Complement Inhibitor Blocks Preterm Birth and Protects Fetal Brain in Mouse Study

Preterm birth, defined as delivery before 37 weeks of gestation, affects roughly 12% of US pregnancies and is the leading cause of neonatal morbidity and mortality. Complications include cerebral palsy, intraventricular hemorrhage, and neonatal sepsis. Although ascending intrauterine infection is a well-recognized driver, effective clinical interventions remain limited to tocolytics, vaginal progesterone, and cervical cerclage—all with modest efficacy. This study investigates whether the complement system, a key arm of innate immunity previously linked to cervical remodeling and myometrial contractions, can be therapeutically targeted to prevent inflammation-induced preterm birth.

The researchers employed a well-validated mouse model in which 25 µg of LPS (E. coli serotype O111:B4) was injected directly into the myometrium of C57BL/6 timed-pregnant mice on embryonic day 15 (E15). Complement activation (C3 deposition) was detectable in cervical tissue within 1 hour of LPS administration and was substantially elevated by 9 hours. Based on this kinetic data, CR2-Crry—a recombinant fusion protein combining complement receptor 2 (CR2) targeting domain with the regulatory protein Crry—was administered intravenously at 20 mg/kg at 1 hour and again at 9 hours post-LPS. CR2 selectively binds to deposited C3 fragments at sites of complement activation, enabling localized inhibition of C3 convertase and blocking all downstream complement effectors.

Treatment with CR2-Crry produced dramatic improvements in delivery outcomes. Vehicle-treated dams delivered in approximately 31 hours post-LPS, while CR2-Crry-treated dams averaged 109 hours. Median gestational age at delivery shifted from 16.0 days (preterm) to 20.0 days (near-term/term), p=0.0006. Vehicle-treated animals produced zero viable pups on average, while CR2-Crry-treated animals produced an average of 2.4 viable pups, p=0.003. A Kaplan–Meier survival curve showed 50% of treated dams were still pregnant at 100 hours post-LPS, compared to 0% of controls. At the tissue level, CR2-Crry significantly reduced cervical C3 deposition (p=0.0024) and macrophage infiltration (Iba1 staining), consistent with a mechanism whereby complement activation drives MMP-9-mediated collagen degradation and cervical dilation.

Beyond maternal outcomes, the study assessed fetal brain tissue. LPS-exposed fetuses from vehicle-treated dams showed elevated complement deposition, higher pro-inflammatory cytokines (including IL-1β, IL-6, TNF-α, MCP-1), and increased macrophage recruitment in brain tissue. CR2-Crry treatment significantly attenuated all of these markers in fetal brain, suggesting that complement-mediated neuroinflammation beginning in utero may be a critical and modifiable pathway contributing to neurodevelopmental sequelae in preterm infants.

The clinical translational potential is bolstered by the fact that a human-targeted complement inhibitor directed at the same CR2 ligand (deposited C3 fragments) has been well tolerated in Phase 1 trials and is currently in Phase 2 development. The site-targeting approach minimizes systemic immunosuppression risk—a key concern with broad complement blockade during pregnancy. Limitations include the reliance on a single murine LPS model, which may not capture the full complexity of human preterm labor, and the absence of long-term neonatal neurodevelopmental outcome data. Nonetheless, this study provides the strongest mechanistic and interventional evidence to date that complement inhibition can prevent inflammation-driven preterm birth and protect the fetal brain.