Understanding and overcoming trade-offs between antibody affinity, stability and specificity

Abstract

As a result, we have identified an antibody that displays excellent conformational specificity as well as natural antibody-like specificity. We also investigated the molecular origins of the high specificity of this unique antibody and found that the net charge of the complementarity-determining regions (CDRs) is a key determinant of its specificity. In particular, we found that increased positive charge (or decreased negative charge) in the CDRs is linked to reduced antibody specificity. We also evaluated the generality of this finding using diverse sets of antibodies, including >100 antibody drugs in the clinic. Surprisingly, we found that antibodies with positively charged CDRs are broadly linked to a higher risk of poor specificity and increased self-association, which is expected to also be associated with increased antibody viscosity and fast antibody clearance in vivo. We are currently expanding upon these findings to develop simple yet robust guidelines for predicting antibody specificity. These findings are expected to improve the generation of potent and safe therapeutic antibodies.