PET imaging facilitates antibody screening for synergistic radioimmunotherapy with a 177Lu-labeled αPD-L1 antibody
Autor: | Mengxin Xu, Zhibo Liu, Peipei Wang, Fang Li, Junyi Chen, Jingyun Ren, Jie Ding, Li Huo |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
medicine.medical_treatment Population Immune checkpoint blockade (ICB) Medicine (miscellaneous) Adenocarcinoma Lutetium Radioimmunotherapy (RIT) B7-H1 Antigen Flow cytometry Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Positron Emission Tomography Computed Tomography Tumor Microenvironment Lutetium-177 (177Lu) medicine Animals Cytotoxic T cell education Immune Checkpoint Inhibitors Pharmacology Toxicology and Pharmaceutics (miscellaneous) Radioisotopes Tumor microenvironment education.field_of_study biology medicine.diagnostic_test business.industry αPD-L1 Immunotherapy Radioimmunotherapy Flow Cytometry Antibodies Neutralizing 030104 developmental biology Microscopy Fluorescence 030220 oncology & carcinogenesis Colonic Neoplasms biology.protein Cancer research Zirconium Drug Screening Assays Antitumor Antibody CD8+ T cell business CD8 Research Paper |
Zdroj: | Theranostics |
ISSN: | 1838-7640 |
Popis: | Rationale: The low response rate of immunotherapy, such as anti-PD-L1/PD-1 and anti-CTLA4, has limited its application to a wider population of cancer patients. One widely accepted view is that inflammation within the tumor microenvironment is low or ineffective for inducing the sufficient infiltration and/or activation of lymphocytes. Here, a highly tumor-selective anti-PD-L1 (αPD-L1) antibody was developed through PET imaging screening, and it was radiolabeled with Lu-177 for PD-L1-targeted radioimmunotherapy (RIT) and radiation-synergized immunotherapy. Methods: A series of αPD-L1 antibodies were radiolabeled with zirconium-89 for PET imaging to screen the most suitable antibodies for RIT. Mice were divided into an immunotherapy group, a RIT group and a radiation-synergized immunotherapy group to evaluate the therapeutic effect. Alterations in the tumor microenvironment after treatment were assessed using flow cytometry and immunofluorescence microscopy. Results: Radiation-synergistic RIT can achieve a significantly better therapeutic effect than immunotherapy or RIT alone. The dosages of the radiopharmaceuticals and αPD-L1 antibodies were reduced, the infiltration of CD4+ and CD8+ T cells in the tumor microenvironment was increased, and no side effects were observed. This radiation-synergistic RIT strategy successfully showed a strong synergistic effect with αPD-L1 checkpoint blockade therapy, at least in the mouse model. Conclusions: PET imaging of 89Zr-labeled antibodies is an effective method for antibody screening. RIT with a 177Lu-labeled αPD-L1 antibody could successfully upregulate antitumor immunity in the tumor microenvironment and turn “cold” tumors “hot” for immunotherapy. |
Databáze: | OpenAIRE |
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