Augmenting immunogenicity workflows with AI and real-world evidence: failure points, tools, and a closed-loop operational blueprint

Immunogenicity undermines the safety and effectiveness of biologics and emerging modalities. Routine workflows are constrained by drug/target interference in binding assays, matrix and dilution biases in functional assays, fragile cellular/innate readouts, and the difficulty of translating titers into patient-level risk. Advances in artificial intelligence (AI) and real-world evidence (RWE) offer practical remedies. This narrative review searched five search engines and databases and included evidence from published original research, reviews, and regulatory data, and reports between 2022 and 2025. It identifies common failure locations and links them to practical AI and RWE solutions. We outline the regulatory and data underpinnings for decision-grade RWE, provide a closed-loop blueprint, and summarize recent developments in T- and B-cell epitope prediction, neoantigen prioritization, and pharmacovigilance/NLP pipelines for case deduplication and normalization: Define laboratory panels and computable phenotypes, map multi-source data to a common model, deduplicate, train transparent internally validated models, externally validate across distributed networks, route outputs to clinic/lab actions, and continuously monitor for drift with auditable updates. AI-augmented RWE can replace assay-centric snapshots in immunogenicity assessment with a learning system that focusses on clinically significant ADA/NAb effects, targets limited laboratory resources, speeds up signal verification, and enhances post-market vigilance.