Optimization of IGF-1R SPECT/CT Imaging Using 111In-Labeled F(ab鈥?2 and Fab Fragments of the Monoclonal Antibody R1507

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• 作者：Sandra Heskamp ; Hanneke W. M. van Laarhoven ; Janneke D. M. Molkenboer-Kuenen ; Wilbert H. Bouwman ; Winette T. A. van der Graaf ; Wim J. G. Oyen ; Otto C. Boerman
• 刊名：Molecular Pharmaceutics
• 出版年：2012
• 出版时间：August 6, 2012
• 年：2012
• 卷：9
• 期：8
• 页码：2314-2321
• 全文大小：382K
• 年卷期：v.9,no.8(August 6, 2012)
• ISSN：1543-8392

文摘

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鈥?₂ and Fab fragments. In vitro, immunoreactivity, binding affinity and internalization of R1507 IgG, F(ab鈥?₂ and Fab were determined using the triple negative IGF-1R-expressing breast cancer cell line SUM149. In vivo, pharmacokinetics of ¹¹¹In-labeled R1507 IgG, F(ab鈥?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鈥?₂ were comparable, whereas the affinity of Fab fragments was significantly lower (K_d: 0.6 nM, 0.7 nM and 3.0 nM for R1507 IgG, F(ab鈥?₂ and Fab, respectively). Biodistribution studies showed that the maximum tumor uptake of ¹¹¹In-R1507 IgG, F(ab鈥?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鈥?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鈥?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 ¹¹¹In-F(ab鈥?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 ¹¹¹In-Fab. ¹¹¹In-F(ab鈥?₂ fragments showed improved targeting of IGF-1R expressing tumors. Tumor-to-blood ratios were twice as high as those obtained with ¹¹¹In-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, ¹¹¹In-F(ab鈥?₂ may be the tracer of choice.

Keywords:

IGF-1R; F(ab鈥?₂; Fab; antibody; SPECT; breast cancer