*Purpose: A recent Phase 2 clinical study indicated that iscalimab, a pathway blocking, non-depleting anti-CD40 antibody, showed non-inferiority on a composite clinical endpoint, and improved renal function compared with tacrolimus. Additionally, allografts in patients treated with iscalimab demonstrated lower chronic allograft damage index (CADI) scores compared with individuals on tacrolimus. These clinical data suggest that the mechanism of action of iscalimab is different to tacrolimus, prompting us to investigate potential underlying molecular differences between the two drugs in transplant patients.

*Methods: To do so, we performed RNA-seq profiling of whole blood samples from the study was performed at baseline before transplant and nine and forty-one weeks post-transplant.

*Results: Our results indicated a high level of heterogeneity in cell proportions across subjects enrolled in the CFZ533X2201 study. Correcting for such differences improved the reliability of differential expression analyses increasing sensitivity allowing us to identify differentially expressed genes between iscalimab- and tacrolimus-treated subjects. By exploring biological processes and pathways differentially activated between iscalimab- and tacrolimus-treated patients, we find that, compared to the latter, the former display reduced B cell activation, T cell recruitment, complement pathway activation and translation of (possibly viral) proteins. Additionally, we examined whether changes in expression of differentially expressed genes are significantly correlated with changes in eGFR, a readout of kidney function, in iscalimab-treated patients but not in tacrolimus-treated ones. We identified 6 candidate markers, the expression of two of which was correlated with eGFR.

*Conclusions: Collectively our results point to underlying molecular differences in the mechanism of action of iscalimab compared to tacrolimus that can be monitored by whole blood gene expression analyses.

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