Monoclonal antibodies have delivered enormous impact for the treatment of diseases and consequently have become one of the most highly engineered protein families. The most clinically successful enhancements to antibody drugs have been modest mutational modifications of natural interactions. A corollary is that the discovery of new antibody interfaces creates new opportunities for biotherapeutic engineering. Our work capitalizes on naturally occurring interactions within antibodies, in a manner that relies on their high sequence and structural homology for design, to create new and generalizable tools for optimization of this important biotherapeutic class.