Oncotarget

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Extension of the in vivo half-life of endostatin and its improved anti-tumor activities upon fusion to a humanized antibody against tumor-associated glycoprotein 72 in a mouse model of human colorectal carcinoma

Sang-Hyun Lee _, In Cheul Jeung, Tae Woo Park, Kyungmin Lee, Dong Gwang Lee, Young-Lai Cho, Tae Sup Lee, Hee-Jun Na, Young-Jun Park, Hee Gu Lee, Mun Sik Jeong, Kwang-Hee Bae, Sang Chul Lee, Hyo Jin Lee, Young-Guen Kwon, Hyo Jeong Hong, Jang-Seong Kim and Jeong-Ki Min

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Oncotarget. 2015; 6:7182-7194. https://doi.org/10.18632/oncotarget.3121

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Abstract

Sang-Hyun Lee1,*, In Cheul Jeung2,*, Tae Woo Park3, Kyungmin Lee1,3, Dong Gwang Lee1,3, Young-Lai Cho4, Tae Sup Lee5, Hee-Jun Na6, Young-Jun Park1, Hee Gu Lee1, Mun Sik Jeong7, Kwang-Hee Bae1, Sang Chul Lee1, Hyo Jin Lee8, Young-Guen Kwon9, Hyo Jeong Hong7, Jang-Seong Kim1, Jeong-Ki Min1,3

1Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea

2Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

3Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea

4Department of Chemistry, Dongguk University, Seoul, Republic of Korea

5Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea

6Scripps Korea Antibody Institute, Chuncheon, Republic of Korea

7Department of Systems Immunology, College of Biomedical Science and Institute of Antibody Research, Kangwon National University, Chuncheon, Republic of Korea

8Department of Internal Medicine and Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea

9Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea

*These authors have contributed equally to this work

Correspondence to:

Jeong-Ki Min, e-mail: jekmin@kribb.re.kr

Jang-Seong Kim, e-mail: jangskim@kribb.re.kr

Hyo Jeong Hong, e-mail: hjhong@kangwon.ac.kr

Keywords: Angiogenesis inhibitors, Colorectal carcinoma, Endostatin, Tumor-associated glycoprotein-72, Vascular Endothelial Growth Factor

Received: September 12, 2014     Accepted: January 09, 2015     Published: January 22, 2015

ABSTRACT

Endostatin is an endogenous angiogenesis inhibitor that exhibits potential anti-tumor efficacy in various preclinical animal models. However, its relatively short in vivo half-life and the long-term, frequent administration of high doses limit its widespread clinical use. In this study, we evaluated whether a fusion protein of murine endostatin (mEndo) to a humanized antibody against tumor-associated glycoprotein 72 (TAG-72), which is highly expressed in several human tumor tissues including colon cancer, can extend the serum half-life and improve the anti-tumor efficacy of endostatin by targeted delivery to the tumor mass. The fusion protein (3E8-mEndo) and mEndo showed improved anti-angiogenic activity in vitro and in vivo, predominantly by interfering with pro-angiogenic signaling triggered by vascular endothelial growth factor (VEGF). Moreover, in mice treated with 3E8-mEndo, we observed a markedly prolonged serum half-life and significantly inhibited tumor growth. The improved anti-tumor activity of 3E8-mEndo can be partially explained by increased local concentration in the tumor mass due to targeted delivery of 3E8-mEndo to implanted colon tumors. Collectively, our data clearly indicate that tumor-targeting antibody fusions to endostatin are a powerful strategy that improves the poor pharmacokinetic profile and anti-tumor efficacy of endostatin.


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