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  • [J Nucl Med.] 89 Zr-Labeled Anti-PD-L1 Antibody PET Monitors Gemcitabine Therapy-Induced Modulation of Tumor PD-L1 Expression

    [J Nucl Med.] 89 Zr-Labeled Anti-PD-L1 Antibody PET Monitors Gemcitabine Therapy-Induced Modulation of Tumor PD-L1 Expression

    성균관의대 / 정경호, 이경한*

  • 출처
    J Nucl Med.
  • 등재일
    2021 May 10
  • 저널이슈번호
    62(5):656-664. doi: 10.2967/jnumed.120.250720. Epub 2020 Sep 11.
  • 내용

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    Abstract
    We developed an 89Zr-labeled anti-programmed death ligand 1 (anti-PD-L1) immune PET that can monitor chemotherapy-mediated modulation of tumor PD-L1 expression in living subjects. Methods: Anti-PD-L1 underwent sulfohydryl moiety-specific conjugation with maleimide-deferoxamine followed by 89Zr radiolabeling. CT26 colon cancer cells and PD-L1-overexpressing CT26/PD-L1 cells underwent binding assays, flow cytometry, and Western blotting. In vivo pharmacokinetics, biodistribution, and PET imaging were evaluated in mice. Results: 89Zr-anti-PD-L1 synthesis was straightforward and efficient. Sodium dodecyl sulfate polyacrylamide gel electrophoresis showed that reduction produced half-antibody fragments, and matrix-assisted laser desorption ionization time-of-flight analysis estimated 2.18 conjugations per antibody, indicating specific conjugation at the hinge-region disulfide bonds. CT26/PD-L1 cells showed 102.2 ± 6.7-fold greater 89Zr-anti-PD-L1 binding than that of weakly expressing CT26 cells. Excellent target specificity was confirmed by a drastic reduction in binding by excess cold antibody. Intravenous 89Zr-anti-PD-L1 followed biexponential blood clearance. PET/CT image analysis demonstrated decreases in major organ activity over 7 d, whereas high CT26/PD-L1 tumor activity was maintained. Again, this was suppressed by excess cold antibody. Treatment of CT26 cells with gemcitabine for 24 h augmented PD-L1 protein to 592.4% ± 114.2% of the control level and increased 89Zr-anti-PD-L1 binding, accompanied by increased AKT (protein kinase B) activation and reduced phosphatase and tensin homolog (PTEN). In CT26 tumor-bearing mice, gemcitabine treatment substantially increased tumor uptake from 1.56% ± 0.48% to 6.24% ± 0.37% injected dose per gram (tumor-to-blood ratio, 34.7). Immunoblots revealed significant increases in tumor PD-L1 and activated AKT and a decrease in PTEN. Conclusion: 89Zr-anti-PD-L1 showed specific targeting with favorable imaging properties. Gemcitabine treatment upregulated cancer cell and tumor PD-L1 expression and increased 89Zr-anti-PD-L1 uptake. 89Zr-anti-PD-L1 PET may thus be useful for monitoring chemotherapy-mediated tumor PD-L1 modulation in living subjects.

     

     

    Affiliations

    Kyung-Ho Jung  1   2 , Jin Won Park  3 , Jin Hee Lee  1   2 , Seung Hwan Moon  1 , Young Seok Cho  1 , Kyung-Han Lee  4   2
    1 Department of Nuclear Medicine, Samsung Medical Center, Seoul, Korea.
    2 Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea; and.
    3 Scripps Korea Antibody Institute, Chuncheon-si, Gangwon-do, Korea.
    4 Department of Nuclear Medicine, Samsung Medical Center, Seoul, Korea khleenm@naver.com.

  • 키워드
    89Zr; PD-L1; antibody; cancer; gemcitabine; immuno-PET.
  • 연구소개
    면역관문 억제치료는 면역감시를 회피하는 암 치료에 있어 획기적으로 이용되고 있으며, 그중 PD-L1은 유망한 표적입니다. 이번 논문은 상대적으로 반감기가 길어 항체기반 PET 프로브에 유용한 89Zr를 PD-L1 항체에 site-specific 하게 표지하여 암의 PD-L1 발현을 높은 대조도로 영상하고, 항암제(gemcitabine)에 의해 증가된 PD-L1 발현의 변화를 성공적으로 모니터링 하였으며 이와 관련된 신호전달 체계를 밝힘으로써 JNM 5월호 표지논문에 게재 되었습니다. 89Zr-anti-PD-L1 PET을 이용한 영상기술을 통해 더 나아가 면역관문 치료제의 효능을 항진 시킬 수 있는 항암제를 선별하여 병합치료에 이용할 수 있는 유용한 기술이 될 수 있다고 생각합니다.
  • 편집위원

    방사성핵종 표지 Anti-PD-L1 항체 영상을 이용하여 종양의 PD-L1 발현을 비침습적으로 평가할 수 있는 것을 보여준 연구결과임. 면역치료에 관심이 있는 연구자 및 종양 핵의학 임상가에게 관심을 끌 연구로 생각됨.

    2021-06-30 16:09:18

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