ANTI-IL-6 ANTIBODY CLAZAKIZUMAB IN LATE ANTIBODY-MEDIATED REJECTION – MOLECULAR REBOUND PHENOMENA UNDER IL-6 BLOCKADE?
Bibliographic record
Abstract
Introduction: 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. Conclusion: 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".