Cancer drugs that block cell signaling by means of epidermal growth factor receptors (EGFRs) have had some success in the clinic, but over time, and with certain receptor-bearing cancers, these therapies fail when used as single agents. Increasingly, drug developers are turning to combinations of drugs, which are challenging to test in trials and add to the cost of therapy. Researchers at Genentech had previously created “two-in-one antibodies” that target two common cancer targets, HER2 and VEGF, through the same binding site. Now they show that with this approach they can create other potentially clinically useful molecules with dual binding specificities. Antibodies that bind EGFR were generated by phage display, and subsequently selected for the ability to bind HER3. The researchers show through competition experiments that the resulting antibody, MEHD7945A, binds either or both ligands at the same region of the molecule. MEHD7945A inhibits receptor binding in vitro and was a more potent inhibitor of HER3-dependent growth in culture, as well as in 12 xenograft models, than antibodies with single specificities. Whereas most bispecific antibodies combine two distinct antigen-binding molecules, here the two specificities reside in the same binding site, which might potentiate its effects and could simplify manufacture. (Cancer Cell 20, 472–486, 2011)