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

Kidney TransplantationBackground. Targeting interleukin-6 (IL-6) was shown to counteract donor-specific antibody production and antibodymediated 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.

Absence of IL-6 Receptor Blockade Effect on the Outcomes of Transplant Glomerulopathy in the Absence of Anti-HLA Donor-specific Antibodies

“…These results were associated with a reduction in eGFR decline compared with placebo, with subsequent normalization after converting the placebo group to clazakizumab, 13 and no effect on donor-derived cell-free DNA or CXCL10. 25 At the same time, 2 patients withdrew because of diverticular disease complications, and serious infections occurred in 5 subjects, highlighting the need for careful monitoring in patients treated with IL-6/IL-6 receptor-interfering drugs. Massat al 26 showed instead a "standard" eGFR reduction in a limited cohort of cAMR TCZ treated after the failure of conventional therapies; however, the pre-TG trajectory of eGFR was not available, and 3 of 9 patients were DSA -.…”

“…These results were associated with a reduction in eGFR decline compared with placebo, with subsequent normalization after converting the placebo group to clazakizumab, 13 and no effect on donor-derived cell-free DNA or CXCL10. 25 At the same time, 2 patients withdrew because of diverticular disease complications, and serious infections occurred in 5 subjects, highlighting the need for careful monitoring in patients treated with IL-6/IL-6 receptor-interfering drugs.…”

Emerging Therapies for Antibody-Mediated Rejection in Kidney Transplantation

“…However, Mayer et al recently published a secondary endpoint analysis of the effect of clazakizumab treatment on biomarkers indicative of tissue damage (donor-derived cellfree DNA) and parenchymal inflammation (C-X-X motif chemokine ligand) in 20 kidney transplant recipients with late AMR [35]. Patients were randomized to treatment with clazakizumab or matching placebo for 12 weeks (part A), followed by all patients receiving clazakizumab for 52 weeks (part B).…”

Multi‐centre analytical performance verification of an IVD assay to quantify donor‐derived cell‐free DNA in solid organ transplant recipients

“…Several studies have examined the clinical utility of this assay in transplant surveillance, initially presenting single-centre experiences and demonstrating the robustness and value of implementing dd-cfDNA clinical laboratory NGS testing. [26][27][28][29][30][31][32][33][34][35][36] However, evaluation of analytical performance metrics among different users has not yet been reported.…”