Fc-modified HIT-like monoclonal antibody as a novel treatment for sepsis

Abstract

Sepsis is characterized by multiorgan system dysfunction that occurs because of infection. It is associated with high morbidity and mortality and is 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 multiorgan 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. We propose that interventions that stabilize NETs and sequester NDPs may be protective in sepsis. We showed that platelet factor 4 (PF4), a platelet-associated chemokine, binds and compacts NETs, increasing their resistance to DNase I. We 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 DNase resistance. However, the Fc portion of this antibody activates the immune response and increases thrombotic risk, negating any protective effects in sepsis. Therefore, we 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.

Targeting Neutrophils in Sepsis: From Mechanism to Translation

“…In addition, in several observational studies, administration of antiplatelet therapy has been shown to be associated with improved outcome in patients with sepsis (Eisen et al, 2012;Chen et al, 2015). Recently, a novel treatment which stabilizes NETs to enhance their capacity of capturing bacteria and prevent the release of antibacterial compounds causing tissue damage has been discovered (Gollomp et al, 2020). Researchers developed an antibody that binds to complexes of NETs and platelet factor 4 (PF4), a protein released by activated platelets, which causes the NETs to resist degradation and improves their ability to capture bacteria.…”

“…Neutrophil extracellular traps (NETs) in sepsis are also not controlled properly, and play an important role in tissue damage and coagulation disturbance. combined with antibiotics, this treatment significantly reduced the severity of illness, decreased the levels of bacteria circulating in the blood, and improved survival in the animal sepsis model (Gollomp et al, 2020). A large-scale clinical trial which evaluates the efficacy of antiplatelet therapy in sepsis is currently underway and may provide interesting results in the future (Eisen et al, 2017; Table 1).…”

Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease

“…In addition, in the murine model it has been shown that binding of a monoclonal antibody to NET complexes in sepsis increases the overall survival. This seems mainly due to the fact that antibody binding protects NETs from DNase I, resulting in less toxic NET-associated degradation products [ 138 ].…”

Potential therapeutics in pediatric acute respiratory distress syndrome: what does the immune system have to offer? A narrative review

“…However, a more nuanced view of NETs requires an acknowledgement of their beneficial antimicrobial properties. Studies investigating NET stability offer insight into balancing the beneficial and toxic effects of NETs in vivo (80). Platelet factor 4 (PF4), a platelet-associated chemokine, binds, compacts, and stabilizes NETs in the microvasculature, increasing their resistance to DNase I. PF4 increased NET-mediated bacterial capture, reduced the release of NET degradation products, and improved outcomes in murine sepsis (80).…”