Presenter of 1 Presentation
O039 - COMPLEMENT-ENHANCING ANTIBODIES AGAINST STREPTOCOCCUS PNEUMONIAE (ID 165)
Abstract
Background
Monoclonal antibodies (mAbs) that boost the host immune system are attractive
therapeutic candidates for infectious diseases harboring antibiotic resistance or with
emerging non-vaccine serotypes. Recent studies have shown that specific point
mutations in the Fc domain of antibodies can enhance antibody clustering into
hexameric structures, required for a more efficient complement activation. This study
examines the efficacy of capsule-specific human mAbs as a therapeutic approach
against S. pneumoniae.
Methods
Hexamerization-enhancing mutations were introduced in anti-capsule monoclonal antibdies. The functionality of new engeneered antibodies was assessed by flow cytometry and bacteria counting. To test their potencial in vivo, bacteriemic pneumonia model was stablished using BALB/c mice.
Results
We show that serogroup-6 specific mAbs harboring the hexamer-enhancing E430G or
E345K point mutation potently increase complement activation and phagocytosis of
clinical isolates of this serogroup. Bacterial killing assays demonstrated the strong
potency of engineered antibodies to induce neutrophil-dependent killing of serotype-6B.
Moreover, we compared the protective capacity of wildtype antibody with its
counterpart E345K variant against a mouse model of bacteremic pneumonia. Passive
immunization with either antibody before intranasal challenge with serotype-6A
induced increased degree of protection against pneumococcal bacteremia when mice
were treated with the complement-enhancing E345K mutant.
Conclusions
This study represents a first systematic approach to design effective therapeutic
antibodies against S. pneumoniae with increased potency to activate the human
complement system.