Date: Tuesday, June 14, 2016
Session Time: 2:30pm-4:00pm
Presentation Time: 2:54pm-3:06pm
Location: Veterans Auditorium
Study purpose: Classical complement may play a key role in ABMR. A promising therapeutic approach could be complement inhibition at the level of key component C1. In this single ascending dose part of a first-in-human phase 1 trial (NCT02502903) we evaluated the tolerability and activity of TNT009, a high-affinity humanized monoclonal antibody directed against serine protease C1s. Methods: In a double-blind, randomized, placebo-controlled phase 1 trial, 48 healthy volunteers received either a single dose of TNT009 or placebo by IV infusion (3:1 randomization; 7 cohorts: 0.3-100 mg/kg). To determine the effect of TNT009 on ex vivo HLA antibody-triggered complement activation, serum samples from dosed subjects were added as a complement source in a modified solid phase assay. C3d deposition was detected on HLA haplotype-coated flow beads pre-incubated with pooled inactivated sera obtained from sensitized patients. Results were expressed as the mean of C3d MFI determined on 16 defined bead populations. Results. Single doses of 3-100 mg/kg TNT009 led to a >85% inhibition of HLA antibody-triggered C3d bead deposition. At doses of 10, 30, 60 or 100 mg/kg this effect lasted for 2 to at least 14 days. C3d test results showed a tight dose-effect relationship without major inter-individual differences. Similarly, in vitro spiking of sera with TNT009 revealed uniform and strong complement inhibition at concentrations >30 [mu]g/mL. Conclusion. We demonstrate that TNT009 allows for prolonged and complete classical pathway inhibition in vivo. Future studies will clarify whether TNT009 is able to block antibody-mediated injury as a strategy to prevent or treat ABMR.
CITATION INFORMATION: Mühbacher J, Jilma B, Wahrmann M, Marinova L, Eskandary F, Gilbert J, Panicker S, Böhmig G. Blockade of HLA Antibody-Triggered Classical Complement Activation by High-Affinity Humanized Monoclonal Anti-C1s Antibody TNT009 – Results of a First-in-Human Phase 1 Trial. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Mühbacher J, Jilma B, Wahrmann M, Marinova L, Eskandary F, Gilbert J, Panicker S, Böhmig G. Blockade of HLA Antibody-Triggered Classical Complement Activation by High-Affinity Humanized Monoclonal Anti-C1s Antibody TNT009 – Results of a First-in-Human Phase 1 Trial. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/blockade-of-hla-antibody-triggered-classical-complement-activation-by-high-affinity-humanized-monoclonal-anti-c1s-antibody-tnt009-results-of-a-first-in-human-phase-1-trial/. Accessed January 19, 2020.
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