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

INTRODUCTION

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.

METHODS

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.

CONCLUSION

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