Precise, Specific, and Sensitive De Novo Antibody Design Across Multiple Cases

The precision design of antibodies, which naturally recognize diverse molecules through six variable loops, remains a critical challenge in therapeutic molecule discovery. In this study, we demonstrate that precise, sensitive, and specific antibody design can be achieved without prior antibody information across six distinct target proteins. For each target, binders were identified from a yeast display scFv library of approximately 10 ⁶ sequences, constructed by combining 10 ² designed light chain sequences with 10 ⁴ designed heavy chain sequences. Binders with varying binding strengths were identified for all six targets, including a case where no experimentally resolved target protein structure was available, demonstrating the highest level of precision compared to previous de novo antibody design reports. For one of the targets, antibodies produced in the IgG format exhibited affinity, activity, and developability, comparable to a commercial antibody, highlighting the sensitivity of the design method. Furthermore, binders capable of distinguishing closely related protein subtypes or mutants were identified, demonstrating that the method can achieve high molecular specificity. These findings underscore the effectiveness of precision molecular design based on atomic-accuracy structure prediction. This study establishes computational antibody design as a viable approach for generating therapeutic molecules with tailored properties, with promising potential for achieving the efficacy and safety required for successful therapeutics.