RT Journal Article
SR Electronic
T1 Tumor Uptake of Anti-CD20 Fabs Depends on Tumor Perfusion
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1971
OP 1977
DO 10.2967/jnumed.116.176784
VO 57
IS 12
A1 Claudia Theresa Mendler
A1 Annette Feuchtinger
A1 Irina Heid
A1 Michaela Aichler
A1 Calogero D’Alessandria
A1 Sabine Pirsig
A1 Birgit Blechert
A1 Hans-Jürgen Wester
A1 Rickmer Braren
A1 Axel Walch
A1 Arne Skerra
A1 Markus Schwaiger
YR 2016
UL http://jnm.snmjournals.org/content/57/12/1971.abstract
AB 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.