EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma

Jeong Won Lee, Rebecca L. Stone, Sun Joo Lee, Eun Ji Nam, Ju Won Roh, Alpa M. Nick, Hee Dong Han, Mian M.K. Shahzad, Hye Sun Kim, Lingegowda S. Mangala, Nicholas B. Jennings, Shenlan Mao, John Gooya, Dowdy Jackson, Robert L. Coleman, Anil K. Sood

Research output: Contribution to journalArticle

Abstract

Purpose: EphA2 overexpression is frequently observed in endometrial cancers and is predictive of poor clinical outcome. Here, we use an antibody drug conjugate (MEDI-547) composed of a fully human monoclonal antibody against both human and murine EphA2 (1C1) and the tubulin polymerization inhibitor monomethylauristatin F. Experimental Design: EphA2 expression was examined in endometrial cancer cell lines by Western blot. Specificity of MEDI-547 was examined by antibody degradation and internalization assays. Viability and apoptosis were investigated in endometrial cancer cell lines and orthotopic tumor models. Results: EphA2 was expressed in the Hec-1A and Ishikawa cells but was absent in the SPEC-2 cells. Antibody degradation and internalization assays showed that the antibody drug conjugate decreased EphA2 protein levels and was internalized in EphA2-positive cells (Hec-1A and Ishikawa). Moreover, in vitro cytotoxicity and apoptosis assays showed that the antibody drug conjugate decreased viability and increased apoptosis of Hec-1A and Ishikawa cells. In vivo therapy experiments in mouse orthotopic models with this antibody drug conjugate resulted in 86% to 88% growth inhibition (P < 0.001) in the orthotopic Hec-1A and Ishikawa models compared with controls. Moreover, the mice treated with this antibody drug conjugate had a lower incidence of distant metastasis compared with controls. The antitumor effects of the therapy were related to decreased proliferation and increased apoptosis of tumor and associated endothelial cells. Conclusions: The preclinical data for endometrial cancer treatment using MEDI-547 show substantial antitumor activity.

Original languageEnglish (US)
Pages (from-to)2562-2570
Number of pages9
JournalClinical Cancer Research
Volume16
Issue number9
DOIs
StatePublished - May 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Lee, J. W., Stone, R. L., Lee, S. J., Nam, E. J., Roh, J. W., Nick, A. M., Han, H. D., Shahzad, M. M. K., Kim, H. S., Mangala, L. S., Jennings, N. B., Mao, S., Gooya, J., Jackson, D., Coleman, R. L., & Sood, A. K. (2010). EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma. Clinical Cancer Research, 16(9), 2562-2570. https://doi.org/10.1158/1078-0432.CCR-10-0017