Potential of monoclonal antibodies against neonatal sepsis

Summary

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Infants, and 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 years, little improvement has been made in the development of preventative treatment strategies for severe bacterial infections in infants. At the same time, rising antibiotic resistance calls for new ways to prevent and treat bacterial 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 immune system of the newborn. We focus on three key components of antibacterial defense: antibodies, complement, and neutrophils. All three components are deficient in (preterm) infants. Using blood from umbilical cords (which is non-invasive for newborns), we developed laboratory models that more accurately reflect the neonatal immune system than widely used cell-lines. These age-appropriate models allowed us to test the potential of new antibody-based therapies. We used a technique to modify antibodies which enhances their complement-activating potential. This modification resulted in higher immune-activation in the neonatal model than conventional therapies like pooled immunoglobulins from healthy donors (IVIG). Additionally, we show that differences in complement profiles in neonates contribute to their vulnerability for gram-negative infections. The results from this thesis underline the need to consider the deficiencies of the immune system of the newborn when developing new antibody-based therapies. Overall, our results show that antibodies that effectively activate the complement system have the potential to protect against severe bacterial infections in newborns.