The Effects of Clazakizumab on Peripheral Blood and Kidney Transcriptomes in Patients With Late Antibody-Mediated Rejection.
Transcriptomic profiling of the phase 2 clazakizumab trial in late antibody-mediated rejection showed the expected suppression of IL-6/JAK-STAT and T follicular helper signatures alongside reduced kidney tubular injury, but responses were variable, some patients rebounded on prolonged treatment, and the kidney plasma cell signature was not significantly downregulated.
Background
There are no licensed treatments for antibody-mediated rejection (AMR), a major cause of late kidney allograft loss. Clazakizumab (CLZ), an interleukin (IL)-6-neutralising antibody, showed potential efficacy in a phase 2 trial in late AMR, with a reduction in donor-specific antibodies (DSAs) and in the kidney molecular microscope diagnostic system (MMDx) AMR score — but the mechanisms underpinning those effects were unclear.
Study design
The investigators applied transcriptomic analysis to peripheral blood and kidney tissue from patients treated with clazakizumab for late AMR, using gene module analysis and enrichment for cell-type and pathway signatures, and correlating blood modules against kidney MMDx AMR scores and circulating DSA levels.
Key findings
In peripheral blood, clazakizumab decreased IL-6-associated JAK-STAT signalling pathway genes and reduced gene modules enriched for T follicular helper cell and activated platelet signatures — cells that contribute to DSA generation and to inflammatory responses to DSA respectively. Responses were variable, however, and some patients showed a rebound in inflammatory signature expression with long-term treatment, indicating variability in the efficacy of IL-6 antagonism. One peripheral blood gene module correlated significantly with the kidney MMDx AMR score and was enriched for monocyte signature genes as well as Fc gamma receptor-mediated phagocytosis and leukocyte transendothelial migration gene sets, suggesting that DSA-activated cells can be detected in blood. In the kidney, clazakizumab was associated with a significant reduction in a damaged tubule gene signature and preservation of podocyte signatures. A kidney plasma cell gene-rich module correlated positively with circulating DSAs but was not significantly downregulated by clazakizumab.
Clinical implications
These results provide mechanistic insight into both the effects and the limitations of IL-6 neutralisation in humans in the context of AMR. The failure to suppress the kidney plasma cell module, together with the variable and sometimes rebounding inflammatory signatures on prolonged treatment, points to why IL-6 blockade may fall short of durable disease control, and identifies peripheral blood modules as candidate non-invasive readouts of intragraft AMR activity.
Category
Transplant
Source
Kidney Int Rep
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