Blockade of HLA Antibody-Triggered Classical Complement Activation in Sera From Subjects Dosed With the Anti-C1s Monoclonal Antibody TNT009-Results from a Randomized First-in-Human Phase 1 Trial

Transplantation. 2017 Oct;101(10):2410-2418. doi: 10.1097/TP.0000000000001804.


Background: Complement may play a key role in antibody-mediated rejection. A promising therapeutic approach may be classical pathway (CP) inhibition at the level of early component C1.

Methods: In this first-in-human, double-blind, randomized placebo-controlled phase 1 trial, we evaluated the safety and complement inhibitory effect of TNT009, a humanized monoclonal anti-C1s antibody. Sixty-four adult healthy volunteers received either single (n = 48; 7 consecutive cohorts, 0.3-100 mg/kg) or 4 weekly infusions (n = 16; 2 consecutive cohorts, 30 and 60 mg/kg per infusion) of TNT009 or placebo. To assess the effect of treatment on complement activity, sera from dosed subjects were analyzed in a CP activation assay evaluating C3d deposition on HLA-coated microbeads spiked with alloantibodies.

Results: Single doses of TNT009 at 3 to 100 mg/kg uniformly and profoundly inhibited HLA antibody-mediated C3d deposition (≥86% after 60 minutes), whereby the duration of CP inhibition (2-14 days) was dose-dependent. Four weekly doses persistently blocked complement for 5 to 6 weeks. Ex vivo serum CP activity was profoundly inhibited when TNT009 concentrations exceeded 20 μg/mL. Infusions were well tolerated without serious or severe adverse events.

Conclusions: Treatment with TNT009 was safe and potently inhibited CP activity. Future studies in patients are required to assess the potential of TNT009 for preventing or treating antibody-mediated rejection.

Trial registration: NCT02502903.

Publication types

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

MeSH terms

  • Adult
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / blood
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Complement Activation / drug effects*
  • Complement C1s / antagonists & inhibitors*
  • Complement C1s / immunology
  • Complement Inactivating Agents / administration & dosage*
  • Complement Inactivating Agents / adverse effects
  • Complement Inactivating Agents / blood
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • HLA Antigens / immunology*
  • Healthy Volunteers
  • Humans
  • Infusions, Intravenous
  • Male
  • Time Factors
  • Treatment Outcome


  • Antibodies, Monoclonal, Humanized
  • Complement Inactivating Agents
  • HLA Antigens
  • TNT009
  • Complement C1s

Associated data

  • EudraCT/2014-003881-26