# Isotype conversion of Staphylococcal-specific IgG into IgM broadens the reactivity to other bacterial pathogens

## TL;DR

Changing specific IgG antibodies into IgM form makes them react to more bacteria, which could improve treatments for infections.

## Contribution

Converting anti-staphylococcal IgG into IgM broadens reactivity to other bacterial pathogens while maintaining functionality.

## Key findings

- Converted IgMs cross-react with Gram-negative bacteria like E. coli and N. meningitidis.
- IgM antibodies induce complement effects on both Gram-positive and Gram-negative bacteria.
- IgM cross-reactivity relies on multivalent binding and can be mimicked by IgG engineering.

## Abstract

Therapeutic antibodies are actively explored as alternative to treat or prevent bacterial infections. However, the narrow antigen specificity of IgG in combination with broad diversity in bacterial surface structures currently hampers the development of therapeutic antibodies against bacteria. Here we reveal that isotype conversion of three highly specific anti-staphylococcal antibodies from IgG into IgM does not only affect Fc effector functions but also modifies the interaction of Fab domains with bacterial surface antigens. These converted IgMs gain cross-reactivity for a broad range of bacterial species, including Gram-negatives such as Escherichia coli and Neisseria meningitidis and even protect against invasive infection with Streptococcus pyogenes in vivo. Mechanistic studies show that enhanced cross-specificity by IgM is conferred by changed ligand specificity and multivalent binding to high-density antigens. Altogether, these findings provide important insights for the development of antibody therapy for bacterial infections.

•IgGs considered specific for S. aureus cross-react to other human pathogens as IgM•Cross-reactive IgMs recognize several human pathogens with exposed GlcNAc moieties•These IgMs induce complement effects on Gram-positive and Gram-negative bacteria•IgM cross-reactivity requires multivalency and can be mimicked by IgG engineering

IgGs considered specific for S. aureus cross-react to other human pathogens as IgM

Cross-reactive IgMs recognize several human pathogens with exposed GlcNAc moieties

These IgMs induce complement effects on Gram-positive and Gram-negative bacteria

IgM cross-reactivity requires multivalency and can be mimicked by IgG engineering

The narrow antigen specificity of IgGs hampers their utility for antibacterial therapies. Muts et al. show that conversion of highly specific IgGs into IgM induces broader reactivity toward several human pathogens while preserving functional activity. These findings may accelerate development of broadly reactive antibodies to prevent and treat bacterial infections.