Anti-interleukin-6 Antibody Clazakizumab in Antibody-mediated Kidney Transplant Rejection: Effect on Donor-derived Cell-free DNA and C-X-C Motif Chemokine Ligand 10

Abstract

Targeting interleukin-6 (IL-6) was shown to counteract donor-specific antibody production and antibody-mediated rejection (AMR) activity. It is not known whether, or to what extent, IL-6 antagonism modulates biomarkers indicative of tissue damage (donor-derived cell-free DNA [dd-cfDNA]) and parenchymal inflammation (C-X-C motif chemokine ligand [CXCL] 10).

Methods: We report a secondary endpoint analysis of a phase 2 trial of anti-IL-6 antibody clazakizumab in late AMR (ClinicalTrials.gov, NCT03444103). Twenty kidney transplant recipients were randomized to treatment with clazakizumab or placebo over 12 wk (part A), followed by an extension in which all recipients received clazakizumab through week 52 (part B). Biomarkers were evaluated at day 0 and after 12 and 52 wk, respectively.

Results: Fractional dd-cfDNA (dd-cfDNA[%]) did not significantly change under clazakizumab, with no differences between study arms (clazakizumab versus placebo) at week 12 (1.65% [median; interquartile range: 0.91%-2.78%] versus 0.97% [0.56%-2.30%]; P = 0.25) and no significant decrease from weeks 12 to 52 (1.15% [0.70%-2.38%] versus 1.0% [0.61%-1.70%]; P = 0.25). Similarly, urine CXCL10 was not different between groups at week 12 (55.7 [41.0-91.4] versus 60.2 [48.8-208.7.0] pg/mg creatinine; P = 0.44) and did not change over part B (CXCL10 [pg/mg creatinine]: from 58 [46.3-93.1] to 67.4 [41.5-132.0] pg/mL creatinine; P = 0.95). Similar results were obtained for serum CXCL10. There was no association between biomarker levels and resolution of molecular and morphologic AMR activity.

Conclusions: Our results suggest that IL-6 blockade does not significantly affect levels of dd-cfDNA[%] and CXCL10. Subtle responses to this therapeutic principle may be overlooked by early biomarker surveillance.

Conflict of interest statement

T.V. and S.C. are employed by CareDx Inc., Brisbane, San Francisco, CA. G.A.B. is member of the steering committee for an ongoing pivotal phase 3 trial evaluating clazakizumab in chronic active antibody-mediated rejection (ClinicalTrials.gov number, NCT03744910; sponsored by CSL Behring). The other authors declare no conflicts of interest.

Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.

Figures

Graphical abstract

FIGURE 1.

Trial protocol. Twenty kidney allograft recipients with late DSA-positive AMR were randomized 1:1 to receive clazakizumab or placebo for 12 wk (part A). After 12 wk, all patients were scheduled to receive clazakizumab (part B). Two patients allocated to receive clazakizumab were withdrawn from the study because of serious adverse events (diverticular disease complications). Both completed part A. One was withdrawn shortly before, the other after the first dose of clazakizumab in part B. At day 0 and after 12 and 52 wk, biologic material was collected and stored for biomarker evaluation (secondary endpoint analysis). Tested biomarkers included plasma dd-cfDNA and CXCL10 in urine and serum. AMR, antibody-mediated rejection; CXCL, C-X-C motif chemokine ligand; dd-cfDNA, donor-derived cell-free DNA; DSA, donor-specific antibody; MMDx, Molecular Microscope Diagnostic System.

FIGURE 2.

Biomarkers in relation to clazakizumab treatment. Fractions of dd-cfDNA[%] (A) and concentrations of CXCL10 in urine (B) and serum (C) are shown after 12 wk (end of part A; clazakizumab [Claza] vs placebo) and from week 12 to week 52 in the open-label extension (part B; all patients on clazakizumab), respectively. Box plots indicate the median, interquartile range, and the minimum and maximum of the measures (outliers are indicated by circles and extreme outliers by asterisks). The unpaired Mann-Whitney U test was used for comparisons between study arms and the paired Wilcoxon test to test for differences over time in the overall cohort. Cr, creatinine; CXCL, C-X-C motif chemokine ligand; dd-cfDNA, donor-derived cell-free DNA.

FIGURE 3.

Individual course of biomarker levels in relation to treatment allocation. Biomarkers included (A) fractions of % and concentrations of CXCL10 in urine (B) and serum (C). Two patients in the Claza arm were withdrawn from the trial, and for week 52 no biomarker results are available. Two samples did not yield valid dd-cfDNA results (1 collected at day 0, the other at week 52). Claza, clazakizumab; Cr, creatinine; CXCL, C-X-C motif chemokine ligand; dd-cfDNA, donor-derived cell-free DNA; Pcb, placebo.

FIGURE 4.

Biomarkers in relation to persistent molecular or morphologic AMR persistence. Fractions of dd-cfDNA[%] (A) and concentrations of CXCL10 in urine (B) and serum (C) are shown at the end of the trial, in relation to molecular (AMR score U test was used. AMR, antibody-mediated rejection; Cr, creatinine; CXCL, C-X-C motif chemokine ligand; dd-cfDNA, donor-derived cell-free DNA.