Kenneth J. Moise Jr, MD, discusses potential of FcRn blockade to reduce invasive treatment in HDFN

Hemolytic disease of the fetus and newborn (HDFN) remains a serious pregnancy complication driven by maternal immunoglobulin (IgG) antibodies that cross the placenta and destroy fetal red blood cells. In a recent discussion, Kenneth Moise, MD, professor of Women’s Health at Dell Medical School at the University of Texas at Austin, described emerging data on neonatal Fc receptor (FcRn) blockade as a potential medical alternative to invasive fetal transfusion.^1,2

Moise explained that the neonatal Fc receptor is central to maternal-fetal antibody transfer. “So we know the FcRn, or what’s called the neonatal FC receptor, is the primary receptor to transfer antibody from the mother to the fetus. It’s on the placenta,” he said. While this physiologic process provides passive immunity to the fetus, it also allows pathogenic antibodies to cross. “So for the most part, good antibody crosses the placenta, but in cases like red cell elimination, bad antibodies can cross also,” he noted.

Targeting FcRn blocks placental antibody transfer and lowers circulating maternal IgG levels. “When you target FcRn and alloimmunization, you actually target 2 different approaches—first, placental passage, which is blocking that, and you also drop the maternal titer. It’s a dual approach,” Moise said. By preventing IgG recycling in endothelial cells, FcRn blockade promotes degradation of IgG, reducing both protective and pathogenic antibodies.

A key concern has been fetal exposure to the FcRn-blocking agent. Preclinical studies in monkeys and in vitro placental models demonstrated minimal placental transfer. In a small clinical cohort, drug levels were assessed in fetal blood obtained during cordocentesis and in cord blood at delivery. “There were almost undetectable levels of nipocalimab present,” Moise said, adding that this agent is tightly bound to the receptor and does not readily cross into the fetal circulation.

Another concern is the impact on neonatal immunity. Because FcRn blockade reduces transplacental IgG transfer, infants are born with lower IgG levels. In the phase 2 study, some infants received intravenous immune globulin in early life. “Their antibody levels did drop a bit, as you would expect them to do,” Moise said. IgG levels nadired between 4 and 24 weeks before rising into the normal range as endogenous production increased.

Importantly, other immune components were not affected. “Nipocalimab doesn’t affect all your other immunity, your T cells, your IgM, your IgA, none of those antibodies or T cells are affected,” Moise stated. Clinically, infection rates were consistent with typical pediatric illnesses. “We didn’t see any overt infections in these children, even though some of them had low IgG levels initially,” he said, noting only routine infections and isolated cases of respiratory syncytial virus and COVID-19 without lasting sequelae.

Vaccination responses were also evaluated. In preclinical studies, neonatal monkeys responded to immunization. In the human cohort, most infants received routine vaccines and demonstrated measurable responses, although only 1 vaccine was formally assessed. “At this point, again, we are reassured that they will get a response to their vaccinations,” Moise said, while emphasizing the need for larger studies. The ongoing phase 3 AZALEA trial (NCT05912517) will include a larger sample to further evaluate safety and immunologic outcomes.

Currently, management of severe HDFN relies on serial ultrasound surveillance and intrauterine transfusion. “You don’t do it once. You do it 4 to 6 times during the pregnancy, and each time you do it, there’s a risk to the baby being born prematurely or even losing the baby,” Moise said.

He characterized FcRn blockade as transformative. “I think this is a real game changer when it comes to treating this disease,” Moise said. Beyond HDFN, he suggested potential application in other antibody-mediated fetal conditions, including congenital heart block and fetal and neonatal alloimmune thrombocytopenia.

Long-term data remain limited, and Moise emphasized that broader conclusions await results from larger trials. However, early findings suggest that FcRn blockade may offer a noninvasive strategy to reduce maternal antibody–mediated fetal injury while maintaining acceptable neonatal immune outcomes.

Disclosure

Moise reports no relevant disclosures.

References

1. de Winter DP, Moise KJ, Ling LE, et al. Infant immunity after maternal nipocalimab in severe hemolytic disease of the fetus and newborn. NEJM Evid. 2026;5(2):EVIDoa2500097. doi:10.1056/EVIDoa2500097
2. Moise KJ Jr, Ling LE, Oepkes D, et al. Nipocalimab in early-onset severe hemolytic disease of the fetus and newborn. N Engl J Med. 2024;391(6):526-537. doi:10.1056/NEJMoa2314466