Protein recognition processes are the basis for most normal and pathological biological function; therefore, the control of binding attributes is central to the design of protein biopharmaceuticals. At our present state of knowledge, the fastest and most robust route to desired binding properties is by directed evolution. A panoply of selection platforms have been developed to engineer proteins- for example, protein surface display on: mRNA, ribosomes, phage, E. coli, yeast, or mammalian cells. Given the ready availability of these powerful capabilities, the significant question is now: what to make? Or, more specifically, what biophysical properties will maximize efficacy while minimizing toxicity of a given protein drug? Quantitative modeling and measurements of pharmacokinetics, receptor trafficking, and binding kinetics are necessary to formulate specific hypotheses that can then be tested by synthesis of proteins with the desired properties. Particular examples of this approach will be presented, from amongst the following topics: tumor targeting; immunocytokine engineering; huntingtin aggregation antagonism; or antigenic cross presentation in cancer vaccines.

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