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 1, * , In Cheul Jeung 2, * , Tae Woo Park 3 , Kyungmin Lee 1, 3 , Dong Gwang Lee 1, 3 , Young-Lai Cho 4 , Tae Sup Lee 5 , Hee-Jun Na 6 , Young-Jun Park 1 , Hee Gu Lee 1 , Mun Sik Jeong 7 , Kwang-Hee Bae 1 , Sang Chul Lee 1 , Hyo Jin Lee 8 , Young-Guen Kwon 9 , Hyo Jeong Hong 7 , Jang-Seong Kim 1 , Jeong-Ki Min 1, 3 1 Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea 2 Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea 3 Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea 4 Department of Chemistry, Dongguk University, Seoul, Republic of Korea 5 Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea 6 Scripps Korea Antibody Institute, Chuncheon, Republic of Korea 7 Department of Systems Immunology, College of Biomedical Science and Institute of Antibody Research, Kangwon National University, Chuncheon, Republic of Korea 8 Department of Internal Medicine and Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea 9 Department 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.