Prediction of polyreactive and nonspecific single-chain fragment variables through structural biochemical features and protein language-based descriptors

BACKGROUND: Monoclonal antibodies (mAbs) have been used as therapeutic agents, which must overcome many developability issues after the discovery from in vitro display libraries. Especially, polyreactive mAbs can strongly bind to a specific target and weakly bind to off-target proteins, which leads to poor antibody pharmacokinetics in clinical development. Although early assessment of polyreactive mAbs is important in the early discovery stage, experimental assessments are usually time-consuming and expensive. Therefore, computational approaches for predicting the polyreactivity of single-chain fragment variables (scFvs) in the early discovery stage would be promising for reducing experimental efforts. RESULTS: Here, we made prediction models for the polyreactivity of scFvs with the known polyreactive antibody features and natural language model descriptors. We predicted 19,426 protein structures of scFvs with trRosetta to calculate the polyreactive antibody features and investigated the classifying performance of each factor for polyreactivity. In the known polyreactive features, the net charge of the CDR2 loop, the tryptophan and glycine residues in CDR-H3, and the lengths of the CDR1 and CDR2 loops, importantly contributed to the performance of the models. Additionally, the hydrodynamic features, such as partial specific volume, gyration radius, and isoelectric points of CDR loops and scFvs, were newly added to improve model performance. Finally, we made the prediction model with a robust performance ([Formula: see text] ) with an ensemble learning of the top 3 best models. CONCLUSION: The prediction models for polyreactivity would help assess polyreactive scFvs in the early discovery stage and our approaches would be promising to develop machine learning models with quantitative data from high throughput assays for antibody screening. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12859-022-05010-4.