Optimization of IGF-1R SPECT/CT imaging using 111In-labeled F(ab')2 and Fab fragments of the monoclonal antibody R1507

S. Heskamp, H. van Laarhoven, J. Molkenboer-Kuenen, W. Bouwman, W. van der Graaf, W. Oyen and O. Boerman

Department of Medical Oncology and ‡Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre , Nijmegen, The Netherlands.
Aug, 2012



The insulin-like growth factor 1 receptor (IGF-1R) is a potential new target for the treatment of breast cancer. Patients with breast cancer lesions that express IGF-1R may benefit from treatment with anti-IGF-1R antibodies. IGF-1R expression can be visualized using radiolabeled R1507, a monoclonal antibody directed against IGF-1R. However, antibodies clear slowly from the circulation, resulting in low tumor-to-background ratios early after injection. Therefore, we aimed to accelerate targeting of IGF-1R using radiolabeled R1507 F(ab')2 and Fab fragments. In vitro, immunoreactivity, binding affinity and internalization of R1507 IgG, F(ab')2 and Fab were determined using the triple negative IGF-1R-expressing breast cancer cell line SUM149. In vivo, pharmacokinetics of (111)In-labeled R1507 IgG, F(ab')2 and Fab were studied in mice bearing subcutaneous SUM149 xenografts. SPECT/CT images were acquired and the biodistribution was measured ex vivo. The in vitro binding characteristics of radiolabeled R1507 IgG and F(ab')2 were comparable, whereas the affinity of Fab fragments was significantly lower (Kd: 0.6 nM, 0.7 nM and 3.0 nM for R1507 IgG, F(ab')2 and Fab, respectively). Biodistribution studies showed that the maximum tumor uptake of (111)In-R1507 IgG, F(ab')2 and Fab was 31.8\% ID/g (72 h p.i.), 10.0\% ID/g (6 h p.i.), and 1.8\% ID/g (1 h p.i.), respectively. However, maximal tumor-to-blood ratios for F(ab')2 (24 h p.i.: 7.5) were more than twice as high as those obtained with R1507 (72 h p.i.: 2.8) and Fab (6 h p.i.: 2.8). Injection of an excess of unlabeled R1507 significantly reduced tumor uptake, suggesting that the uptake of R1507 IgG and F(ab')2 was specific for IGF-1R, while the major fraction of the tumor uptake of Fab was nonspecific. IGF-1R-expressing xenografts were visualized with (111)In-F(ab')2 SPECT/CT as early as 6 h p.i., while with R1507 IgG, the tumor could be visualized after 24 h. No specific targeting was observed with (111)In-Fab. (111)In-F(ab')2 fragments showed improved targeting of IGF-1R expressing tumors. Tumor-to-blood ratios were twice as high as those obtained with (111)In-R1507, and adequate tumor targeting on SPECT/CT images was observed as early as 6 h p.i. For individualization and optimization of IGF-1R targeted therapy, (111)In-F(ab')2 may be the tracer of choice.