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Bevacizumab radioimmunotherapy (RIT) with accelerated blood clearance using the avidin chase Ryan Yudistiro, Hirofumi Hanaoka, Natsumi Katsumata, Aiko Yamaguchi, and Yoshito Tsushima Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00027 • Publication Date (Web): 07 May 2018 Downloaded from http://pubs.acs.org on May 8, 2018
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Molecular Pharmaceutics
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Bevacizumab radioimmunotherapy (RIT) with accelerated blood clearance using the avidin chase
Ryan Yudistiro1, Hirofumi Hanaoka2,*, Natsumi Katsumata1, Aiko Yamaguchi2, Yoshito Tsushima1,3 1. Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi 371-8511, Japan 2. Department of Bioimaging Information Analysis, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi 371-8511, Japan 3. Research Program for Diagnostic and Molecular Imaging, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), 3-3922 Showa, Maebashi 371-8511, Japan
*Corresponding author: Dr. Hirofumi Hanaoka, Department of Bioimaging Information Analysis, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371-8511 Japan. Tel.: +81-27-220-8403; Fax: +81-27-220-8409. Email:
[email protected] ACS Paragon Plus Environment
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Molecular Pharmaceutics
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ABSTRACT The overexpression of vascular endothelial growth factor (VEGF) in varying types of solid tumor renders radioimmunotherapy (RIT) with the anti-VEGF antibody bevacizumab (BV) a promising treatment. However, the slow blood clearance of BV, which may increase the occurrence risk of hematotoxicity, hinders the application of BV-RIT. Using the avidin chase is a long-known blood clearance enhancement strategy for biotinylated-mAb. To enhance RIT efficacy by increasing the radioactivity dose, we evaluated the ability of avidin to accelerate the blood clearance of yttrium-90 (90Y)-labeled biotinylated BV (90YBt-BV) in a xenograft mouse model of triple-negative breast cancer (TNBC). The biodistribution study in the TNBC xenograft mice confirmed the high and specific tumor accumulation of the indium-111 (111In)-BV. The blood clearance enhancement effect of the avidin chase was demonstrated in the normal mouse studies with
111
In-Bt-BV. In the
subsequent biodistribution studies with the tumor-bearing mice, an optimized dose of avidin injection subsequent to
111
In-Bt-BV with an appropriate biotin valency successfully
accelerated the blood clearance of
111
In-Bt-BV without impairing its tumor accumulation
level. The avidin chase enabled an increase in the maximum tolerated dose of 90Y-Bt-BV to twice as much as that of 90Y-BV in tumor-bearing mice and thereby significantly improved the therapeutic effect of
90
Y-Bt-BV compared to
underscored the potential usefulness of
90
90
Y-BV (p4).
The biodistribution of the radioactivity of
Figure 4.
111
In-BV or
avidin in normal mice. A: At 24 h after the injection of
111
In-Bt(n)-BV with
In-BV or
(mean±SD, n>3). Significant differences were observed between 111
111
In-BV (*p
