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Dransfield, Daniel T.; Cohen, Edward H.; Chang, Qing; Sparrow, Lindsay G.; Bentley, John D.; Dolezal, Olan; Xiao, Xiaowen; Peat, Thomas S.; Newman, Janet; Pilling, Patricia A.; Phan, Tram; Priebe, Ilka; Brierley, Gemma V.; Kastrapeli, Niksa; Kopacz, Kris; Martik, Diana; Wassaf, Dina; Rank, Douglas; Conley, Greg; Huang, Yan; Adams, Timothy E.; Cosgrove, Leah

A Human Monoclonal Antibody against Insulin-Like Growth Factor-II Blocks the Growth of Human Hepatocellular Carcinoma Cell Lines In vitro and In vivo

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  • Media type: E-Article
  • Title: A Human Monoclonal Antibody against Insulin-Like Growth Factor-II Blocks the Growth of Human Hepatocellular Carcinoma Cell Lines In vitro and In vivo
  • Contributor: Dransfield, Daniel T.; Cohen, Edward H.; Chang, Qing; Sparrow, Lindsay G.; Bentley, John D.; Dolezal, Olan; Xiao, Xiaowen; Peat, Thomas S.; Newman, Janet; Pilling, Patricia A.; Phan, Tram; Priebe, Ilka; Brierley, Gemma V.; Kastrapeli, Niksa; Kopacz, Kris; Martik, Diana; Wassaf, Dina; Rank, Douglas; Conley, Greg; Huang, Yan; Adams, Timothy E.; Cosgrove, Leah
  • Published: American Association for Cancer Research (AACR), 2010
  • Published in: Molecular Cancer Therapeutics, 9 (2010) 6, Seite 1809-1819
  • Language: English
  • DOI: 10.1158/1535-7163.mct-09-1134
  • ISSN: 1538-8514; 1535-7163
  • Origination:
  • Footnote:
  • Description: Abstract Elevated expression of insulin-like growth factor-II (IGF-II) is frequently observed in a variety of human malignancies, including breast, colon, and liver cancer. As IGF-II can deliver a mitogenic signal through both IGF-IR and an alternately spliced form of the insulin receptor (IR-A), neutralizing the biological activity of this growth factor directly is a potential alternative option to IGF-IR–directed agents. Using a Fab-displaying phage library and a biotinylated precursor form of IGF-II (1–104 amino acids) as a target, we isolated Fabs specific for the E-domain COOH-terminal extension form of IGF-II and for mature IGF-II. One of these Fabs that bound to both forms of IGF-II was reformatted into a full-length IgG, expressed, purified, and subjected to further analysis. This antibody (DX-2647) displayed a very high affinity for IGF-II/IGF-IIE (KD value of 49 and 10 pmol/L, respectively) compared with IGF-I (∼10 nmol/L) and blocked binding of IGF-II to IGF-IR, IR-A, a panel of insulin-like growth factor–binding proteins, and the mannose-6-phosphate receptor. A crystal complex of the parental Fab of DX-2647 bound to IGF-II was resolved to 2.2 Å. DX-2647 inhibited IGF-II and, to a lesser extent, IGF-I–induced receptor tyrosine phosphorylation, cellular proliferation, and both anchorage-dependent and anchorage-independent colony formation in various cell lines. In addition, DX-2647 slowed tumor progression in the Hep3B xenograft model, causing decreased tumoral CD31 staining as well as reduced IGF-IIE and IGF-IR phosphorylation levels. Therefore, DX-2647 offers an alternative approach to targeting IGF-IR, blocking IGF-II signaling through both IGF-IR and IR-A. Mol Cancer Ther; 9(6); 1809–19. ©2010 AACR.
  • Access State: Open Access