PD-L1 Detection in Tumors Using [(64)Cu]Atezolizumab with PET

Bioconjug Chem. 2016 Sep 21;27(9):2103-10. doi: 10.1021/acs.bioconjchem.6b00348. Epub 2016 Aug 9.

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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal* / metabolism
  • Antibodies, Monoclonal* / pharmacokinetics
  • Antibodies, Monoclonal, Humanized
  • B7-H1 Antigen / metabolism*
  • Biological Transport
  • CHO Cells
  • Cell Line, Tumor
  • Copper Radioisotopes*
  • Cricetinae
  • Cricetulus
  • Female
  • Humans
  • Mice
  • Positron Emission Tomography Computed Tomography*
  • Tissue Distribution

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • B7-H1 Antigen
  • CD274 protein, human
  • Copper Radioisotopes
  • atezolizumab