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

Hocheol Lim, Kyoung Tai No

Research output: Contribution to journalArticlepeer-review


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 (AUC = 0.840) 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.

Original languageEnglish
Article number520
JournalBMC bioinformatics
Issue number1
Publication statusPublished - 2022 Dec

Bibliographical note

Funding Information:
This research was financially supported by the Ministry of Trade, Industry, and Energy (MOTIE), Korea, under the “Infrastructure Support Program for Industry Innovation” (reference number P0014714) supervised by the Korea Institute for Advancement of Technology (KIAT).

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Computer Science Applications
  • Applied Mathematics


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