When panning for antibodies against epitopes that impose a strong selective pressure for non-specific binders, the resulting molecules may exhibit poor binding specificity and unsatisfactory pharmacokinetic (PK) profiles. Highly-charged epitopes are a key example, where charge-based interactions saturate the binding pool. A leading pharmaceutical company was developing a high-affinity antibody for the highly-charged interleukin-21 receptor (IL-21R), an important player in the immune system’s cytokine response1. By leveraging Twist Bioscience’s Combinatorial Variant Library (CVL) Technology in combination with structure-guided library design and model-based selection, the company was able to enrich functional antibody variants with desirable characteristics and identify a stable lead with high-affinity for IL-21R.