title: PD-L1 Detection in Tumors Using [(64)Cu]Atezolizumab with PET.
abstract: The programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pair is a major immune checkpoint pathway exploited by cancer cells to develop and maintain immune tolerance. With recent approvals of anti-PD-1 and anti-PD-L1 therapeutic antibodies, there is an urgent need for noninvasive detection methods to quantify dynamic PD-L1 expression in tumors and to evaluate the tumor response to immune modulation therapies. To address this need, we assessed [(64)Cu]atezolizumab for the detection of PD-L1 expression in tumors. Atezolizumab (MPDL3208A) is a humanized, human and mouse cross-reactive, therapeutic PD-L1 antibody that is being investigated in several cancers. Atezolizumab was conjugated with DOTAGA and radiolabeled with copper-64. The resulting [(64)Cu]atezolizumab was assessed for in vitro and in vivo specificity in multiple cell lines and tumors of variable PD-L1 expression. We performed PET-CT imaging, biodistribution, and blocking studies in NSG mice bearing tumors with constitutive PD-L1 expression (CHO-hPD-L1) and in controls (CHO). Specificity of [(64)Cu]atezolizumab was further confirmed in orthotopic tumor models of human breast cancer (MDAMB231 and SUM149) and in a syngeneic mouse mammary carcinoma model (4T1). We observed specific binding of [(64)Cu]atezolizumab to tumor cells in vitro, correlating with PD-L1 expression levels. Specific accumulation of [(64)Cu]atezolizumab was also observed in tumors with high PD-L1 expression (CHO-hPD-L1 and MDAMB231) compared to tumors with low PD-L1 expression (CHO, SUM149). Collectively, these studies demonstrate the feasibility of using [(64)Cu]atezolizumab for the detection of PD-L1 expression in different tumor types.
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science and ‡Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University , Baltimore, Maryland, United States.
authors.forename: Wojciech G
authors.initials: WG
authors.lastname: Lesniak
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science and ‡Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University , Baltimore, Maryland, United States.
authors.forename: Samit
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science and ‡Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University , Baltimore, Maryland, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gabrielson
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science and ‡Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University , Baltimore, Maryland, United States.
authors.forename: Ala
authors.initials: A
authors.lastname: Lisok
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science and ‡Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University , Baltimore, Maryland, United States.
authors.forename: Bryan
authors.initials: B
authors.lastname: Wharram
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science and ‡Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University , Baltimore, Maryland, United States.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science and ‡Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University , Baltimore, Maryland, United States.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Nimmagadda
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen / Q000378:metabolism*; D001692:Biological Transport; D016466:CHO Cells; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D051379:Mice; D000072078:Positron Emission Tomography Computed Tomography; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D003301:Copper Radioisotopes; C000594389:atezolizumab