Date: Sunday, April 30, 2017
Session Time: 4:30pm-6:00pm
Presentation Time: 4:54pm-5:06pm
Study purpose. Complement inhibition may be an attractive strategy to prevent antibody-mediated allograft injury. One promising therapeutic target may be the enzymatic activity of key classical pathway (CP) component C1. In this first-in-human trial (NCT02502903) we evaluated the impact of 4 weeks treatment with TNT009, a humanized anti-C1s antibody on CP activity in healthy individuals and kidney transplant recipients with late antibody-mediated rejection (ABMR). Methods. Sixteen healthy volunteers received 4 weekly IV doses of TNT009 or placebo (6:2 randomization, two cohorts: 30 or 60 mg/kg). Subsequently, 10 kidney transplant recipients diagnosed with late ABMR were treated with TNT009 (initial test dose of 10 mg/kg followed by 4 weekly doses of 60 mg/kg). To assess ex vivo HLA antibody-triggered complement activation, sera from dosed subjects were analysed on microbeads sensitized with HLA antibodies using the read-out of C3d fixation. Results. Baseline C3d deposition levels were not significantly different between healthy volunteers and transplant recipients (mean C3d MFI: 4882±754 versus 4367±1030, p=0.15). In healthy volunteers, multiple doses of TNT009 led to a persistent (≥4 weeks) and >80% inhibition of HLA antibody-triggered C3d deposition (and in parallel CH50 activity). Similarly, sustained complement inhibition was also achieved in the cohort of ABMR patients, with a comparable degree of CP blockade. CP inhibition tightly correlated with plasma levels of TNT009. Conclusion. Multiple doses of TNT009 allowed for a prolonged and near complete CP inhibition both in healthy volunteers and ABMR patients. Our results provide a valuable basis for future studies evaluating the effect of prolonged C1s blockade on the course of antibody-mediated rejection.
CITATION INFORMATION: Muhlbacher J, Jilma B, Wahrmann M, Eskandary F, Gilbert J, Panicker S, Böhmig G. Multiple Dosing of Anti-C1s Antibody TNT009 – Effect on HLA Antibody-Triggered Complement Activation in Healthy Volunteers and Kidney Transplant Recipients with Antibody-Mediated Rejection. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Muhlbacher J, Jilma B, Wahrmann M, Eskandary F, Gilbert J, Panicker S, Böhmig G. Multiple Dosing of Anti-C1s Antibody TNT009 – Effect on HLA Antibody-Triggered Complement Activation in Healthy Volunteers and Kidney Transplant Recipients with Antibody-Mediated Rejection. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/multiple-dosing-of-anti-c1s-antibody-tnt009-effect-on-hla-antibody-triggered-complement-activation-in-healthy-volunteers-and-kidney-transplant-recipients-with-antibody-mediated-rejection/. Accessed August 13, 2020.
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