EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma.
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.
Lee
Jeong-Won
JW
Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Stone
Rebecca L
RL
Lee
Sun Joo
SJ
Nam
Eun Ji
EJ
Roh
Ju-Won
JW
Nick
Alpa M
AM
Han
Hee-Dong
HD
Shahzad
Mian M K
MM
Kim
Hye-Sun
HS
Mangala
Lingegowda S
LS
Jennings
Nicholas B
NB
Mao
Shenlan
S
Gooya
John
J
Jackson
Dowdy
D
Coleman
Robert L
RL
Sood
Anil K
AK
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
D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D007155:Immunologic Factors; D009842:Oligopeptides; C513576:monomethylauristatin F; D036104:Receptor, EphA2
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