Leveraging large language models to predict antibody biological activity against influenza A hemagglutinin.

Monoclonal antibodies (mAbs) represent one of the most prevalent FDA-approved treatments for autoimmune, infectious, and cancer diseases. However, their discovery and development remains a time-consuming and costly process. Recent advancements in machine learning (ML) and artificial intelligence (AI) have shown significant promise in revolutionizing antibody discovery field. Models that predict antibody biological activity enable in silico evaluation of binding and functional properties; such models can prioritize antibodies with the highest likelihood of success in laboratory testing procedures. We explore an AI model for predicting the binding and receptor blocking activity of antibodies against influenza A hemagglutinin (HA) antigens. Our model is developed with the Molecular Aligned Multi-Modal Architecture and Language (MAMMAL) framework for biologics discovery to predict antibody-antigen interactions using only sequence information. To evaluate the model's performance, we tested it under various data split conditions to mimic real-world scenarios. Our model achieved an area under the receiver operating characteristic (AUROC) score of ≥ 0.91 for predicting the activity of existing antibodies against seen HAs and an AUROC score of 0.9 for unseen HAs. For novel antibody activity prediction, the AUROC was 0.73, which further declined to 0.63-0.66 under stringent constraints on similarity to existing antibodies. These results demonstrate the potential of AI foundation models to transform antibody design by reducing dependence on extensive laboratory testing and enabling more efficient prioritization of antibody candidates. Moreover, our findings emphasize the critical importance of diverse and comprehensive antibody datasets to improve the generalization of prediction models, particularly for novel antibody development.