title: EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jeong-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stone
authors.forename: Sun Joo
authors.initials: SJ
authors.lastname: Lee
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Nam
authors.forename: Ju-Won
authors.initials: JW
authors.lastname: Roh
authors.forename: Alpa M
authors.initials: AM
authors.lastname: Nick
authors.forename: Hee-Dong
authors.initials: HD
authors.lastname: Han
authors.forename: Mian M K
authors.initials: MM
authors.lastname: Shahzad
authors.forename: Hye-Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Jennings
authors.forename: Shenlan
authors.initials: S
authors.lastname: Mao
authors.forename: John
authors.initials: J
authors.lastname: Gooya
authors.forename: Dowdy
authors.initials: D
authors.lastname: Jackson
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D018796:Immunoconjugates / Q000378:metabolism / Q000494:pharmacology*; D007155:Immunologic Factors / Q000378:metabolism / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D007155:Immunologic Factors; D009842:Oligopeptides; C513576:monomethylauristatin F; D036104:Receptor, EphA2
references.citation: Eur J Nucl Med Mol Imaging. 2007 Dec;34(12):2024-36
references.pmid: 17673999
references.citation: Cancer. 2009 Jun 15;115(12):2684-92
references.pmid: 19396818
references.citation: J Biol Chem. 2006 Apr 14;281(15):10540-7
references.pmid: 16484228
references.citation: Am J Pathol. 2003 Apr;162(4):1037-42
references.pmid: 12651595
references.citation: Blood. 2003 Aug 15;102(4):1458-65
references.pmid: 12714494
references.citation: Oncologist. 2007 Sep;12(9):1084-95
references.pmid: 17914078
references.citation: Blood. 2001 May 15;97(10):3197-204
references.pmid: 11342449
references.citation: Bioconjug Chem. 2006 May-Jun;17(3):831-40
references.pmid: 16704224
references.citation: Bioconjug Chem. 2006 Jan-Feb;17(1):114-24
references.pmid: 16417259
references.citation: Clin Cancer Res. 2007 Dec 15;13(24):7487-95
references.pmid: 18094433
references.citation: CA Cancer J Clin. 2005 Jan-Feb;55(1):10-30
references.pmid: 15661684
references.citation: Nat Rev Mol Cell Biol. 2005 Jun;6(6):462-75
references.pmid: 15928710
references.citation: Cancer Res. 2003 Aug 1;63(15):4375-83
references.pmid: 12907607
references.citation: J Natl Cancer Inst. 2006 Nov 1;98(21):1558-70
references.pmid: 17077358
references.citation: Clin Adv Hematol Oncol. 2006 Mar;4(3):225-31
references.pmid: 16728934
references.citation: Clin Cancer Res. 2006 Aug 15;12(16):4916-24
references.pmid: 16914580
references.citation: Nat Clin Pract Oncol. 2007 Apr;4(4):245-55
references.pmid: 17392715
references.citation: Clin Cancer Res. 2004 Feb 1;10(3):897-908
references.pmid: 14871965
references.citation: Am J Pathol. 2002 Sep;161(3):929-38
references.pmid: 12213721
references.citation: Expert Opin Ther Targets. 2005 Dec;9(6):1179-87
references.pmid: 16300469
references.citation: J Natl Cancer Inst. 2009 Sep 2;101(17):1193-205
references.pmid: 19641174
references.citation: Cancer Res. 2005 Oct 15;65(20):9517-24
references.pmid: 16230417
references.citation: Cancer Res. 2008 Nov 15;68(22):9367-74
references.pmid: 19010911
references.citation: Int J Oncol. 2009 Oct;35(4):725-9
references.pmid: 19724908
references.citation: Anticancer Res. 2007 Sep-Oct;27(5B):3525-8
references.pmid: 17972512
references.citation: Cytokine Growth Factor Rev. 2004 Dec;15(6):419-33
references.pmid: 15561600
references.citation: J Med Chem. 2005 Mar 10;48(5):1344-58
references.pmid: 15743178
references.citation: Nat Biotechnol. 2003 Jul;21(7):778-84
references.pmid: 12778055
references.citation: Cancer Res. 2006 Feb 15;66(4):2328-37
references.pmid: 16489038
references.citation: Blood. 2003 Jan 15;101(2):391-8
references.pmid: 12393555
references.citation: Clin Adv Hematol Oncol. 2006 Jun;4(6):459-68
references.pmid: 16981669
references.citation: Cancer Res. 2006 Apr 1;66(7):3351-4, discussion 3354
references.pmid: 16585151
references.citation: Int J Oncol. 1994 Jun;4(6):1163-71
references.pmid: 21567033
references.citation: Lancet. 2005 Aug 6-12;366(9484):491-505
references.pmid: 16084259
references.citation: Ann Oncol. 2007 Mar;18(3):409-20
references.pmid: 17150999