THE TWO BINDING SITES of most antibodies can bind only one type of antigen. However, Genentech researchers have now designed a "two-in-one" antibody that reshapes its binding sites to recognize and tightly bind two completely different antigens (Science 2009, 323, 1610). This ability could be extended to other antibodies and antigens and could lead to improved dual-target therapies for cancers and autoimmune diseases.
A few other researchers have previously created antibody molecules with dual binding capabilities, according to a commentary about the work by Dennis R. Burton of Scripps Research Institute and Paul W. H. I. Parren of Genmab, a biotech firm in the Netherlands that focuses on antibody-based cancer treatments. But they write that the Genentech process is the first to engineer dual specificity "into a naturally occurring and stable antibody [type] that should pose no obstacles for manufacturing and that has been well validated for clinical use."
Genentech's Germaine Fuh and colleagues created variants of the anticancer drug Herceptin, an antibody that binds HER2, a breast cancer growth factor receptor. They identified those variants that could also bind the tumor growth promoter VEGF and then enhanced binding for both antigens by modifying the antibody protein. Crystal structures show that the antibody uses several of the same amino acid positions to bind the two antigens, but conformational flexibility in one part of the binding site contributes to the site's adaptability.
In mice, the engineered antibody inhibits growth of tumors that depend on the antigens.