Potential of monoclonal antibodies against neonatal sepsis: lessons from age-specific in vitro models

Abstract

Infants, especially those born prematurely, are highly vulnerable to sepsis, a life-threatening condition that remains one of the leading causes of newborn mortality worldwide. Over the past decades, limited progress has been made in developing preventive strategies against severe bacterial infections in this population. At the same time, rising antibiotic resistance calls for new ways to prevent and treat these infections safely and effectively. This thesis explores how newborns can be better protected against bacterial infections by studying the interplay between monoclonal antibodies and the neonatal immune system. We focus on three key components of antibacterial defense: antibodies, complement, and neutrophils - all of which are known to be deficient in preterm infants. Using blood from umbilical cords, we developed laboratory models that more accurately reflect the immune system of newborns than conventional cell-line models. These age-appropriate models allowed us to test the potential of new antibody-based therapies. We engineered antibodies to enhance their complement-activating potential and found that these modified antibodies triggered stronger immune responses in neonatal models compared to conventional therapies, such as pooled immunoglobulins from healthy donors (IVIG). Furthermore, we show that differences in complement profiles in neonates contribute to their increased susceptibility to Gram-negative infections. Together, the results of this thesis highlight the importance of considering the immunological characteristics of newborns when developing new antibody-based therapies. Antibodies that effectively activate the complement system may offer a promising strategy to protect newborns from severe bacterial infections.