Differential EphA2 epitope display on normal versus malignant cells.
The EphA2 receptor tyrosine kinase is overexpressed in many different types of human cancers where it functions as a powerful oncoprotein. Dramatic changes in the subcellular localization and function of EphA2 have also been linked with cancer, and in particular, unstable cancer cell-cell contacts prevent EphA2 from stably binding its ligand on the surface of adjoining cells. This change is important in light of evidence that ligand binding causes EphA2 to transmit signals that negatively regulate tumor cell growth and invasiveness and also induce EphA2 degradation. On the basis of these properties, we have begun to target EphA2 on tumor cells using agonistic antibodies, which mimic the consequences of ligand binding. In our present study, we show that a subset of agonistic EphA2 antibodies selectively bind epitopes on malignant cells, which are not available on nontransformed epithelial cells. We also show that such epitopes arise from differential cell-cell adhesions and that the stable intercellular junctions of nontransformed epithelial cells occlude the binding site for ligand, as well as this subset of EphA2 antibodies. Finally, we demonstrate that antibody targeting of EphA2 decreases tumor cell growth as measured using xenograft tumor models and found that the mechanism of antibody action relates to EphA2 protein degradation in vivo. Taken together, these results suggest new opportunities for therapeutic targeting of the large number of different cancers that express EphA2 in a manner that could minimize potential toxicities to normal cells.
Coffman
Karen T
KT
MedImmune, Inc., 35 West Watkins Mill Road, Gaithersburg, MD 20878, USA.
Hu
Min
M
Carles-Kinch
Kelly
K
Tice
David
D
Donacki
Nanci
N
Munyon
Karyn
K
Kifle
Giza
G
Woods
Robert
R
Langermann
Solomon
S
Kiener
Peter A
PA
Kinch
Michael S
MS
D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D002450:Cell Communication / Q000276:immunology; D000939:Epitopes / Q000096:biosynthesis / Q000276:immunology*; D005260:Female; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D036104:Receptor, EphA2 / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000912:Antibodies, Neoplasm; D000939:Epitopes; D036104:Receptor, EphA2