A Randomized Clinical Trial of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection

Abstract

Background: Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy.

Methods: We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab.

Results: Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m² per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab.

Conclusions: Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.

Keywords: antibody-mediated rejection; chronic rejection; interleukin-6; monoclonal antibody; randomized controlled trial; renal transplantation.

Graphical abstract

Figure 1.

Trial flowchart.

Figure 2.

Antibody and biopsy results. Percentages (in relation to baseline values) of (A) peak DSA MFI, DSA levels interpolated from dilution experiments, and the median MFI detected for non-DSA, (B) rejection-associated molecular classifiers (ABMR, T cell–mediated rejection [TCMR], all rejection), and (C) morphologic single lesion scores (g, ptc, C4d) are shown in relation to treatment allocation (clazakizumab, part A/B: red closed boxplots; placebo, part A: open boxplots; placebo, part B [switch to clazakizumab]: red hatched boxplots). We applied unpaired Mann–Whitney U tests for group comparisons (clazakizumab versus placebo) at the end of part A, and paired Wilcoxon test to evaluate changes under clazakizumab (overall cohort) in the open-label extension (part B). (D) shows proportions of ABMR categories and C4d scoring results obtained in index, 11-week and 51-week biopsies.

Figure 3.

Serum Ig concentrations. Shown are the percent levels (in relation to values at baseline) of (A) IgG, IgM, and (B) IgG subclasses for patients randomized to clazakizumab (red closed boxplots) or placebo (part A: open boxplots; part B: red hatched boxplots). We used unpaired Mann–Whitney U test for group comparisons (clazakizumab versus placebo) at the end of part A and paired Wilcoxon test to evaluate changes under clazakizumab (overall cohort) in the open-label extension (part B).

Figure 4.

Kidney allograft function. The individual course of eGFR is shown for patients allocated to receive clazakizumab (A) versus placebo (B). (C) shows median, IQR, and individual levels of eGFR in relation to treatment allocation in part A (clazakizumab: red line, bars and asterisks; placebo: black lines, bars and circles). (D) shows individual (dashed lines) and mean eGFR slopes (solid lines; shaded areas represent 95% CIs) in relation to treatment in part A (clazakizumab: red lines; placebo: black lines).