Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: Late antibody-mediated rejection (ABMR) is well established as a major cause of kidney allograft failure. Targeting interleukin-6 (IL-6), a pro-inflammatory cytokine involved in B cell activation and development may represent a promising therapeutic strategy. One may argue that the effects of prolonged blockade of the IL-6/IL-6 receptor axis may be overcome by rebound phenomena, as earlier described for anti-IL-6R monoclonal antibodies, which lead to a profound accumulation of serum IL-6. In quest of a similar effect of anti-IL-6 treatment, we monitored biological samples from an ongoing bi-center, randomized controlled phase 2 pilot trial evaluating the safety and efficacy of anti-IL-6 antibody clazakizumab in late ABMR (www.clinicaltrials.gov, NCT03444103).
*Methods: In this secondary endpoint analysis of the trial, we report on 15 study subjects who have received 3 months of treatment with clazakizumab (n=7; 25 mg s.c. monthly) vs. placebo (n=8). IL-6, IL-6R and gp130 RNA was determined by real-time qPCR (peripheral blood) and microarray analysis (protocol biopsies performed after 12 weeks of treatment). For detection of total IL-6, unbound IL-6, soluble IL-6 receptor (sIL-6R) and serum amyloid P component (SAP) measurement on a protein level, magnetic bead-based immunoassays were used.
*Results: After 12 weeks of clazakizumab treatment, median serum levels of total IL-6 (but not levels of unbound IL-6) increased from 2.0 pg/ml at baseline to 10,050 pg/ml (p=0.001, placebo group: 1.7 pg/ml to 1.1 pg/ml). IL-6 blockade, however, did not result in significant changes of RNA expression of IL-6, IL-6R and gp130, neither in peripheral blood nor in kidney biopsies (Fig. 1). Treatment did not have any impact on serum concentrations of soluble IL-6R. In support of effective anti-inflammatory activity of treatment, serum levels of SAP and CRP were substantially reduced.
*Conclusions: Our results may argue against a role of potentially harmful rebound phenomena within the IL-6/IL-6R axis under treatment with the anti-IL-6 antibody clazakizumab.
To cite this abstract in AMA style:Borski A, Haindl S, Duerr M, Budde K, Schranz S, Eskandary FA, Doberer K, Halloran PF, Chong E, Jilma B, Böhmig GA, Wahrmann M. Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Rejection – Molecular Rebound Phenomena Under IL-6 Blockade? [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/anti-il-6-antibody-clazakizumab-in-late-antibody-mediated-rejection-molecular-rebound-phenomena-under-il-6-blockade/. Accessed March 8, 2021.
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