A Randomized Clinical Trial of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection

J Am Soc Nephrol. 2021 Mar;32(3):708-722. doi: 10.1681/ASN.2020071106. Epub 2020 Dec 18.


Background: Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy.

Methods: We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab.

Results: Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab.

Conclusions: Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.

Keywords: antibody-mediated rejection; chronic rejection; interleukin-6; monoclonal antibody; randomized controlled trial; renal transplantation.

Publication types

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

MeSH terms

  • Adult
  • Allografts
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Double-Blind Method
  • Female
  • Glomerular Filtration Rate
  • Graft Rejection / immunology
  • Graft Rejection / physiopathology
  • Graft Rejection / therapy*
  • Humans
  • Infections / etiology
  • Interleukin-6 / antagonists & inhibitors*
  • Interleukin-6 / immunology
  • Isoantibodies / blood
  • Kidney Transplantation / adverse effects*
  • Male
  • Middle Aged
  • Tissue Donors
  • Treatment Outcome
  • Young Adult


  • Antibodies, Monoclonal, Humanized
  • IL6 protein, human
  • Interleukin-6
  • Isoantibodies
  • clazakizumab