R01AI169543

Rapid Response for Pandemics: Single Cell Sequencing and Deep Learning to Predict Antibody Sequences against an Emerging Antigen - Abstract

One of the "holy grails" in immunology is to be able to directly predict tight-binding variable chain antibody sequences in silico against foreign or non-self "antigenic" proteins. Immunoglobulin chain rearrangement can potentially encode approximately 10^16 different variants of antibody heavy and light chain sequences. However, only a small fraction of the sequence space is generally accessed for evolving antibodies against foreign proteins.

The computational challenge is to go from a model of the structure of an antigen to predicting a set of antibody chain sequences that can bind tightly to the antigen. If solved, it might be possible to move in less than 24 hours from the first cryo-electron-microscopic structure of a novel viral protein to advance a set of potent antibody-like molecular candidates for testing.

Towards solving this problem, this project aims to develop a deep learning architecture that will take as input thermodynamic, quantum mechanical (density functional), and local structure-based network topographical features of the antigens and their cognate antibodies, and will output their respective binding affinity constants. We will design a generative adversarial network (GAN), which we think is uniquely suited for regression-based machine learning approaches for the immune system, to discover associations between the epitope and the variable chain features.

This approach requires a large data stream of antigen and cognate antibody sequences, which until recently was difficult to obtain. A recently described single B-cell receptor (BCR) specific tagging method coupled with single cell deep sequencing ("Linking B Cell Receptor to Antigen Specificity through Sequencing" or LIBRA-SEQ) can rapidly isolate and sequence the BCR variable chain coding regions that can bind with high selectivity to antigenic epitopes.

Towards the specific project goals, in Task 1, LIBRA-SEQ will be used to rapidly identify and generate candidate immunoglobulin coding sequences in response to specific linear and nonlinear epitopes (against controls), chosen through computational/molecular modeling and prioritized with SARS-CoV-2 spike protein epitopes (but not restricted to these), injected into a mouse model, to generate large training sets. In Task 2, these training sets, along with other data sets already available in public databases, will generate a series of structural features (described above), which will be used to train the GAN. In Task 3, the predicted epitope-antibody interactions will be validated by direct experiments with synthetic antibody and phage-display systems.

Thus, the proposed strategy combines foundational principles in evolutionary biology, genomics, structural chemistry, and computer science to the solution of a general biological engineering problem. Results from this project are expected to lay the foundations for a rigorously tested and fully automated machine-learning system that could rapidly generate synthetic antibody candidates from the structure of a novel virus protein, which can enhance the rapid response ability against a future pandemic. The ability to develop targeted antibody therapy against non-infectious or chronic diseases, and on the production of antibody-based industrial enzymes, will also be dramatically enhanced if this project were to be successful.

The Team: The team-leads of this multi-institutional research project comprise a computer scientist, a protein crystallographer, an immunologist, and a molecular biologist.

Keck Graduate Institute Of Applied Life Sciences

NOT APPLICABLE

93.310 - Trans-NIH Research Support

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

California United States

State-Wide

NIH Directors Emergency Transformative Research Awards (R01 Clinical Trial Optional) (RFA-RM-20-020)

COVID-19 $1,219,945 (40%) percent of this Project Grant was funded by COVID-19 emergency acts including the CARES Act.
Amendment Since initial award the End Date has been extended from 08/31/24 to 08/31/25 and the total obligations have increased 66% from $1,851,627 to $3,071,572.