Affinity Maturation Enhances Antibody Specificity but Compromises Conformational Stability

Abstract

Summary: Monoclonal antibodies (mAbs) have recently emerged as one of the most promising classes of biotherapeutics. A potential advantage of B cell-derived mAbs as therapeutic agents is that they have been subjected to natural filtering mechanisms, which may enrich for B cell receptors (BCRs) with favorable biophysical properties. Here, we evaluated 400 human mAbs for polyreactivity, hydrophobicity, and thermal stability using high-throughput screening assays. Overall, mAbs derived from memory B cells and long-lived plasma cells (LLPCs) display reduced levels of polyreactivity, hydrophobicity, and thermal stability compared with naive B cell-derived mAbs. Somatic hypermutation (SHM) is inversely associated with all three biophysical properties, as well as BCR expression levels. Finally, the developability profiles of the human B cell-derived mAbs are comparable with those observed for clinical mAbs, suggesting their high therapeutic potential. The results provide insight into the biophysical consequences of affinity maturation and have implications for therapeutic antibody engineering and development. : Shehata et al. analyze the biophysical properties of human antibodies derived from multiple B cell subsets and find that somatic hypermutation is associated with increased antibody specificity but diminished conformational stability. The results provide insight into the biophysical consequences of affinity maturation and have implications for antibody discovery and engineering. Keywords: B cells, monoclonal antibodies, developability, polyreactivity, hydrophobicity, conformational stability