A complement modulated, broadly reactive anti-PhtD antibody improves potency and protection during Streptococcus pneumoniae infection

Streptococcus pneumoniae (Spn) remains a serious health threat due to growing antibiotic resistance and serotype replacement. Monoclonal antibodies (MAbs) are an alternate approach for combating infections and can be engineered to drive specific effector functions for improved in vivo potency. Here, we characterize a DNA-encoded MAb targeting the conserved pneumococcal histidine triad protein D (PhtD3 DMAb) and evaluate efficacy in a lethal Spn murine infection model. Expression of MAb PhtD3 on DNA plasmid improved overall antibody durability; meanwhile, incorporation of the complement-enhancing E430G Fc-modification increased antibody affinity for C1q and was dose-sparing at challenge. Structural analysis by cryo-EM resolved the binding footprint of PhtD-PhtD3 MAb, suggesting cross-reactivity with other Pht-family proteins while providing rationale for the design of broadly targeting vaccines. We also demonstrate the breadth of MAb PhtD3 against a panel of Spn strains, including multiple drug-resistant isolates. These findings support DNA expression of MAbs and Fc-engineering as a valuable strategy to improve durability and efficacy of antibodies against lung bacterial pathogens.