Therapeutic Efficacy of C-Kit-Targeted Radioimmunotherapy Using 90Y-Labeled Anti-C-Kit Antibodies in a Mouse Model of Small Cell Lung Cancer |
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| Authors: | Chisato Yoshida Atsushi B Tsuji Hitomi Sudo Aya Sugyo Tatsuya Kikuchi Mitsuru Koizumi Yasushi Arano Tsuneo Saga |
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| Institution: | 1. Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.; 2. Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.; 3. Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.; University of Navarra, Spain, |
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| Abstract: | Small cell lung cancer (SCLC) is an aggressive tumor and prognosis remains poor. Therefore, the development of more effective therapy is needed. We previously reported that high levels of an anti-c-kit antibody (12A8) accumulated in SCLC xenografts. In the present study, we evaluated the efficacy of two antibodies (12A8 and 67A2) for radioimmunotherapy (RIT) of an SCLC mouse model by labeling with the 90Y isotope.Methods
111In- or 125I-labeled antibodies were evaluated in vitro by cell binding, competitive inhibition and cellular internalization assays in c-kit-expressing SY cells and in vivo by biodistribution in SY-bearing mice. Therapeutic efficacy of 90Y-labeled antibodies was evaluated in SY-bearing mice upto day 28 and histological analysis was conducted at day 7.Results111In]12A8 and 111In]67A2 specifically bound to SY cells with high affinity (8.0 and 1.9 nM, respectively). 67A2 was internalized similar to 12A8. High levels of 111In]12A8 and 111In]67A2 accumulated in tumors, but not in major organs. 111In]67A2 uptake by the tumor was 1.7 times higher than for 111In]12A8. 90Y]12A8, but not 90Y]67A2, suppressed tumor growth in a dose-dependent manner. Tumors treated with 3.7 MBq of 90Y]12A8, and 1.85 and 3.7 MBq of 90Y]67A2 (absorbed doses were 21.0, 18.0 and 35.9 Gy, respectively) almost completely disappeared approximately 2 weeks after injection, and regrowth was not observed except for in one mouse treated with 1.85 MBq 90Y]67A2. The area of necrosis and fibrosis increased depending on the RIT effect. Apoptotic cell numbers increased with increased doses of 90Y]12A8, whereas no dose-dependent increase was observed following 90Y]67A2 treatment. Body weight was temporarily reduced but all mice tolerated the RIT experiments well.ConclusionTreatment with 90Y]12A8 and 90Y]67A2 achieved a complete therapeutic response when SY tumors received an absorbed dose greater than 18 Gy and thus are promising RIT agents for metastatic SCLC cells at distant sites. |
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