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Fujiwara K, Koyama K, Suga K, et al. A (90)Y-labelled anti-ROBO1 monoclonal antibody exhibits antitumour activity against hepatocellular carcinoma xenografts during ROBO1-targeted radioimmunotherapy. EJNMMI Res. 2014;4:29doi: 10.1186/s13550-014-0029-3.
Fujiwara, K., Koyama, K., Suga, K., Ikemura, M., Saito, Y., Hino, A., Iwanari, H., Kusano-Arai, O., Mitsui, K., Kasahara, H., Fukayama, M., Kodama, T., Hamakubo, T., & Momose, T. (2014). A (90)Y-labelled anti-ROBO1 monoclonal antibody exhibits antitumour activity against hepatocellular carcinoma xenografts during ROBO1-targeted radioimmunotherapy. EJNMMI research, 429. https://doi.org/10.1186/s13550-014-0029-3
Fujiwara, Kentaro, et al. "A (90)Y-labelled anti-ROBO1 monoclonal antibody exhibits antitumour activity against hepatocellular carcinoma xenografts during ROBO1-targeted radioimmunotherapy." EJNMMI research vol. 4 (2014): 29. doi: https://doi.org/10.1186/s13550-014-0029-3
Fujiwara K, Koyama K, Suga K, Ikemura M, Saito Y, Hino A, Iwanari H, Kusano-Arai O, Mitsui K, Kasahara H, Fukayama M, Kodama T, Hamakubo T, Momose T. A (90)Y-labelled anti-ROBO1 monoclonal antibody exhibits antitumour activity against hepatocellular carcinoma xenografts during ROBO1-targeted radioimmunotherapy. EJNMMI Res. 2014 Jun 01;4:29. doi: 10.1186/s13550-014-0029-3. eCollection 2014. PMID: 25006547; PMCID: PMC4077627.
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EJNMMI Res. 2014 Jun 01;4:29. doi: 10.1186/s13550-014-0029-3. eCollection 2014.

A (90)Y-labelled anti-ROBO1 monoclonal antibody exhibits antitumour activity against hepatocellular carcinoma xenografts during ROBO1-targeted radioimmunotherapy.

EJNMMI research

Kentaro Fujiwara, Keitaro Koyama, Kosuke Suga, Masako Ikemura, Yasutaka Saito, Akihiro Hino, Hiroko Iwanari, Osamu Kusano-Arai, Kenichi Mitsui, Hiroyuki Kasahara, Masashi Fukayama, Tatsuhiko Kodama, Takao Hamakubo, Toshimitsu Momose

Affiliations

  1. Department of Radiology, Graduate School of Medicine, The University of Tokyo, 3-1, Hongo 7-Chome, Bunkyo-ku 113-8655, Tokyo, Japan.
  2. SANKYO LABO SERVICE Co., Ltd., 2-13-16, Nishiichinoe, Edogawaku 132-0023, Tokyo, Japan.
  3. Department of Pathology, Graduate School of Medicine, The University of Tokyo, 3-1, Hongo 7-Chome, Bunkyo-ku 113-8655, Tokyo, Japan.
  4. FUJIFILM RI Pharma Co., Ltd., 453-1, Shimo-Okura, Matsuo-Machi, Sammu-City 289-1592, Chiba, Japan.
  5. Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku 153-8904, Tokyo, Japan.
  6. Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku 153-8904, Tokyo, Japan ; Institute of Immunology Co., Ltd., 1-1-1 Koraku, Bunkyo 112-0004, Tokyo, Japan.
  7. Department of Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku 153-8904, Tokyo, Japan.

PMID: 25006547 PMCID: PMC4077627 DOI: 10.1186/s13550-014-0029-3

Abstract

BACKGROUND: ROBO1 is a membrane protein that functions in axon guidance. ROBO1 contributes to tumour metastasis and angiogenesis and may have potential as a target protein of immunotherapy because ROBO1 is specifically expressed at high levels in hepatocellular carcinoma. In this study, we examined biodistribution and radioimmunotherapy (RIT) using a radioisotope-labelled anti-ROBO1 monoclonal antibody (MAb) against hepatocellular carcinoma models.

METHODS: ROBO1-positive HepG2 human hepatocellular carcinoma xenograft nude mice were used in this study. We conjugated anti-ROBO1 MAb with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and the conjugates were labelled with (111)In and (90)Y. To study biodistribution, the (111)In-DOTA-anti-ROBO1 MAb was injected into HepG2 xenograft mice via the tail vein. To evaluate any antitumour effect, a RIT study was performed, and the (90)Y-DOTA-anti-ROBO1 MAb was injected via the tail vein. Tumour volume, mouse weight, and blood cell count were periodically measured throughout the experiments. The tumours and organs of mice were collected, and a histopathological analysis was carried out.

RESULTS: The tumour uptake of (111)In-anti-ROBO1 MAb in HepG2 xenograft mice was 15.0% ± 0.69% injected dose per gram at 48 h after injection. Immunotherapy with cold-anti-ROBO1 MAb (70 μg) did not cause a significant antitumour effect. RIT with 6.7 MBq of (90)Y-anti-ROBO1 MAb caused significant tumour growth suppression. Transient body weight loss and bone-marrow suppression were observed. Histopathological analyses of tumours revealed the fatal degeneration of tumour cells, significant reduction of the Ki-67 index, and an increase of the apoptosis index. Normal organs showed no significant injury, but a transient reduction of hematopoietic cells was observed in the spleen and in the sternal bone marrow.

CONCLUSIONS: These results suggest that RIT with (90)Y-anti-ROBO1 MAb is a promising treatment for ROBO1-positive hepatocellular carcinoma.

Keywords: 90Y; Biodistribution; Hepatocellular carcinoma; ROBO1; Radioimmunotherapy

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