title: Noninvasive Imaging of Tumor PD-L1 Expression Using Radiolabeled Anti-PD-L1 Antibodies.
abstract: Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive antitumor activity. Patients with tumors expressing PD-L1 are most likely to respond to this treatment. The aim of our study was to develop a noninvasive imaging technique to determine tumor PD-L1 expression in vivo. This could allow selection of patients that are most likely to benefit from anti-PD-1/PD-L1 treatment and to monitor PD-L1 expression during therapy. The monoclonal antibody PD-L1.3.1 was radiolabeled with Indium-111 ((111)In) and characterized using PD-L1-expressing MDA-MB-231 cells. Subsequently, the optimal antibody dose and time point for imaging was determined in mice with MDA-MB-231 xenografts. Finally, SPECT/CT imaging was performed in xenograft models with different PD-L1 expression levels and tumor sections were analyzed for PD-L1 expression using IHC. The optimal antibody dose of (111)In-PD-L1.3.1 (Kd = 1 nmol/L) for SPECT/CT imaging was ≤1 μg. Highest tumor-to-normal tissue contrast was obtained at days 3 and 7 after injection. (111)In-PD-L1.3.1 SPECT/CT showed efficient accumulation in high PD-L1-expressing tumors (MDA-MB-231 and SK-Br-3), whereas no specific uptake was observed in tumors with low or no detectable levels of PD-L1 (SUM149, BT474, and MCF-7). SPECT/CT and autoradiography showed a very heterogeneous distribution of (111)In-PD-L1.3.1 within the tumor. In conclusion, this is the first study showing the feasibility of noninvasive in vivo imaging of PD-L1 expression in tumors. (111)In-PD-L1.3.1 showed efficient and specific uptake in PD-L1 expressing xenografts. This technique may enable patient selection for PD-1 and PD-L1-targeted therapy.
authors.affiliation: Departments of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, the Netherlands. sandra.heskamp@radboudumc.nl.
authors.forename: Sandra
authors.initials: S
authors.lastname: Heskamp
authors.affiliation: Laboratory Medicine-Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Willemijn
authors.initials: W
authors.lastname: Hobo
authors.affiliation: Departments of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Janneke D M
authors.initials: JD
authors.lastname: Molkenboer-Kuenen
authors.affiliation: CRCM, Immunity and Cancer, Inserm, U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM 105; CNRS, UMR7258, Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.affiliation: Departments of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.affiliation: Laboratory Medicine-Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
authors.affiliation: Departments of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen / Q000276:immunology* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D005260:Female; D064593:Heterografts; D006801:Humans; D007205:Indium Radioisotopes / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011485:Protein Binding; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D007205:Indium Radioisotopes