# The Effects of Clazakizumab on Peripheral Blood and Kidney Transcriptomes in Patients With Late Antibody-Mediated Rejection

## TL;DR

This study explores how clazakizumab, an IL-6 neutralizing antibody, affects blood and kidney gene activity in patients with late antibody-mediated rejection.

## Contribution

The study provides new mechanistic insights into IL-6 neutralization effects in antibody-mediated rejection using transcriptomic data from both blood and kidney tissues.

## Key findings

- Clazakizumab reduced IL-6-related pathways and T follicular helper cell signatures in peripheral blood.
- Kidney gene activity showed reduced tubule damage and preserved podocyte signatures with clazakizumab treatment.
- Some patients experienced rebound inflammation, suggesting variable efficacy of IL-6 antagonism.

## Abstract

There are no licensed treatments for antibody-mediated rejection (AMR), a major cause of late kidney allograft loss. Clazakizumab (CLZ), an interleukin (IL)-6–neutralizing antibody, showed potential efficacy in a phase 2 trial in late AMR, with a reduction in donor-specific antibodies (DSAs) and kidney molecular microscope diagnostic system (MMDx) AMR score, but the underpinning mechanisms are unclear.

Using peripheral blood transcriptomics, we identified a decrease in IL-6–associated “JAK-STAT signaling” pathway genes with CLZ, and a reduction in gene modules that enriched for T follicular helper cell and activated platelet signatures, cells that contribute to DSA generation and inflammatory responses to DSA respectively. However, responses were variable, and some patients showed a rebound in the expression of inflammatory signatures with long-term CLZ treatment, indicating variability in the efficacy of IL-6 antagonism. One peripheral blood gene module significantly correlated with kidney MMDx AMR score and enriched for monocyte signature genes, as well as “Fc gamma receptor–mediated phagocytosis” and “leukocyte transendothelial migration” gene sets, suggesting that cells activated by DSAs can be detected in peripheral blood. In the kidney, CLZ-treatment was associated with a significant reduction in a damaged tubule gene signature and preservation of podocyte signatures. We also found a kidney plasma cell gene–rich module that positively correlated with circulating DSAs; however, this was not significantly downregulated by CLZ.

Overall, our results provide mechanistic insights into the effects and limitations, of IL-6 neutralization in humans in the context of AMR.