Focused learning by antibody language models using preferential masking of non-templated regions

ABSTRACT Existing antibody language models ( LMs ) are pre-trained using a masked language modeling ( MLM ) objective with uniform masking probabilities. While these models excel at predicting germline residues, they often struggle with mutated and non-templated residues, which are crucial for antigen-binding specificity and concentrate in the complementarity-determining regions ( CDRs ). Here, we demonstrate that preferential masking of the non-templated CDR3 is a compute-efficient strategy to enhance model performance. We pre-trained two antibody LMs ( AbLMs ) using either uniform or preferential masking and observed that the latter improves residue prediction accuracy in the highly variable CDR3. Preferential masking also improves antibody classification by native chain pairing and binding specificity, suggesting improved CDR3 understanding and indicating that non-random, learnable patterns help govern antibody chain pairing. We further show that specificity classification is largely informed by residues in the CDRs, demonstrating that AbLMs learn meaningful patterns that align with immunological understanding.