1. EphB2 as a therapeutic antibody drug target for the treatment of colorectal cancer.
- Author
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Mao W, Luis E, Ross S, Silva J, Tan C, Crowley C, Chui C, Franz G, Senter P, Koeppen H, and Polakis P
- Subjects
- Adenocarcinoma enzymology, Adenocarcinoma immunology, Animals, Antibodies, Monoclonal immunology, Cell Line, Tumor, Colonic Neoplasms enzymology, Colonic Neoplasms immunology, Female, Humans, Immunotoxins immunology, Mice, Mice, Nude, Receptor, EphB2 biosynthesis, Receptor, EphB2 immunology, Xenograft Model Antitumor Assays, Adenocarcinoma therapy, Antibodies, Monoclonal pharmacology, Colonic Neoplasms therapy, Immunotoxins pharmacology, Receptor, EphB2 antagonists & inhibitors
- Abstract
Analysis of human colorectal cancer specimens revealed overexpression of the EphB2 receptor tyrosine kinase. Monoclonal antibodies (MAbs) to extracellular sequence of EphB2 were raised and tested for activity against colorectal cancer cells. One of the MAbs, 2H9, effectively blocked the interaction of ephB2 with ephrin ligands and inhibited the resulting autophosphorylation of the receptor. However, this antibody did not affect the proliferation of cancer cells expressing ephB2. Immunocytochemical analysis revealed rapid internalization of the MAb 2H9 on binding ephB2, suggesting that target-dependent cell killing could be achieved with an antibody-drug conjugate. When MAb 2H9 was conjugated to monomethylauristatin E through a cathepsin B-cleavable linker, it specifically killed ephB2-expressing cancer cells in vitro and in vivo. Our results suggest that ephB2 is an attractive target for immunoconjugate cancer therapy.
- Published
- 2004
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