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Blocking ADAM17 Function with a Monoclonal Antibody Improves Sepsis Survival in a Murine Model of Polymicrobial
Hemant K Mishra1, Jing Ma1, Daniel Mendez1
1Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
Abstract:
Sepsis is the culmination of hyperinflammation and immune suppression in response to severe infection. Neutrophils are critical early responders to bacterial infection but can become highly dysfunctional during sepsis and other inflammatory disorders. The transmembrane protease ADAM17 (a disintegrin and metalloproteinase 17) is expressed by leukocytes and most other cells and has many substrates that regulate inflammation. We have reported that conditional knockout mice lacking ADAM17 in all leukocytes had a survival advantage during sepsis, which was associated with improved neutrophil effector functions. These and other findings indicate aberrant ADAM17 activity during sepsis. For this study, we evaluated for the first time the effects of an ADAM17 function blocking monoclonal antibody (mAb) on the pathogenesis of polymicrobial sepsis. Mice treated with the ADAM17 mAb MEDI3622 prior to sepsis induction exhibited significantly decreased mortality. When the ADAM17 mAb was combined with antibiotic administration, sepsis survival was markedly enhanced compared to either intervention alone, which was associated with a significant reduction in plasma levels of various inflammation-related factors. MEDI3622 and antibiotic administration after sepsis induction also significantly improved survival. Our results indicate that the combination of blocking ADAM17 as an immune modulator and appropriate antibiotics may provide a new therapeutic avenue for sepsis treatment.
Insights
Blocking ADAM17 (a disintegrin and metalloproteinase 17) with a monoclonal antibody improved survival in sepsis models. Combining this immune modulator with antibiotics significantly enhanced treatment efficacy, offering a potential new sepsis therapy.
Area of Science:
- Immunology
- Molecular Biology
- Pathogenesis of Sepsis
Background:
- Sepsis involves hyperinflammation and immune suppression, with neutrophils playing a key role.
- Dysfunctional neutrophils are observed in sepsis, and ADAM17 (a disintegrin and metalloproteinase 17) activity is implicated.
- Previous studies showed a survival advantage in sepsis when ADAM17 was conditionally knocked out in leukocytes.
Purpose of the Study:
- To evaluate the efficacy of an ADAM17 function-blocking monoclonal antibody (mAb) in a polymicrobial sepsis model.
- To assess the combined therapeutic effect of ADAM17 blockade and antibiotic administration in sepsis.
Main Methods:
- Utilized a polymicrobial sepsis model in mice.
- Administered the ADAM17 mAb (MEDI3622) either before or after sepsis induction.
- Evaluated survival rates and plasma levels of inflammation-related factors.
- Combined ADAM17 mAb treatment with antibiotic therapy.
Main Results:
- Treatment with the ADAM17 mAb MEDI3622 significantly decreased mortality in mice with sepsis.
- Combining the ADAM17 mAb with antibiotics markedly enhanced sepsis survival compared to either treatment alone.
- Combined therapy led to a significant reduction in plasma levels of inflammation-related factors.
- Post-sepsis induction administration of MEDI3622 and antibiotics also improved survival.
Conclusions:
- Blocking ADAM17 activity with a monoclonal antibody is a promising immunomodulatory strategy for sepsis.
- The combination of ADAM17 blockade and antibiotics represents a potential novel therapeutic approach for sepsis treatment.
- Targeting ADAM17 may restore neutrophil function and mitigate sepsis-induced inflammation.
