#604 Effect of felzartamab anti-CD38 treatment on the molecular phenotype of antibody-mediated rejection in kidney transplant biopsies

Le résumé fourni par la source

Abstract Background and Aims A recent randomized controlled trial demonstrated that treatment with CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence post-treatment in some patients. Method This study examined the molecular effects of 6-months felzartamab treatment on biopsies from the trial using genome-wide microarray analysis, comparing pre-treatment, end-of-treatment (24 week) and post-treatment (week 52) biopsies from 10 felzartamab and 10 placebo patients. Results Felzartamab reduced molecular ABMR activity scores in all 9 patients with baseline ABMR activity, selectively suppressing interferon gamma (IFNG)-inducible and natural killer (NK) cell transcripts, with minimal effect on ABMR-induced endothelial transcripts and no effect on T cell transcripts. Suppression was often incomplete when ABMR activity was intense, and molecular recurrence was nearly universal by week 52. In genome-wide transcriptome analysis, felzartamab impacted 58 genes between baseline and week 24. Ten of the top 20 differentially expressed genes were decreased, including those associated with ABMR activity. Functional enrichment analysis confirmed the suppression of 12 ABMR-related pathways, reflecting downregulation of NK- and IFNG-induced genes. Of the top 20 differentially expressed genes, 10 were increased. These genes likely represented normal parenchymal genes previously suppressed by ABMR activity, all of which decreased after therapy as ABMR activity returned by week 52. Felzartamab suppressed both IFNG-inducible and NK-expressed ABMR activity genes. From baseline to week 52, felzartamab affected 166 genes. 17 of the top 20 genes were injury-inducible and decreased by week 52, indicating lasting recovery from ABMR-related parenchymal injury after 24 weeks of therapy. Conclusion Felzartamab selectively suppressed IFNG-inducible and NK cell transcripts, offering parenchymal benefits and potentially slowing progression to kidney failure despite near-universal molecular recurrence by week 52.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.