR-PD-L1-mAb in cell lines and in tumors with varying levels of PD-L1 expression. We performed SPECT/CT imaging, biodistribution and blocking studies in NSG mice bearing tumors with constitutive PD-L1 expression (CHO-PDL1) and in controls (CHO). Results were confirmed in triple negative breast cancer (TNBC) (MDAMB231 and SUM149) and non-small cell lung cancer (NSCLC) (H2444 and H1155) xenografts with varying levels of PD-L1 expression. There was specific binding of [111In]PD-L1-mAb and NIR-PD-L1-mAb to tumor cells in vitro, correlating with PD-L1 expression levels. In mice bearing subcutaneous and orthotopic tumors, there was specific and persistent high accumulation of signal intensity in PD-L1 positive tumors (CHO-PDL1, MDAMB231, H2444) but not in controls. These results demonstrate that [111In]PD-L1-mAb and NIR-PD-L1-mAb can detect graded levels of PD-L1 expression in human tumor xenografts in vivo. As a humanized antibody, these findings suggest clinical translation of radiolabeled versions of MPDL3280A for imaging. Specificity of NIR-PD-L1-mAb indicates the potential for optical imaging of PD-L1 expression in tumors in relevant pre-clinical as well as clinical settings.
authors: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.
authors: Samit
authors: S
authors: Chatterjee
authors: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.
authors: Wojciech G
authors: WG
authors: Lesniak
authors: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.
authors: Matthew
authors: M
authors: Gabrielson
authors: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.
authors: Ala
authors: A
authors: Lisok
authors: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.
authors: Bryan
authors: B
authors: Wharram
authors: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.
authors: Polina
authors: P
authors: Sysa-Shah
authors: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.
authors: Babak Behnam
authors: BB
authors: Azad
authors: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors: Martin G
authors: MG
authors: Pomper
authors: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors: Sridhar
authors: S
authors: Nimmagadda
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology*; D060890:B7-H1 Antigen / Q000276:immunology*; D016466:CHO Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging*; D045744:Cell Line, Tumor; D003412:Cricetulus; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes; D008175:Lung Neoplasms / Q000000981:diagnostic imaging*; D051379:Mice; D016688:Mice, Inbred NOD; D009368:Neoplasm Transplantation; D061848:Optical Imaging / Q000379:methods*; D000072098:Single Photon Emission Computed Tomography Computed Tomography; D014183:Transplantation, Heterologous; D064726:Triple Negative Breast Neoplasms / Q000000981:diagnostic imaging*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D007205:Indium Radioisotopes; C000594389:atezolizumab
keywords: MPDL3280A; immune escape; immunotherapy; molecular imaging; personalized medicine