Maternal transplacental transfer of nipocalimab negligible in foetuses, neonates

In the phase II UNITY study, foetuses and neonates whose mums were receiving nipocalimab for early-onset (≤24 weeks gestational age [GA]) severe haemolytic disease of the foetus and newborn (EOS-HDFN) had minimal exposure to the drug.

“Undetectable or negligible levels of nipocalimab were observed in available foetal and neonatal samples and were well below the effective concentration for >90 percent FcRn* RO**, indicating that drug exposure was minimal following maternal dosing between 14 and 35 weeks GA,” said the researchers.

Of the five foetal samples, nipocalimab was detected in only one, with a concentration of 0.04 µg/mL. “[This was] well below the threshold concentration of 10 µg/mL for full FcRn RO, indicating negligible transplacental transfer of nipocalimab,” they said.

Nipocalimab was also detected in only one of 11 neonatal samples (concentration 0.7 µg/mL). The occupied FcRn measured at birth was 15.8 percent, signifying absence of full FcRn RO. The immunoglobulin G (IgG) level at birth was 162 mg/dL, which was within the range observed in other neonates (92–306 mg/dL) delivered by maternal participants who also met the primary endpoint but had no detectable nipocalimab at birth. [SMFM 2024, abstract 503]

At postnatal week 4, nipocalimab was undetectable in all available neonatal samples.

IgG concentrations

In five samples available at the first intrauterine transfusion (IUT), foetal to maternal IgG concentration ratios were 48:157, 43:196, 46:177, 43:197, and 43:152 mg/dL. According to the researchers, these were below values expected in typical pregnancies. [Obstet Gynecol 2009;114:1326-1331; Am J Reprod Immunol 1998;39:24-26]

At birth, median neonatal serum IgG was 181 mg/dL. IgG values were below the normal range at birth (lower limit of normal [LLN]: 636 mg/dL) in all neonates delivered by maternal participants who received nipocalimab within 2–3 weeks of delivery and supplemented with IV Ig ~2–3 days predelivery. “[The] low neonatal IgG levels is in line with the expected mechanism of action of nipocalimab inhibition of maternal transplacental IgG transfer,” said the researchers.

At postnatal week 4, median neonatal serum IgG was 305 mg/dL. The total IgG concentrations in neonates/infants remained near or just below the LLN and followed the normal trend for physiologic nadir between weeks 4 and 24.

A rare, life-threatening condition

HDFN is a rare, life-threatening condition that occurs when maternal IgG alloantibodies attack foetal red blood cells. Symptoms may range from mild jaundice to neurotoxic hyperbilirubinaemia in the neonate, to life-threatening foetal anaemia requiring invasive intervention. [Expert Rev Hematol 2017;10:7,607-616]

Pregnancies affected by severe HDFN might require repeat IUT, which are complex invasive surgical procedures tied to increased foetal mortality and premature birth rates. [Obstet Gynecol 2011;118:1323-1329; Case Rep Pediatr 2017;2017:6927813; BJOG 2013;120:847-852]

Nipocalimab, a high-affinity, fully human IgG monoclonal antibody designed to selectively block the IgG binding site on FcRn, is being studied across a broad range of IgG autoantibody/alloantibody-based diseases. [Clin Pharmacol Ther 2019;105:1031-1039, Am J Obstet Gynecol 2019;220:498.e1-498.e9] “Inhibition of FcRn may prevent IgG alloantibody transfer to the foetus and lower maternal serum IgG alloantibodies,” said the researchers.

Thirteen mums with a singleton pregnancy (GA 8–14 weeks) and history of EOS-HDFN were given IV nipocalimab 30 or 45 mg/kg weekly between 14 and 35 weeks GA, with an expected delivery at 37 weeks GA. Of the 13 pregnancies, 12 led to live births, while one led to foetal loss owing to IUT complications at 22 weeks GA.

Addressing an unmet need

To date, there are no nonsurgical interventions approved for pregnancies at high risk of EOS-HDFN in the US. Nipocalimab is the only anti-FcRn being evaluated for this rare and potentially life-threatening condition. [https://www.jnj.com/media-center/press-releases/johnson-johnson-highlights-innovation-in-hemolytic-disease-of-the-fetus-and-newborn-hdfn-at-the-society-for-maternal-fetal-medicines-smfm-2024-pregnancy-meeting]

“The potential for nipocalimab exposure in the foetus and newborn will be further evaluated in a phase III study,” the researchers concluded.