A Comprehensive Benchmark of Computational Models for Antibody--Antigen Binding Affinity

arXiv:2506.04235v3 Announce Type: replace-cross Abstract: Computational antibody design requires benchmarks that measure functional binding rather than similarity to natural sequences. Here we present AbBiBench, which treats the antibody--antigen complex as the evaluation unit and harmonizes 216,560 experimental measurements spanning 13 antibodies and 9 antigens. We compare 20 computational approaches without task-specific training or fine-tuning. The analyses show that global structure-conditioned inverse folding yields the strongest and most consistent affinity rankings, whereas antibody-specific fine-tuning does not consistently improve performance. Across models, rankings are more useful for prioritizing likely affinity gains than for excluding weak variants. In a subsequent case study, multi-objective evaluation of model-generated F045-092 CDR-H3 variants for H1N1 binding revealed a trade-off between predicted binding potential and evolutionary sequence plausibility; all 21 selected candidates produced H1-reactive ELISA signals. AbBiBench provides an open framework for developing and evaluating function-aware antibody design methods.