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Multimodality Imaging of IL-18–Binding Protein-Fc Therapy of Experimental Lung Metastasis

Authors' Affiliations: ¹ The Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California and ² Departments of Radiology and Medical Physics, School of Medicine and Public Health, University of Wisconsin - Madison, Madison, Wisconsin

Requests for reprints: Xiaoyuan Chen, The Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, P095, Stanford, CA 94305-5484. Phone: 650-725-0950; Fax: 650-736-7925; E-mail: shawchen{at}stanford.edu.

Purpose: Interleukin (IL)-18 plays important roles in cancer progression and metastasis. The goal of this study is to identify cell lines that are most sensitive to stand alone IL-18–binding protein (IL-18bp)-Fc treatment, to study the pharmacokinetics and tumor targeting efficiency of IL-18bp-Fc, and to evaluate the efficacy of IL-18bp-Fc in treating breast cancer experimental lung metastasis by multimodality imaging.

Experimental Design: Reverse transcription-PCR, ELISA, and other cell-based assays were done on murine 4T1, CT-26, and B16F10 cells. The most IL-18bp-Fc–sensitive 4T1 cells were stably transfected with firefly luciferase (fLuc) and injected i.v. into female BALB/C mice to establish the experimental lung metastasis model. Tumor targeting efficiency and pharmacokinetics of IL-18bp-Fc was assessed by ⁶⁴Cu-DOTA-IL-18bp-Fc positron emission tomography (PET) and biodistribution studies. Two groups of fLuc-4T1 experimental lung metastasis tumor-bearing mice were each given saline or IL-18bp-Fc (1 mg/kg) daily i.p. Bioluminescence imaging, ¹⁸F-FDG PET, and computed tomography scans were done to evaluate the treatment efficacy. Ex vivo experiments were also carried out to validate the imaging results.

Results: IL-18bp-Fc had high and specific accumulation in the fLuc-4T1 lung metastasis tumor as evidenced by both PET and biodistribution studies. Bioluminescence imaging, ¹⁸F-FDG PET, and computed tomography scans all revealed that IL-18bp-Fc treatment was effective in inhibiting the lung metastasis tumor progression, validated by ex vivo examination of the lung.

Conclusions: IL-18bp-Fc therapy can inhibit 4T1 breast cancer experimental lung metastasis. Noninvasive multimodality molecular imaging is a powerful tool for evaluating the tumor targeting efficiency/pharmacokinetics of the drug and effective monitoring of the therapeutic response.