Protection induced by a human monoclonal antibody recognizing two different epitopes in a conserved region of streptococcal M proteins

Group A streptococci have evolved multiple strategies to evade human antibodies, making it challenging to create effective vaccines or antibody treatments. Here, we have generated antibodies derived from the memory B cells of an individual who had successfully cleared a group A streptococcal infection. The antibodies bind with high affinity to the central region on the surface-bound M protein. One antibody could effectively promote vital immune functions, including phagocytosis and in vivo protection. Remarkably, this antibody only interacts through dual-Fab cis mode, where the Fabs bind to two distinct epitopes in M protein, and with conserved binding across strains. In contrast, another antibody binding to a single epitope in the same region does not bypass the M protein’s virulent effects. A broadly-binding, protective monoclonal antibody is a strong candidate for anti-streptococcal therapy. It also highlights the concept of dual-Fab binding and the accessibility of conserved regions for immune antibody targeting.