FlowDesign: Improved design of antibody CDRs through flow matching and better prior distributions.

Abstract

Designing antibodies with desired binding specificity and affinity is essential for pharmaceutical research. While diffusion-based models have advanced the co-design of the complementarity-determining region (CDR) sequences and structures, challenges remain, including non-informative priors, incompatibility with discrete amino acid types, and impractical computational costs in large-scale sampling. To address these, we propose FlowDesign, a sequence-structure co-design approach via flow matching, offering (1) flexible prior selection, (2) direct matching of discrete distributions, and (3) enhanced efficiency for large-scale sampling. By leveraging various priors, data-driven structural models proved the most informative. FlowDesign outperformed baselines in amino acid recovery (AAR), root-mean-square deviation (RMSD), and Rosetta energy. We also applied FlowDesign to design antibodies targeting the HIV-1 receptor CD4. FlowDesign yielded antibodies with improved binding affinity and neutralizing potency compared with the antibody ibalizumab across multiple HIV mutants, validated by biolayer interferometry (BLI) and pseudovirus neutralization. This highlights FlowDesign's potential in antibody and protein design. A record of this paper's transparent peer review process is included in the supplemental information.