Iain Rogers explained the selection problem in antibody discovery using the famous analogy of an infinite number of monkeys using infinite typewriters. Given an infinite amount of time, the non-human primates will eventually write out the optimal sequence for antibodies that can be used as a therapeutic or diagnostic tool. The problem however is how you find that sequence in the infinite noise of the writers’ room.
Therefore, the goal for new solutions to the selection problem is to get more information earlier in the drug discovery process for more efficiency and to avoid wasted efforts. This led the team to investigate sequencing functional antibodies from human serum. If successful, this would mean a better chance that the resulting sequences were binding, efficacious in vivo, and have neutralisation properties.
Their resulting paper looked at de novo protein sequencing of antibodies for neutralising against the SARS-CoV-2 vaccination. The team used a human blood sample from a patient who was immunised with a vaccine. They isolated the IgG population which were specific to their target of interest.
Their innovation, REpAb Sequencing, uses three mass spectrometry branches. One sequence looked at the intact antibody molecules, a second used a simple digestion to look at the subunits like the Fab and the Fc region, and a third used proteases for further digestion to produce peptides.
Rogers noted that this took a huge amount of work, with hundreds of mass spectrometry runs. All the data was crunched along with B cell sequencing data to return a full length mAb sequence.
The results showed a higher success rate in identifying neutralising antibodies compared to traditional B cell sequencing methods, suggesting a complementary approach to antibody discovery. Rogers noted that the technology can be applied across various species and used to preselect antibodies, potentially reducing costs and time in the antibody development process.
The presentation concluded with potential future applications in vaccine development and epitope mapping. Rogers emphasized the importance of early access to epitope information in the antibody discovery process.
