尼泊钙单抗治疗早发型严重胎儿和新生儿溶血病。
Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn.
机构信息
From Dell Medical School, University of Texas at Austin, and the Comprehensive Fetal Care Center, Dell Children's Medical Center - both in Austin (K.J.M.); Janssen Pharmaceuticals, Cambridge, MA (L.E.L., J.H.L., A.M., V.S., L.B.S., M.L.T., S.S.-K., Y.K.); the Departments of Obstetrics (D.O., E.J.T.J.V.) and Pediatrics (E.L.), Leiden University Medical Center, Leiden, the Netherlands; the Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm (E.T.); the Feto-Maternal Unit, Liverpool Hospital, Liverpool, NSW, Australia (J.S.); the Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University (U.J.S., G.B.), and the Department of Thrombosis and Hemostasis, Giessen University Hospital (U.J.S.) - both in Giessen, Germany; the University of Birmingham and the Fetal Medicine Center, Birmingham Women's and Children's NHS Foundation Trust, Birmingham (M.D.K.), and University College London Hospitals NHS Foundation Trust, London (P.P.) - all in the United Kingdom; the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Irving Medical Center (R.S.M.), the Department of Pediatrics, Division of Hematology-Oncology, Weill Cornell Medical College (J.B.B.), and NewYork-Presbyterian Hospital (J.B.B.) - all in New York; the Department of Obstetrics and Gynecology, University Hospitals KU Leuven, Leuven, and the Department of Obstetrics, Gynecology, and Fertility, GZA Campus Sint-Augustinus, Wilrijk - both in Belgium (R.D.); Centre Hospitalier Universitaire Sainte-Justine Research Center, Université de Montréal, Montreal (F.A.), and Mount Sinai Hospital Toronto and University of Toronto, Toronto (R.W.) - both in Canada; UPMC Magee-Womens Hospital, Pittsburgh (S.P.E.); the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Cincinnati Medical Center, Cincinnati (K.M.); the Department of Obstetrics and Gynecology, University of California, San Francisco, and Zuckerberg San Francisco General Hospital - both in San Francisco (M.E.N.); San Cecilio University Hospital, Granada, Spain (O.O.-H.); the Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland (L.P.); University of Utah Health, Salt Lake City (R.M.S.); and Streisand Biomedical Consulting, Wayland, MA (J.B.S.).
出版信息
N Engl J Med. 2024 Aug 8;391(6):526-537. doi: 10.1056/NEJMoa2314466.
BACKGROUND
In early-onset severe hemolytic disease of the fetus and newborn (HDFN), transplacental transfer of maternal antierythrocyte IgG alloantibodies causes fetal anemia that leads to the use of high-risk intrauterine transfusions in order to avoid fetal hydrops and fetal death. Nipocalimab, an anti-neonatal Fc receptor blocker, inhibits transplacental IgG transfer and lowers maternal IgG levels.
METHODS
In an international, open-label, single-group, phase 2 study, we assessed treatment with intravenous nipocalimab (30 or 45 mg per kilogram of body weight per week) administered from 14 to 35 weeks' gestation in participants with pregnancies at high risk for recurrent early-onset severe HDFN. The primary end point was live birth at 32 weeks' gestation or later without intrauterine transfusions as assessed against a historical benchmark (0%; clinically meaningful difference, 10%).
RESULTS
Live birth at 32 weeks' gestation or later without intrauterine transfusions occurred in 7 of 13 pregnancies (54%; 95% confidence interval, 25 to 81) in the study. No cases of fetal hydrops occurred, and 6 participants (46%) did not receive any antenatal or neonatal transfusions. Six fetuses received an intrauterine transfusion: five fetuses at 24 weeks' gestation or later and one fetus before fetal loss at 22 weeks and 5 days' gestation. Live birth occurred in 12 pregnancies. The median gestational age at delivery was 36 weeks and 4 days. Of the 12 live-born infants, 1 received one exchange transfusion and one simple transfusion and 5 received only simple transfusions. Treatment-related decreases in the alloantibody titer and IgG level were observed in maternal samples and cord blood. No unusual maternal or pediatric infections were observed. Serious adverse events were consistent with HDFN, pregnancy, or prematurity.
CONCLUSIONS
Nipocalimab treatment delayed or prevented fetal anemia or intrauterine transfusions, as compared with the historical benchmark, in pregnancies at high risk for early-onset severe HDFN. (Funded by Janssen Research and Development; UNITY ClinicalTrials.gov number, NCT03842189.).
背景
在早发性严重胎儿和新生儿溶血病（HDFN）中，母体抗红细胞 IgG 同种异体抗体通过胎盘转移导致胎儿贫血，这需要进行高风险的宫内输血以避免胎儿水肿和胎儿死亡。Nipocalimab 是一种抗新生儿 Fc 受体阻断剂，可抑制胎盘 IgG 转移并降低母体 IgG 水平。
方法
在一项国际性、开放性、单组、2 期研究中，我们评估了从 14 周至 35 周妊娠期间，给处于早发性严重 HDFN 高危妊娠的参与者静脉注射 nipocalimab（每周每公斤体重 30 或 45mg）的治疗效果。主要终点是在没有宫内输血的情况下活产至少 32 周，该主要终点以历史基准（0%；有临床意义的差异为 10%）为对照。
结果
在研究中，13 例妊娠中有 7 例（54%；95%置信区间，25%~81%）在 32 周妊娠或之后活产且没有宫内输血。没有胎儿水肿的病例，6 名参与者（46%）没有接受任何产前或新生儿输血。6 名胎儿接受了宫内输血：5 名在 24 周妊娠或之后，1 名在妊娠 22 周零 5 天胎儿丢失前。12 例妊娠活产。分娩的中位妊娠周数为 36 周零 4 天。在 12 例活产婴儿中，1 例接受了 1 次换血和 1 次单纯输血，5 例仅接受了单纯输血。母体样本和脐血中观察到与治疗相关的同种异体抗体滴度和 IgG 水平下降。未观察到异常的母体或儿科感染。严重不良事件与 HDFN、妊娠或早产一致。
结论
与历史基准相比，nipocalimab 治疗在早发性严重 HDFN 的高危妊娠中延迟或预防了胎儿贫血或宫内输血。（由 Janssen Research and Development 资助；UNITY ClinicalTrials.gov 编号，NCT03842189）。
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