Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial

Blood. 2019 Feb 28;133(9):893-901. doi: 10.1182/blood-2018-06-856930. Epub 2018 Dec 17.


Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis. This trial tested the hypothesis that the anti-C1s antibody sutimlimab would ameliorate hemolytic anemia. Ten patients with cold agglutinin disease participated in the phase 1b component of a first-in-human trial. Patients received a test dose of 10-mg/kg sutimlimab followed by a full dose of 60 mg/kg 1 to 4 days later and 3 additional weekly doses of 60 mg/kg. All infusions were well tolerated without premedication. No drug-related serious adverse events were observed. Seven of 10 patients with cold agglutinin disease responded with a hemoglobin increase >2 g/dL. Sutimlimab rapidly increased hemoglobin levels by a median of 1.6 g/dL within the first week, and by a median of 3.9 g/dL (interquartile range, 1.3-4.5 g/dL; 95% confidence interval, 2.1-4.5) within 6 weeks (P = .005). Sutimlimab rapidly abrogated extravascular hemolysis, normalizing bilirubin levels within 24 hours in most patients and normalizing haptoglobin levels in 4 patients within 1 week. Hemolytic anemia recurred when drug levels were cleared from the circulation 3 to 4 weeks after the last dose of sutimlimab. Reexposure to sutimlimab in a named patient program recapitulated the control of hemolytic anemia. All 6 previously transfused patients became transfusion-free during treatment. Sutimlimab was safe, well tolerated, and rapidly stopped C1s complement-mediated hemolysis in patients with cold agglutinin disease, significantly increasing hemoglobin levels and precluding the need for transfusions. This trial was registered at as #NCT02502903.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anemia, Hemolytic / etiology
  • Anemia, Hemolytic / prevention & control*
  • Anemia, Hemolytic, Autoimmune / complications
  • Anemia, Hemolytic, Autoimmune / drug therapy*
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Complement C1s / antagonists & inhibitors*
  • Complement C1s / immunology
  • Female
  • Follow-Up Studies
  • Hemolysis / drug effects*
  • Humans
  • Male
  • Middle Aged
  • Prognosis
  • Prospective Studies
  • Severity of Illness Index*


  • Antibodies, Monoclonal, Humanized
  • Complement C1s
  • sutimlimab

Associated data