Claudia Theresa Mendler1,2, Annette Feuchtinger3, Irina Heid4, Michaela Aichler3, Calogero D'Alessandria5, Sabine Pirsig5, Birgit Blechert5, Hans-Jürgen Wester6, Rickmer Braren4, Axel Walch3, Arne Skerra2, Markus Schwaiger5. 1. Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany claudia.mendler@wzw.tum.de. 2. Munich Center for Integrated Protein Science (CIPS-M) and Lehrstuhl für Biologische Chemie, Technische Universität München, Freising (Weihenstephan), Germany. 3. Research Unit Analytical Pathology, Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany. 4. Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, München, Germany; and. 5. Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany. 6. Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany.
Abstract
Antibodies have become an established treatment modality in cancer therapy during the last decade. However, these treatments often suffer from an insufficient and heterogeneous response despite validated antigen or target receptor expression in the tumor. In fact, therapeutic success depends on both the presence of the tumor antigen and its accessibility by the antibody. In search of a suitable preclinical animal model to evaluate the mechanisms of tumor heterogeneity and hemodynamics, we characterized two exemplary non-Hodgkin lymphoma subtypes with comparable CD20 expression and metabolism, SUDHL-4 and Granta-519, using multimodal imaging techniques. METHODS: To investigate in vivo biodistribution, two differently modified αCD20 antigen-binding fragments (Fab), prepared by PASylation with a 200-residue polypeptide tag comprising Pro, Ala, and Ser (PAS200) and by fusion with an albumin-binding domain (ABD), were radiolabeled with 125I and intravenously injected into immunocompromised mice bearing corresponding xenografts. RESULTS: Validation with 18F-FDG revealed a similar distribution in vital tumor tissue 1 h after injection. However, large differences in tumor uptake were observed when the CD20-specific radiotracers 125I-Fab-ABD and 125I-Fab-PAS200 were applied (respective percentages injected dose per gram at 24 h after injection: 12.3 and 2.4 for Granta-519 vs. 5.8 and 1.2 for SUDHL-4). Three-dimensional light-sheet fluorescence microscopy with Cy5-Fab-PAS200 confirmed better tracer extravasation in the Granta-519 tumors. Moreover, dynamic contrast-enhanced (DCE) MRI revealed significantly reduced perfusion in the SUDHL-4 tumors. CONCLUSION: Tracer uptake was highly dependent on local tumor perfusion and Fab permeation in the SUDHL-4 and Granta-519 tumors. Thus, the SUDHL-4 xenograft offers an excellent model for investigating the influence of therapies affecting tumor angiogenesis.
Antibodies have become an established treatment modality in cancer therapy during the last decade. However, these treatments often suffer from an insufficient and heterogeneous response despite validated antigen or target receptor expression in the tumor. In fact, therapeutic success depends on both the presence of the tumor antigen and its accessibility by the antibody. In search of a suitable preclinical animal model to evaluate the mechanisms of tumor heterogeneity and hemodynamics, we characterized two exemplary non-Hodgkin lymphoma subtypes with comparable CD20 expression and metabolism, SUDHL-4 and Granta-519, using multimodal imaging techniques. METHODS: To investigate in vivo biodistribution, two differently modified αCD20 antigen-binding fragments (Fab), prepared by PASylation with a 200-residue polypeptide tag comprising Pro, Ala, and Ser (PAS200) and by fusion with an albumin-binding domain (ABD), were radiolabeled with 125I and intravenously injected into immunocompromised mice bearing corresponding xenografts. RESULTS: Validation with 18F-FDG revealed a similar distribution in vital tumor tissue 1 h after injection. However, large differences in tumor uptake were observed when the CD20-specific radiotracers 125I-Fab-ABD and 125I-Fab-PAS200 were applied (respective percentages injected dose per gram at 24 h after injection: 12.3 and 2.4 for Granta-519 vs. 5.8 and 1.2 for SUDHL-4). Three-dimensional light-sheet fluorescence microscopy with Cy5-Fab-PAS200 confirmed better tracer extravasation in the Granta-519 tumors. Moreover, dynamic contrast-enhanced (DCE) MRI revealed significantly reduced perfusion in the SUDHL-4 tumors. CONCLUSION: Tracer uptake was highly dependent on local tumor perfusion and Fab permeation in the SUDHL-4 and Granta-519 tumors. Thus, the SUDHL-4 xenograft offers an excellent model for investigating the influence of therapies affecting tumor angiogenesis.
Authors: Irina Heid; Marija Trajkovic-Arsic; Fabian Lohöfer; Georgios Kaissis; Felix N Harder; Moritz Mayer; Geoffrey J Topping; Friderike Jungmann; Barbara Crone; Moritz Wildgruber; Uwe Karst; Lucia Liotta; Hana Algül; Hsi-Yu Yen; Katja Steiger; Wilko Weichert; Jens T Siveke; Marcus R Makowski; Rickmer F Braren Journal: Eur J Nucl Med Mol Imaging Date: 2022-09-08 Impact factor: 10.057
Authors: Alexander Wurzer; Christof Seidl; Alfred Morgenstern; Frank Bruchertseifer; Markus Schwaiger; Hans-Jürgen Wester; Johannes Notni Journal: Chemistry Date: 2017-09-14 Impact factor: 5.236