Deep learning guided optimization of human antibody against SARS-CoV-2 variants with broad neutralization

Sisi Shan, Shitong Luo, Ziqing Yang, Junxian Hong, Yufeng Su, Fan Ding, Lili Fu, Chenyu Li, Peng Chen, Jianzhu Ma, Xuanling Shi, Qi Zhang, Bonnie Berger, Linqi Zhang, Jian Peng

Research output: Contribution to journalArticlepeer-review


The ability of viruses to mutate and evade the human immune system and neutralizing antibodies remains an obstacle to antiviral and vaccine development. Many neutralizing antibodies, including some approved for emergency use authorization (EUA), reduced or lost activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Here, we introduce a geometric deep learning algorithm that efficiently enhances antibody affinity to achieve broader and more potent neutralizing activity against such variants. We demonstrate the utility of our approach on a human antibody P36-5D2, which is effective against SARS-CoV-2 Alpha, Beta, and Gamma but not Delta. We show that our geometric neural network model optimizes this antibody’s complementarity-determining region (CDR) sequences to improve its binding affinity against multiple SARS-CoV-2 variants. Through iterative optimization of the CDR regions and experimental measurements, we enable expanded antibody breadth and improved potency by ∼10- to 600-fold against SARS-CoV-2 variants, including Delta. We have also demonstrated that our approach can identify CDR changes that alleviate the impact of two Omicron mutations on the epitope. These results highlight the power of our deep learning approach in antibody optimization and its potential application to engineering other protein molecules. Our optimized antibodies can potentially be developed into antibody drug candidates for current and emerging SARS-CoV-2 variants.
Original languageEnglish (US)
Article numbere2122954119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number11
StatePublished - Mar 15 2022


  • severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
  • COVID-19
  • computational biology
  • deep learning
  • geometric neural networks
  • SARS-CoV-2 variants
  • broadly neutralizing antibodies

ASJC Scopus subject areas

  • General


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