DapPep: Domain Adaptive Peptide-agnostic Learning for Universal T-cell Receptor-antigen Binding Affinity Prediction

Abstract: Identifying T-cell receptors (TCRs) that interact with antigenic peptides provides the technical basis for developing vaccines and immunotherapies. The emergent deep learning methods excel at learning antigen binding patterns from known TCRs but struggle with novel or sparsely represented antigens. However, binding specificity for unseen antigens or exogenous peptides is critical. We introduce a domain-adaptive peptide-agnostic learning framework DapPep for universal TCR-antigen binding affinity prediction to address this challenge. The lightweight self-attention architecture combines a pre-trained protein LLM with an inner-loop self-supervised regime to enable robust TCR-peptide representations. Extensive experiments on various benchmarks demonstrate that DapPep consistently outperforms existing tools, showcasing robust generalization capability, especially for data-scarce settings and unseen peptides. Moreover, DapPep proves effective in challenging clinical tasks such as sorting reactive T cells in tumor neoantigen therapy and identifying key positions in 3D structures.