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Anti-drug immune responses are a unique risk factor for biotherapeutics, and undesired immunogenicity can alter pharmacokinetics, compromise drug efficacy, and in some cases even threaten patient safety. To fully capitalize on the promise of biotherapeutics, more efficient and generally applicable protein deimmunization tools are needed. Mutagenic deletion of a protein's T cell epitopes is one powerful strategy to engineer immunotolerance, but deimmunizing mutations must maintain protein structure and function. Here, EpiSweep, a structure-based protein design and deimmunization algorithm, has been used to produce a panel of seven beta-lactamase drug candidates having 27-47% reductions in predicted epitope ... More