Preclinical molecular imaging to study the biodistribution of antibody derivatives in oncology

Jan Feije Warnders

    Research output: ThesisThesis fully internal (DIV)

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    The successful use of antibodies for the treatment of cancer has spurred the interest in the development of antibody derivatives, such as Bispecific T-cell engagers (BiTEs) and nanobody constructs. Molecular imaging may facilitate drug development of BiTEs and nanobody constructs and decision making throughout this process. By radiolabeling antibody derivatives with zirconium-89 (89Zr), their pharmacokinetic profile, organ distribution and tumor uptake can be studied non-invasively by 89Zr-PET. In addition, fluorescent labeling of antibody derivatives enables studying their distribution within tumors, at a microscopic level. Furthermore, injecting fluorescently labeled nanobodies, that target tumor tissue, may facilitate real-time visualization of tumors in an intraoperative setting.
    Given the overexpression on a variety of tumor cells, EpCAM, CEA and HER3 are interesting targets for BiTEs and nanobodies. In order to facilitate their drug development, an anti-EpCAM BiTE, anti-CEA BiTE and anti-HER3 nanobody construct have been radiolabeled with 89Zr. 89Zr-PET was used to study their organ distribution and tumor uptake. Radiolabeling of the anti-CEA BiTE was additionally used to study its in vivo integrity in serum and tumors. The obtained preclinical data have been used to setup a clinical trial, in which 89Zr-PET is used to study organ distribution and tumor uptake of this anti-CEA BiTE in cancer patients.
    This thesis also describes the selection and preclinical evaluation of anti-HER2 nanobodies, fluorescently labeled with IRDye 800CW. Shortly after injection, the best performing nanobody enabled tumor visualization of HER2-positive tumors using optical imaging. It accumulated quicker in these tumors than 800CW-trastuzumab, a fluorescently labeled anti-HER2 drug.
    Translated title of the contributionPreklinische moleculaire beeldvorming om de biodistributie te bestuderen van antilichaam derivaten binnen de oncologie
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    • Kosterink, Jos, Supervisor
    • de Vries, Liesbeth, Supervisor
    • Lub-de Hooge, Marjolijn, Co-supervisor
    • Hendrikse, N. H., Assessment committee, External person
    • Elsinga, Philip, Assessment committee
    • Gietema, Jourik, Assessment committee
    Award date4-Jul-2018
    Place of Publication[Groningen]
    Publication statusPublished - 2018

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