title: 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.
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.
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: In Cheul
authors.initials: IC
authors.lastname: Jeung
authors.affiliation: Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Park
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea.
authors.forename: Kyungmin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea.
authors.forename: Dong Gwang
authors.initials: DG
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Dongguk University, Seoul, Republic of Korea.
authors.forename: Young-Lai
authors.initials: YL
authors.lastname: Cho
authors.affiliation: Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Tae Sup
authors.initials: TS
authors.lastname: Lee
authors.affiliation: Scripps Korea Antibody Institute, Chuncheon, Republic of Korea.
authors.forename: Hee-Jun
authors.initials: HJ
authors.lastname: Na
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Hee Gu
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Systems Immunology, College of Biomedical Science and Institute of Antibody Research, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: Mun Sik
authors.initials: MS
authors.lastname: Jeong
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Kwang-Hee
authors.initials: KH
authors.lastname: Bae
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Sang Chul
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine and Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
authors.affiliation: Department of Systems Immunology, College of Biomedical Science and Institute of Antibody Research, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Hong
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Jang-Seong
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea.
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Min
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry*; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D043169:Endostatins / Q000737:chemistry*; D006023:Glycoproteins / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D043169:Endostatins; D006023:Glycoproteins; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C047052:tumor-associated antigen 72; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: angiogenesis inhibitors; colorectal carcinoma; endostatin; tumor-associated glycoprotein-72; vascular endothelial growth factor