Anti-interleukin-6 Antibody Clazakizumab in Antibody-mediated Renal Allograft Rejection: Accumulation of Antibody-neutralized Interleukin-6 Without Signs of Proinflammatory Rebound Phenomena

Abstract

Background. Blockade of interleukin-6 (IL-6) has emerged as a promising therapeutic option for antibody-mediated rejection. Subtherapeutic anti-IL-6 antibody level or treatment cessation following prolonged cytokine neutralization may result in proinflammatory rebound phenomena via accumulation of IL-6 and/or modulated gene expression of major components of the IL-6/IL-6 receptor (IL-6R) axis. Methods. We evaluated biologic material obtained from a randomized controlled, double-blind phase 2 trial designed to evaluate the safety and efficacy of the anti-IL-6 monoclonal antibody clazakizumab in late antibody-mediated rejection. Twenty kidney transplant recipients, allocated to clazakizumab or placebo, received 4-weekly doses over 12 wks, followed by a 40-wk extension where all recipients received clazakizumab. Serum proteins were detected using bead-based immunoassays and RNA transcripts using quantitative real-time polymerase chain reaction (peripheral blood) or microarray analysis (serial allograft biopsies). Results. Clazakizumab treatment resulted in a substantial increase in median total (bound and unbound to drug) serum IL-6 level (1.4, 8015, and 13 600 pg/mL at 0, 12, and 52 wks), but median level of free (unbound to drug) IL-6 did not increase (3.0, 2.3, and 2.3 pg/mL, respectively). Neutralization of IL-6 did not boost soluble IL-6R or leukocyte or allograft expression of IL-6, IL-6R, and glycoprotein 130 mRNA. Cessation of treatment at the end of the trial did not result in a meaningful increase in C-reactive protein or accelerated progression of graft dysfunction during 12 mo of follow-up. Conclusion. Our results argue against clinically relevant rebound phenomena and modulation of major components of the IL-6/IL-6R axis following prolonged IL-6 neutralization with clazakizumab.

Biopsy-based transcriptomics in the diagnosis of kidney transplant rejection

“…The lack of good treatment options for AMR makes it hard to compare histological and molecular definitions of disease for their ability to best stratify patients for treatment, or to potentially integrate both modalities for best diagnostic ability. Clinical trials that include molecular analysis are limited, and more are needed [39][40][41][42][43][44]. Molecular scores of AMR probability or of injury-repair response (IRRAT) in patients with histological AMR predict future eGFR or graft loss, providing evidence for prognostic (if not diagnostic) superiority of molecular analysis in this context [45 between "histological AMR" and "molecular AMR", for example sampling of the biopsy tissue, poor application of Banff rules by pathologists [46] BBT have also been investigated in incomplete AMR phenotypes, including cases that are "MVIpositive, C4d-negative, DSA-negative", and cases with histological lesions of AMR below threshold, either with a DSA ("probable AMR") or without a DSA (isolated v, g, cg, and TMA).…”

“…The lack of good treatment options for AMR makes it hard to compare histological and molecular definitions of disease for their ability to best stratify patients for treatment, or to potentially integrate both modalities for best diagnostic ability. Clinical trials that include molecular analysis are limited, and more are needed [39–44]. Molecular scores of AMR probability or of injury-repair response (IRRAT) in patients with histological AMR predict future eGFR or graft loss, providing evidence for prognostic (if not diagnostic) superiority of molecular analysis in this context [45 ▪ ].…”

New treatment for antibody-mediated rejection: interleukin-6 inhibitors

“…However, due to infectious complications impacting some participants, the dosage was reduced to 12.5 mg in later studies. These findings underscore the importance of establishing appropriate entry criteria and the necessity for vigilant monitoring when administering clazakizumab [ 1 , 19 – 21 ].…”

“…While the success rate of the procedure depends on multiple factors, it is generally quite high. The 1-year survival rate for KT exceeds 90%, while the 10-year rate is around 77.6% [ 1 , 2 ]. As such, KT often represents a vital life-extending treatment.…”

“…As such, KT often represents a vital life-extending treatment. However, it necessitates ongoing management and involves a complex regimen of immunosuppressants to prevent rejection, which is a central aspect of care [ 1 , 3 ].…”