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A human monoclonal antibody bivalently binding two different epitopes in streptococcal M protein mediates immune function.

Wael BahnanLotta J HapponenHamed KhakzadVibha Kumra AhnlideTherese de NeergaardSebastian WrightonOscar AndréEleni BratanisDi TangThomas HellmarkLars BjörckOonagh ShannonLars MalmströmJohan MalmstömPontus Nordenfelt
Published in: EMBO molecular medicine (2022)
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 in the central region of the surface-bound M protein. Such antibodies are typically non-opsonic. However, one antibody could effectively promote vital immune functions, including phagocytosis and in vivo protection. Remarkably, this antibody primarily interacts through a bivalent dual-Fab cis mode, where the Fabs bind to two distinct epitopes in the M protein. The dual-Fab cis-binding phenomenon is conserved across different groups of M types. In contrast, other antibodies binding with normal single-Fab mode to the same region cannot bypass the M protein's virulent effects. A broadly binding, protective monoclonal antibody could be a candidate for anti-streptococcal therapy. Our findings highlight the concept of dual-Fab cis binding as a means to access conserved, and normally non-opsonic regions, regions for protective antibody targeting.
Keyphrases
  • monoclonal antibody
  • binding protein
  • endothelial cells
  • protein protein
  • dna binding
  • transcription factor
  • amino acid
  • magnetic resonance
  • stem cells
  • bone marrow
  • mesenchymal stem cells