Addressing the antibody germline bias and its effect on language models for improved antibody design.

MOTIVATION: The versatile binding properties of antibodies have made them an extremely important class of biotherapeutics. However, therapeutic antibody development is a complex, expensive, and time-consuming task, with the final antibody needing to not only have strong and specific binding but also be minimally impacted by developability issues. The success of transformer-based language models in protein sequence space and the availability of vast amounts of antibody sequences, has led to the development of many antibody-specific language models to help guide antibody design. Antibody diversity primarily arises from V(D)J recombination, mutations within the CDRs, and/or from a few nongermline mutations outside the CDRs. Consequently, a significant portion of the variable domain of all natural antibody sequences remains germline. This affects the pre-training of antibody-specific language models, where this facet of the sequence data introduces a prevailing bias toward germline residues. This poses a challenge, as mutations away from the germline are often vital for generating specific and potent binding to a target, meaning that language models need be able to suggest key mutations away from germline. RESULTS: In this study, we explore the implications of the germline bias, examining its impact on both general-protein and antibody-specific language models. We develop and train a series of new antibody-specific language models optimized for predicting nongermline residues. We then compare our final model, AbLang-2, with current models and show how it suggests a diverse set of valid mutations with high cumulative probability. AVAILABILITY AND IMPLEMENTATION: AbLang-2 is trained on both unpaired and paired data, and is freely available at https://github.com/oxpig/AbLang2.git.