Antibody double feature
Antibodies typically recognize a single antigen with high affinity and specificity. Is 'one antibody, one antigen epitope' a fixed feature of antibody recognition, or could one antibody recognize two binding sites? To test this question, Bostrom et al. started with the therapeutic monoclonal antibody trastuzumab, which recognizes human epidermal growth factor receptor 2 (HER2). Using phage display, the light chain of the complementarity-determining region was randomized, and variants were selected that bound to vascular endothelial growth factor (VEGF). In some cases, the selected antibodies had lost their affinity for HER2, whereas in other cases, the resulting antibodies had high affinity for both antigens. Solving the crystal structure of an antibody-HER2 complex and an antibody-VEGF complex for a dual-specificity antibody revealed substantial overlap in the binding sites. However, based on alanine scanning mutagenesis, the regions that contributed most significantly to binding energy were largely distinct. An optimized HER2-VEGF antibody with low-nanomolar affinity for both antigens effectively blocked HER2- and VEGF-mediated cell proliferation and tumor growth in a mouse xenograft model. These results highlight an unexpected plasticity in antibody recognition that is reminiscent of the promiscuity sometimes seen in protein interaction domains and that could have important biological and therapeutic implications. (Science 323, 1610–1614, 2009) JK
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