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<p>Soluble Fms-like tyrosine kinase 1 (sFlt-1), a protein secreted by the placenta, plays a central role in the pathogenesis of preeclampsia—a life-threatening pregnancy complication for which no disease-specific treatment currently exists. We developed a strategy to selectively deplete circulating sFlt-1 and then conducted a single-arm, open-label trial to reduce circulating sFlt-1 in women with very preterm preeclampsia. The primary endpoints were safety and tolerability. Extracorporeal apheresis with an adsorber containing high-affinity IgG1 antibodies against sFlt-1 resulted in an approximately 50% reduction of circulating sFlt-1 levels in pregnant baboons. In women with preterm preeclampsia treated with single ascending doses (phase A, <i>n</i> = 7, preapheresis, mean ± s.d., sFlt-1: 15,120 ± 4,484 pg ml<sup>−1</sup>), maternal and fetal vital signs and umbilical artery pulsatility indices remained stable when comparing measures before, during and after apheresis. In women with very preterm preeclampsia treated with multiple doses (phase B, <i>n</i> = 9, median gestational age 30.3 (interquartile range, 29.3−30.9) weeks, systolic and diastolic blood pressures 146 ± 10 and 92 ± 5 mmHg, respectively, and preapheresis circulating sFlt-1 levels 11,960 ± 3,056 pg ml<sup>−1</sup>), each apheresis reduced sFlt-1 levels by 16.7 ± 7.6% and mean arterial pressures by 4.1 ± 7.8 mmHg. Reductions in mean arterial pressures after apheresis strongly correlated with reductions in circulating sFlt-1 (<i>R</i> = 0.63, Spearmanʼs correlation). Pregnancy continued from admission for a median of 10 (range, 3−19) days. Compared to antenatal estimated birth weights, neonatal birth weights generally remained stable or increased among those with the longest extensions. Treatment-related adverse events included mild hypocalcemia (<i>n</i> = 3), skin hemorrhage at the puncture site (<i>n</i> = 1) and false labor (<i>n</i> = 1). Selective removal of sFlt-1 by apheresis appeared to be safe and well tolerated in women with very preterm preeclampsia. Controlled trials are needed to confirm the additional safety and efficacy of this approach. ClinicalTrials.gov registration: <a href="http://clinicaltrials.gov/study/NCT02923206">NCT02923206</a>.</p>

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Targeted removal of soluble Fms-like tyrosine kinase 1 in very preterm preeclampsia: a pilot trial

  • 期刊论文

  • 发表日期：

    2026年4月27日

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  • Ravi Thadhani,
  • Thomas F. Hiemstra,
  • Manu Vatish,
  • Holger Stepan,
  • Ana Sofia Cerdeira,
  • Jeremy Brockelsby,
  • Tim James,
  • Massimiliano Lia,
  • Alissa Cornelis,
  • Elena Krause,
  • Martin R. Spath,
  • Berthold Grüttner,
  • Polina Todorova,
  • Henning Hagmann,
  • Kristen R. Yeung,
  • Bei Xu,
  • Scott Heffernan,
  • Suzanne Pears,
  • Richard Waugh,
  • John Thompson,
  • Jim Iliopoulos,
  • Neroli Sunderland,
  • Murray Killingsworth,
  • Angela Makris,
  • Annemarie Hennessy,
  • Agnes Lo,
  • Adelene Y. Tan,
  • Paul Kussie,
  • Yuchiao Chang,
  • Linda Hanssens,
  • Stefan Miltenyi,
  • Thomas Benzing,
  • S. Ananth Karumanchi

摘要

Soluble Fms-like tyrosine kinase 1 (sFlt-1), a protein secreted by the placenta, plays a central role in the pathogenesis of preeclampsia—a life-threatening pregnancy complication for which no disease-specific treatment currently exists. We developed a strategy to selectively deplete circulating sFlt-1 and then conducted a single-arm, open-label trial to reduce circulating sFlt-1 in women with very preterm preeclampsia. The primary endpoints were safety and tolerability. Extracorporeal apheresis with an adsorber containing high-affinity IgG1 antibodies against sFlt-1 resulted in an approximately 50% reduction of circulating sFlt-1 levels in pregnant baboons. In women with preterm preeclampsia treated with single ascending doses (phase A, n = 7, preapheresis, mean ± s.d., sFlt-1: 15,120 ± 4,484 pg ml−1), maternal and fetal vital signs and umbilical artery pulsatility indices remained stable when comparing measures before, during and after apheresis. In women with very preterm preeclampsia treated with multiple doses (phase B, n = 9, median gestational age 30.3 (interquartile range, 29.3−30.9) weeks, systolic and diastolic blood pressures 146 ± 10 and 92 ± 5 mmHg, respectively, and preapheresis circulating sFlt-1 levels 11,960 ± 3,056 pg ml−1), each apheresis reduced sFlt-1 levels by 16.7 ± 7.6% and mean arterial pressures by 4.1 ± 7.8 mmHg. Reductions in mean arterial pressures after apheresis strongly correlated with reductions in circulating sFlt-1 (R = 0.63, Spearmanʼs correlation). Pregnancy continued from admission for a median of 10 (range, 3−19) days. Compared to antenatal estimated birth weights, neonatal birth weights generally remained stable or increased among those with the longest extensions. Treatment-related adverse events included mild hypocalcemia (n = 3), skin hemorrhage at the puncture site (n = 1) and false labor (n = 1). Selective removal of sFlt-1 by apheresis appeared to be safe and well tolerated in women with very preterm preeclampsia. Controlled trials are needed to confirm the additional safety and efficacy of this approach. ClinicalTrials.gov registration: NCT02923206.