Antibodies are critical components of adaptive immunity, binding with high affinity to pathogenic epitopes. Antibodies undergo rigorous selection to achieve this high affinity, yet some maintain an additional basal level of low affinity, broad reactivity to diverse epitopes, a phenomenon termed 'polyreactivity'. While polyreactivity has been observed in antibodies isolated from various immunological niches, the biophysical properties that allow for promiscuity in a protein selected for high-affinity binding to a single target remain unclear. Using a database of over 1000 polyreactive and non-polyreactive antibody sequences, we created a bioinformatic pipeline to isolate key determinants of polyreactivity. These determinants, which include an increase in inter-loop crosstalk and a propensity for a neutral binding surface, are sufficient to generate a classifier able to identify polyreactive antibodies with over 75% accuracy. The framework from which this classifier was built is generalizable, and represents a powerful, automated pipeline for future immune repertoire analysis.
Keywords: antibody specificity; bioinformatics; biophysics; human; immunology; inflammation; information theory; machine learning; molecular biophysics; mouse; structural biology.
To defend itself against bacteria and viruses, the body depends on a group of proteins known as antibodies. Each subset of antibodies undergoes a rigorous training regimen to ensure it recognizes a single epitope well – that is, one specific region on the surface of foreign, harmful organisms. Most antibodies stick extremely tightly to their one unique epitope, but some can also weakly bind to molecules that are vastly different from their main trained targets. This feature – known as polyreactivity – can in some cases help the immune system fight against multiple strains of viruses. On the other hand, when antibodies are designed in the laboratory to treat diseases, this characteristic can sometimes lead to the failure of pre-clinical trials. Yet it is currently unclear why some antibodies are polyreactive when others are not. To investigate this question, Boughter et al. compared over 1,000 polyreactive and non-polyreactive antibody sequences from a large database, revealing differences in the physical properties of the region of the antibodies that attaches to epitopes. Using these defining features, Boughter et al. went on to design a new piece of freely available, automated software that could predict which antibodies would be polyreactive more than 75% of the time. Such software could ultimately help to guide the design of antibody-based treatments, while bypassing the need for costly laboratory tests.
© 2020, Boughter et al.