Targeted delivery of an antibody-mutant human endostatin fusion protein results in enhanced antitumor efficacy

Seung Uon Shin, Hyun Mi Cho, Jaime Merchan, Jin Zhang, Krisztina Kovacs, Yawu Jing, Sundaram Ramakrishnan, Joseph D. Rosenblatt

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

The antiangiogenic protein endostatin showed considerable preclinical antitumor activity, but limited efficacy in phase I/II trials. Prior studies using an anti-HER2 antibody-murine endostatin fusion showed enhanced antitumor activity compared to anti-HER2 antibody or endostatin given alone, or in combination. We have generated two anti-HER2 human endostatin fusion proteins by fusing either wild-type or a mutant human endostatin (huEndo-P125A) to the 3′ end of a humanized anti-HER2 IgG3 antibody. Antitumor efficacy was examined in murine and human breast tumor models. HuEndo-P125A antibody fusion protein (αHER2-huEndo-P125A) inhibited VEGF and bFGF induced endothelial cell proliferation, and tube formation in vitro, more efficiently than endostatin alone, wild-type endostatin fusion protein (αHER2-huEndo), or parental anti-HER2 antibody (αHER2 IgG3). Wild-type and mutant human endostatin was rapidly cleared from serum in mice (T1/22 = 2.0-2.1 hours), whereas αHER2-huEndo fusion proteins had a significantly prolonged half-life (T1/22 = 40.7-57.5 hours). Treatment of SK-BR-3 breast cancer xenografts with anti-HER2 IgG3-huEndo-P125A fusion resulted in greater inhibition of tumor growth and improved survival, compared to treatment with either αHER2 IgG3 (P = 0.025), human endostatin (P = 0.034), or anti-HER2 IgG3-huEndo (P = 0.016). αHER2-huEndo-P125A specifically inhibited tumors expressing HER2 in mice simultaneously implanted with murine mammary tumor EMT6 cells and with EMT6 engineered to express HER2 antigen (EMT6-HER2). Targeting of endostatin using antibody fusion proteins could improve antitumor activity of either anti-HER2 antibody and/or endostatin and provides a versatile approach that could be applied to other tumor targets with alternative antibody specificities.

Original languageEnglish (US)
Pages (from-to)603-614
Number of pages12
JournalMolecular cancer therapeutics
Volume10
Issue number4
DOIs
StatePublished - Apr 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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