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  • [Clin Cancer Res.] 췌장암의 225Ac-방사선면역치료 효과를 향상시키기 위한 Bioorthogonal Click Chemistry

    Leveraging Bioorthogonal Click Chemistry to Improve 225Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma.

    Memorial Sloan Kettering Cancer Center, Hunter Colleg /Jason S. Lewis*,Brian M. Zeglis*,Sophie Poty*

  • 출처
    Clin Cancer Res.
  • 등재일
    2019 Jan 15
  • 저널이슈번호
    25(2):868-880. doi: 10.1158/1078-0432.CCR-18-1650. Epub 2018 Oct 23.
  • 내용

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    Abstract
    PURPOSE:
    Interest in targeted alpha-therapy has surged due to α-particles' high cytotoxicity. However, the widespread clinical use of this approach could be limited by on-/off-target toxicities. Here, we investigated the inverse electron-demand Diels-Alder ligation between an 225Ac-labeled tetrazine radioligand and a trans-cyclooctene-bearing anti-CA19.9 antibody (5B1) for pretargeted α-radioimmunotherapy (PRIT) of pancreatic ductal adenocarcinoma (PDAC). This alternative strategy is expected to reduce nonspecific toxicities as compared with conventional radioimmunotherapy (RIT).Experimental Design: A side-by-side comparison of 225Ac-PRIT and conventional RIT using a directly 225Ac-radiolabeled immunoconjugate evaluates the therapeutic efficacy and toxicity of both methodologies in PDAC murine models.

    RESULTS:
    A comparative biodistribution study of the PRIT versus RIT methodology underscored the improved pharmacokinetic properties (e.g., prolonged tumor uptake and increased tumor-to-tissue ratios) of the PRIT approach. Cerenkov imaging coupled to PRIT confirmed the in vivo biodistribution of 225Ac-radioimmunoconjugate but-importantly-further allowed for the ex vivo monitoring of 225Ac's radioactive daughters' redistribution. Human dosimetry was extrapolated from the mouse biodistribution and confirms the clinical translatability of 225Ac-PRIT. Furthermore, longitudinal therapy studies performed in subcutaneous and orthotopic PDAC models confirm the therapeutic efficacy of 225Ac-PRIT with the observation of prolonged median survival compared with control cohorts. Finally, a comparison with conventional RIT highlighted the potential of 225Ac-PRIT to reduce hematotoxicity while maintaining therapeutic effectiveness.

    CONCLUSIONS:
    The ability of 225Ac-PRIT to deliver a radiotherapeutic payload while simultaneously reducing the off-target toxicity normally associated with RIT suggests that the clinical translation of this approach will have a profound impact on PDAC therapy.

     


    Author information

    Poty S1, Carter LM2, Mandleywala K2, Membreno R3,4, Abdel-Atti D2, Ragupathi A2, Scholz WW5, Zeglis BM1,3,4,6, Lewis JS1,6,7,8.
    1
    Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. lewisj2@mskcc.org bz102@hunter.cuny.edu potys@mskcc.org.
    2
    Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
    3
    Department of Chemistry, Hunter College of the City University of New York, New York, New York.
    4
    Ph.D. Program in Chemistry, Graduate Center of the City University of New York, New York, New York.
    5
    MabVax Therapeutics, San Diego, California.
    6
    Departments of Radiology and Department of Pharmacology, Weill Cornell Medical College, New York, New York.
    7
    Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
    8
    Radiochemistry and Molecular Imaging Probes Core, Memorial Sloan Kettering Cancer Center, New York, New York.

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