EphB2 as a Therapeutic Antibody Drug Target for the Treatment of Colorectal Cancer
Weiguang Mao1, Elizabeth Luis1, Sarajane Ross1, Johnny Silva1, Christine Tan1, Craig Crowley1, Clarissa Chui1, Gretchen Franz1, Peter Senter2, Hartmut Koeppen1 and Paul Polakis1
1 Departments of Molecular Biology, Protein Chemistry, and Molecular Oncology, Genentech, Inc., South San Francisco, California, and 2 Seattle Genetics, Bothell, Washington
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.
(From 2/04 Cancer Research) |
