Revisiting Structure-Based Filtering for AI-Designed Antibodies: Opportunities, Limits, and What Matters

AI antibody design can generate far more candidates than can be experimentally tested, making post-generation filtering a central bottleneck. We study whether structure-prediction outputs can help prioritize AI-designed antibodies for experimental validation. We evaluate this problem on 4,184 experimentally characterized antibody–antigen pairs, combining newly generated wet-lab measurements with curated affinity data across diverse antigens and assay settings. We introduce two complementary filtering signals: Regional Interaction Contrast (RIC), which captures support for the predicted antibody–antigen interface, and Non-CDR Antibody Confidence (NAC), which measures antibody confidence outside the CDRs. Across AlphaFold 3, Protenix-v2, and ESMFold2, we find a striking difference in what information matters for filtering. Interface evidence is strongest when comparing candidates designed for different antigens, whereas antibody-level reliability is substantially more informative for ranking candidates within the same antigen. In particular, non-CDR antibody confidence consistently outperforms whole-antibody confidence across predictors, revealing an unexpected source of filtering signal beyond the predicted interface. Finally, we examine the information encoded in the predictor outputs themselves. Predicted structures contain substantial but incomplete binding-related signal, revealing both the opportunities and limits of structure-based filtering: better metrics can exploit current predictors more effectively, but their performance ultimately remains constrained by what those predictors can distinguish