Tumor Uptake of Anti-CD20 Fabs Depends on Tumor Perfusion
| Autor: | Axel Walch, Michaela Aichler, Hans-Jürgen Wester, Birgit Blechert, Claudia T Mendler, Rickmer Braren, Calogero D'Alessandria, Arne Skerra, Sabine Pirsig, Markus Schwaiger, Annette Feuchtinger, Irina Heid |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Receptor expression Permeability Immunoglobulin Fab Fragments Mice 03 medical and health sciences 0302 clinical medicine Antigen Cell Line Tumor medicine Animals Humans Radiology Nuclear Medicine and imaging CD20 biology Chemistry Antigens CD20 medicine.disease Tumor antigen Extravasation Lymphoma Protein Transport Cell Transformation Neoplastic 030104 developmental biology 030220 oncology & carcinogenesis Blood Circulation Microvessels biology.protein Cancer research Antibody Perfusion |
| Zdroj: | Journal of Nuclear Medicine. 57:1971-1977 |
| ISSN: | 2159-662X 0161-5505 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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