Evaluation of Clazakizumab (Anti-Interleukin-6) in Patients With Treatment-Resistant Chronic Active Antibody-Mediated Rejection of Kidney Allografts

Abstract

Introduction: Interleukin-6 (IL-6) is an important mediator of inflammation and activation of T cells, B cells, and plasma cells. Excessive IL-6 production is linked to human diseases characterized by unregulated antibody production, including alloimmunity, where persistence of donor-specific antibodies (DSAs), chronic active antibody-mediated rejection (cAMR), and graft loss are noted. Here, we report our experience investigating clazakizumab, a novel IL-6 inhibitor, in treating human leukocyte antigen (HLA)-sensitized patients with cAMR.

Methods: Between February 2018 and January 2019, 10 adults with biopsy-proven cAMR were enrolled in a phase 2, single-center, open-label study. Patients received clazakizumab 25 mg subcutaneously (s.c.) monthly for 12 months, with a 6-month protocol biopsy. Primary end points included patient survival, graft survival, estimated glomerular filtration rate (eGFR), and safety. Secondary end points assessed immune markers (DSAs, IgG, T-regulatory [Treg] cells). At 12 months, stable patients entered a long-term extension (LTE).

Results: LTE patients received clazakizumab for >2.5 years. Mean eGFRs showed significant declines from -24 months to study initiation (0 months) (52.8 ± 14.6 to 38.11 ± 12.23 ml/min per 1.73 m2, P = 0.03). However, after initiation of clazakizumab, eGFR stabilized at (41.6 ± 14.2 and 38.1 ± 20.3 ml/min per 1.73 m2, at 12 and 24 months, respectively). Banff 2017 analysis of pre- and post-treatment biopsies showed reductions in g+ptc and C4d scores. DSA reductions were seen in most patients. Adverse events (AEs) were minimal, and 2 graft losses occurred, both in patients who discontinued clazakizumab therapy at 6 months and 12 months after study initiation.

Conclusion: In this small cohort of patients with cAMR, clazakizumab treatment showed a trend toward stabilization of eGFR and reductions in DSA and graft inflammation. No significant safety issues were observed. A randomized, placebo-controlled clinical trial (IMAGINE) of clazakizumab in cAMR treatment is underway (NCT03744910).

Keywords: HLA-incompatible transplantation; antibody-mediated rejection; anti–IL-6; donor-specific antibodies.

© 2022 International Society of Nephrology. Published by Elsevier Inc.

Figures

Graphical abstract

Figure 1

This figure shows the protocol design. Patients eligible for the study were DSA positive with clinical features and pathologic features of cAMR. All patients received clazakizumab 25 mg s.c. monthly for 6M followed by protocol biopsy. If improvements were seen, patients received clazakizumab monthly for an additional 6M with the option to continue in a LTE if improvements were seen and no AEs/serious AEs noted. AE, adverse event; cAMR, chronic active antibody-mediated rejection; DSA, donor-specific antibody; eGFR, estimated glomerular filtration rate; LTE, long-term extension; M, months; s.c., subcutaneously; SAE, serious adverse event.

Figure 2

Figure 2 shows the study flow enrollment diagram. The study was approved for 10 patients with cAMR. cAMR, chronic active antibody-mediated rejection; M, months.

Figure 3

(a) Shows the individual patient curves of eGFR at study entry and at time points up to 24M after clazakizumab therapy. (b) Shows the mean eGFR at study entry and at time points up to 24M after clazakizumab therapy. Here, a stabilization of eGFR was seen over the 24-month observation. (c) This figure shows the impact of clazakizumab on DSA levels over the 2-year study period. Each line represents a patient, and each patient had only 1 DSA present from study entry and throughout study (n = 8). The DSAs were analyzed at the CSMC HLA Laboratory. Near significant reductions in DSAs were seen at 12 and 24M. CSMC, Cedars-Sinai Medical Center; DQ, human leukocyte antigen – DQ isotype; DR, human leukocyte antigen – DR isotype; DSA, donor-specific antibody; eGFR, estimated glomerular filtration rate; HLA, human leukocyte antigen; M, months; MFI, mean fluorescent intensity; NS, nonsignificant.

Figure 4

(a) This figure shows the mean Banff scores for protocol biopsies performed during the study. Near significant reductions were seen for g+ptc scores, and near significant increase in i-IFTA scores were seen after 6 months of clazakizumab therapy. (b) Shows the individual Banff scores for each patient before and after treatment.

Figure 5

(a) Figure 5a shows pre- and postserum IL-6 levels in patients receiving clazakizumab for treatment of cAMR. The dramatic increase in serum IL-6 levels are due to stabilized IL-6/anti–IL-6 complexes in the blood. Because clazakizumab blocks the IL-6R binding site, no activation signals are possible, as was indicated with low C-reactive protein levels in all patients. (b) shows soluble IL-6R levels in the blood of patients throughout the study. Here, there are no increases in soluble IL-6R as would be seen with tocilizumab (anti–IL-6R). This may be beneficial because circulating IL-6/IL-6R complexes (called super IL-6) could form and cause severe injury at multiple tissue sites. IL-6, interleukin-6; IL-6R, interleukin-6 receptor.

Figure 6

(a) This figure demonstrates the impact of clazakizumab on total IgG levels measured at initiation and every 6M up to 2 years after clazakizumab treatment. Significant decreases in total IgG levels were seen, but levels still remained in the normal range for most patients. (b) This figure shows the impact of clazakizumab treatment on CD4+, CD25+, FoxP3+ Tregs determined before treatment and at 6-month intervals up to 24M after clazakizumab treatment. Here, near significant increases in Treg cells were seen at 24M after clazakizumab treatment. M, months; Tregs, T regulatory.