Clazakizumab treatment effects on peripheral blood and kidney transcriptomes in chronic antibody-mediated rejection

There are currently no licenced treatments for antibody-mediated rejection (ABMR), a major cause of late kidney allograft loss. IL-6 is a cytokine that promotes B cell differentiation to plasma cells, T follicular cell (Tfh) polarisation, and monocyte activation, key processes for antibody generation or effector functions. Clazakizumab (CLZ), an IL-6-neutralising antibody, has been used in a phase 2 trial in patients with ABMR, showing potential efficacy in terms of a reduction in donor-specific antibodies and kidney molecular ABMR (MMDx) score. Here we studied the transcriptional changes occurring in paired blood and kidney samples taken following CLZ treatment during this clinical trial. We observed a reduction in ‘FcγR mediated phagocytosis’, ‘complement and coagulation cascades’ and ‘natural killer (NK) cell mediated cytotoxicity’ gene sets in peripheral blood with short-term CLZ treatment, with variable individual responses and some patients showing a rebound in these pathways in longer-term despite ongoing CLZ treatment. We identified a gene module in blood that showed a significant positive correlation with kidney ABMR MMDx score and was down-regulated with CLZ-treatment, potentially identifying a peripheral blood gene set that can be used to non-invasively assess treatment efficacy. In the kidney, CLZ-treatment was associated with a reduction in a “damaged tubule” gene signature and preservation of podocyte signatures, providing further evidence of its therapeutic efficacy in ABMR.