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  • [Clin Cancer Res.] 131I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment.

    Vrije Universiteit Brussel / Matthias D'Huyvetter*

  • 출처
    Clin Cancer Res.
  • 등재일
    2017 Nov 1
  • 저널이슈번호
    23(21):6616-6628. doi: 10.1158/1078-0432.CCR-17-0310. Epub 2017 Jul 27.
  • 내용

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    Abstract

    Purpose: Camelid single-domain antibody-fragments (sdAb) have beneficial pharmacokinetic properties, and those targeted to HER2 can be used for imaging of HER2-overexpressing cancer. Labeled with a therapeutic radionuclide, they may be used for HER2-targeted therapy. Here, we describe the generation of a 131I-labeled sdAb as a theranostic drug to treat HER2-overexpressing cancer.Experimental Design: Anti-HER2 sdAb 2Rs15d was labeled with 131I using [131I]SGMIB and evaluated in vitro Biodistribution was evaluated in two HER2+ murine xenograft models by micro-SPECT/CT imaging and at necropsy, and under challenge with trastuzumab and pertuzumab. The therapeutic potential of [131I]SGMIB-2Rs15d was investigated in two HER2+ tumor mouse models. A single-dose toxicity study was performed in mice using unlabeled [127I]SGMIB-sdAb at 1.4 mg/kg. The structure of the 2Rs15d-HER2 complex was determined by X-ray crystallography.Results: [131I]SGMIB-2Rs15d bound specifically to HER2+ cells (Kd = 4.74 ± 0.39 nmol/L). High and specific tumor uptake was observed in both BT474/M1 and SKOV-3 tumor xenografted mice and surpassed kidney levels by 3 hours. Extremely low uptake values were observed in other normal tissues at all time points. The crystal structure revealed that 2Rs15d recognizes HER2 Domain 1, consistent with the lack of competition with trastuzumab and pertuzumab observed in vivo [131I]SGMIB-2Rs15d alone, or in combination with trastuzumab, extended median survival significantly. No toxicity was observed after injecting [127I]SGMIB-2Rs15d.Conclusions: These findings demonstrate the theranostic potential of [131I]SGMIB-2Rs15d. An initial scan using low radioactive [*I]SGMIB-2Rs15d allows patient selection and dosimetry calculations for subsequent therapeutic [131I]SGMIB-2Rs15d and could thereby impact therapy outcome on HER2+ breast cancer patients.

     

     

    Author information

    D'Huyvetter M1, De Vos J2,3, Xavier C2, Pruszynski M4, Sterckx YGJ5, Massa S5,6, Raes G5,6, Caveliers V2,7, Zalutsky MR8, Lahoutte T2,7, Devoogdt N2.

    1In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium. mdhuyvet@vub.ac.be.2In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.3Camel-IDS NV/SA, Brussels, Belgium.4Institute of Nuclear Chemistry and Technology, Warsaw, Poland.5Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.6Myeloid Cell Immunology Laboratory, VIB-UGent Center for Inflammation Research, Gent, Belgium.7Nuclear Medicine Department, UZ Brussel, Brussels, Belgium.8Department of Radiology, Duke University Medical Center, Durham, North Carolina.

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