A novel modulator of IL-6R prevents inflammation-induced preterm birth and improves newborn outcome

A novel modulator of IL-6R prevents inflammation-induced preterm birth and improves newborn outcome

Abstract Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. Evidence supports a determinant role for interleukin-6 (IL-6) in the pathophysiology of PTB. Our group developed a small peptide, HSJ633, that antagonizes the interleukin-6 receptor (IL-6R). Binding assays performed o...

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Main Authors: France Côté, Elizabeth Prairie, Estefania Marin Sierra, Christiane Quiniou, Tiffany Habelrih, Wendy Xu, Béatrice Ferri, Xin Hou, Isabelle Lahaie, Nadia Côté, Sarah-Eve Loiselle, Laurence Gobeil, Kevin Sawaya, Aurélie Faucher, Amélie Beaulieu, Sandrine Delisle, Marie-Pénélope Simard, Mohammad Ali Mohammad Nezhady, Véronique Laplante, Allan Reuben, Sidi Mohamed Kalaidji, Emmanuel Bajon, Gael Cagnone, Kelycia B Leimert, Jean-François Gauchat, Luc Gaudreau, Sarah Robertson, William D Lubell, David M Olson, Sylvain Chemtob
Format: Article
Language:English
Published: Springer Nature 2025-07-01
Series:EMBO Molecular Medicine
Subjects:
Inflammation
Interleukin-6
Neonatal Mortality
Non-competitive Modulator
Preterm Birth
Online Access:https://doi.org/10.1038/s44321-025-00257-9
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Summary:Abstract Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. Evidence supports a determinant role for interleukin-6 (IL-6) in the pathophysiology of PTB. Our group developed a small peptide, HSJ633, that antagonizes the interleukin-6 receptor (IL-6R). Binding assays performed on HEK-Blue IL-6 cells reveal that HSJ633 appears to bind to IL-6R on a site remote from the IL-6 binding domain. Concordantly, HSJ633 selectively inhibits STAT3 phosphorylation while preserving the activation of cytoprotective AKT, p38, and ERK 1/2. In vivo, in a murine model of LPS-induced PTB, HSJ633 reduces inflammation in gestational and fetal tissues, preserves the integrity of fetal organs, and improves the survival of neonatal progeny when administered before and after the induction of labor by an inflammatory stimulus. Relevantly, the pharmacological inhibition of STAT3 in mice is sufficient to prevent PTB. Findings reveal first-in-class efficacy of a small peptide inhibitor of IL-6R, namely HSJ633, in impeding the inflammatory cascade associated with PTB and mitigating adverse neonatal outcomes.
ISSN:1757-4684

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