Understanding how Fc-modification transforms a pathogenic HIT-like monoclonal antibody into a novel treatment for sepsis

Kandace Gollomp, scientist from The Childrens Hospital of Philadelphia, lead a research on how Fc-modification transforms a pathogenic HIT-like monoclonal antibody into a novel treatment for sepsis. This study has been published on Blood in this November.

Sepsis is characterized by multi-organ system dysfunction that occurs due to infection. It is associated with high morbidity and mortality and in need of improved therapeutic interventions. Neutrophils play a crucial role in sepsis, releasing neutrophil extracellular traps (NETs) composed of DNA complexed with histones and toxic antimicrobial proteins that ensnare pathogens, but also damage host tissues. At presentation, patients often have a significant NET burden contributing to the multi-organ damage. Therefore, interventions that inhibit NET release would likely be ineffective at preventing NET-based injury. Treatments that enhance NET degradation may liberate captured bacteria and toxic NET degradation products (NDPs) and likely be of limited therapeutic benefit as well. 

Gollomps team proposes that interventions that stabilize NETs and sequester NDPs may be protective in sepsis. They showed that platelet factor 4 (PF4), a platelet-associated chemokine, binds and compacts NETs, increasing their resistance to deoxyribonuclease I. They now show that PF4 increases NET-mediated bacterial capture, reduces the release of NDPs, and improves outcome in murine models of sepsis. A monoclonal antibody, KKO, which binds to PF4-NET complexes, further enhances deoxyribonuclease resistance. However, the Fc portion of this antibody activates the immune response and increases thrombotic risk, negating any protective effects in sepsis. 

Therefore, Gollomps team developed an Fc-modified KKO that does not induce these negative outcomes. Treatment with this antibody augmented the effects of PF4, decreasing NDP release and bacterial dissemination, and increasing survival in murine sepsis models, supporting a novel NET-targeting approach to improve outcomes in sepsis.

 

Sherry