Severe hemolytic disease of the fetus and newborn (HDFN) in early onset can cause fetal anemia, hydrops, and perinatal mortality, often necessitating invasive fetal transfusions. Recent phase 2 results show that antenatal therapy with nipocalimab, a neonatal Fc receptor (FcRn) inhibitor, not only delays or prevents fetal anemia but also appears to be non-toxic to infants, with preserved immune system development at 96 weeks of age. These results imply that FcRn inhibitors used during pregnancy may provide a safer alternative to invasive fetal procedures. The study was published in The New England Journal of Medicine Evidence by Derek P. and colleagues.
Nipocalimab decreases the transfer of pathogenic maternal immunoglobulin G (IgG) from mother to fetus by inhibiting FcRn, thus decreasing fetal exposure to hemolytic antibodies. Although previous studies showed clinical efficacy in reducing fetal anemia, there were concerns about fetal exposure to the drug, suppression of neonatal IgG, and immune function. This analysis was conducted to assess fetal and neonatal pharmacokinetics of nipocalimab and immune recovery in infants up to 96 weeks.
UNITY was a single-group, open-label phase 2 study enrolling pregnant women at high risk of early severe HDFN. Participants received nipocalimab intravenously once a week at 30 or 45 mg/kg from 14 to 35 weeks of gestation, unless prematurely discontinued for safety reasons or the start of intrauterine transfusion. Pharmacokinetic evaluations were conducted in maternal blood, fetal material, cord blood, colostrum, and breast milk. Outcomes included neonatal and infant IgG, FcRn receptor occupancy, rates of infection, and immune responses to vaccines up to 96 weeks postpartum. Safety analyses included 12 live births from 13 pregnancies, with one pregnancy resulting in fetal loss due to complications of intrauterine transfusion. All 13 pregnancies were at high risk for severe HDFN.
Key findings
Maternal nipocalimab levels remained above pharmacologically active concentrations (>10 μg/ml) during the weekly dosing cycles.
In contrast, fetal and infant levels were low. Nipocalimab levels were ≤10 μg/ml in fetal and infant samples, including 0.04 μg/ml in one of four fetal cordocentesis, 0.7 μg/ml in one of 11 cord blood samples, <4 μg/ml in three of seven colostrum samples, and <2 μg/ml in two of nine breast milk samples, reflecting low placental and postnatal transfer.
Infants had low IgG levels at birth, with a median cord blood IgG of 175 mg/dl (range 92-941 mg/dl).
IgG levels followed a physiological curve, with nadirs at 24 weeks (median 273 mg/dl, range 153-429 mg/dl) and normalization to the normal range between 16 and 96 weeks in all but one infant (median 762 mg/dl, range 407-925 mg/dl).
This is consistent with transient IgG suppression without long-term immune dysfunction.
In 12 live-born infants, antenatal nipocalimab exposure was associated with low detectable drug levels in fetal and infant samples.
Despite low IgG levels at birth, IgG levels normalized with time, and infants exhibited normal infection courses and appropriate vaccine-induced immunity through nearly two years of follow-up.
In high-risk HDFN pregnancies, antenatal nipocalimab administration led to low fetal and neonatal exposure to the drug, transiently low IgG levels at birth, and maintained infant immunity through 96 weeks. The lack of unexpected infections or impaired vaccine responses also supports the potential of nipocalimab as a safe and effective prenatal treatment for HDFN.
Reference:
de Winter, D. P., Moise, K. J., Ling, L. E., Oepkes, D., Tiblad, E., Joanne Verweij, E. J. T., Smoleniec, J., Sachs, U. J., Bein, G., Kilby, M. D., Miller, R. S., Devlieger, R., Streisand, J. B., Bredius, R. G. M., Cafone, J., Lam, E., Leu, J. H., Mirza, A., Nelson, R. M., … Lopriore, E. (2026). Infant immunity after maternal nipocalimab in severe hemolytic disease of the fetus and newborn. NEJM Evidence, 5(2), EVIDoa2500097. https://doi.org/10.1056/EVIDoa2500097
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