*Purpose: Blockade of costimulatory molecule CD40 by the Fc-silent immunosuppressive drug Iscalimab has shown to inhibit acute alloreactivity in non-human primates and is currently being investigated for prevention of rejection in a CNI-free regimen in transplant patients. Interaction of CD40 on B cells with its ligand on T cells serves as the co-stimulatory factor for B cell activation, proliferation and differentiation, and we were interested in exploring how Iscalimab affected B cell activation in the context of kidney transplantation.

*Methods: We measured the number and composition of B cells in kidney transplant recipients who enrolled into the CFZ533X2201 study in the first year after transplantation. Recipients received Iscalimab (n=3) or tacrolimus (n=3) in combination with mycophenolate mofetil and steroids. Additionally, we examined the functional effects of Iscalimab on B cell functions from healthy donors. We also performed RNA-seq profiling of blood samples from CFZ533X2201 collected at baseline before transplant and nine and forty-one weeks post-transplant.

*Results: Serial flow cytometric monitoring of samples from Iscalimab-treated patients demonstrated that this agent does not affect the numbers of circulating B cells. In these 3 subjects a complete saturation was found of the CD40-Iscalimab epitope, while a different epitope (HB14) of CD40 was detectable. CD40 occupancy by Iscalimab lead to a 2-fold decrease in memory B cells in the Iscalimab group: 15-26% (range) vs range: 34-65% (range) tacrolimus group. To investigate the effect of CD40 blockade on B cell functions, co-cultures of alloantigen-stimulated B cells with induced follicular T helper cells in the presence of Iscalimab were performed. Proliferation of these allo-activated B cells and their subsequent differentiation towards memory class switched B cells and plasma blasts was significantly inhibited. Activation of these B cells was also inhibited, as shown by the diminished expression of co-stimulatory molecules CD86 and CD40-(HB14). At the transcriptomic level, analyses of biological pathways in whole blood RNAseq data showed evidence of reduced B cell activation in Iscalimab treated patients in comparison to allograft recipients on tacrolimus.

*Conclusions: Our sub-study shows that blockade of the Iscalimab-specific CD40 epitope inhibits T cell dependent B cell activation resulting in reduced B cell differentiation in vitro and in vivo after kidney transplantation. These results were consistent with reduction in a transcriptomic signature associated with B cell activation in patients treated with Iscalimab but not tacrolimus. Collectively our results suggests that one of the mechanisms of action of Iscalimab in kidney transplantation is suppression of B cell activation.

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