Monoclonal antibody (mAb) therapies represent one of the most important treatment opportunities in modern medicine. They are being used to treat and cure numerous diseases, including different types of cancer and autoimmune diseases. However, viruses, especially RNA viruses, evolve rapidly and can escape many mAbs. During the SARS-CoV-2 pandemic, variants of concern (VoC) quickly escaped available therapeutics and outpaced typical discovery and approval pipelines. During this time, our group led a global consortium, CoVIC, to compare over 400 candidate antibody therapeutics against SARS-CoV-2.
The vast majority were escaped by one or more variants, but a few remained effective. These mAbs emerged from a development pipeline termed STage-Enhanced Maturation (STEM) that kept pace ahead of each newly emergent VoC. The results of this pipeline were a sequential array of parent-to-child antibody variations, each of which became more broadly effective than the last.
Here, we use high-resolution cryo-Electron Microscopy (cryo-EM) to understand how these mAbs kept ahead of VoCs. We visualize and characterize the specific changes that occurred in their evolution and optimization, and identify the key interactions that make the matured mAbs superior binders and neutralizers for all known SARS-CoV-2 VoCs. Our goal is to deepen our understanding of antibody evolution and optimized antigen neutralization.
