Effect of felzartamab on the molecular phenotype of antibody-mediated rejection in kidney transplant biopsies
A molecular analysis of the felzartamab antibody-mediated rejection trial showed the anti-CD38 antibody selectively suppressed natural-killer-cell and interferon-gamma-driven rejection activity, with near-universal molecular recurrence after stopping treatment but lasting reductions in tissue injury that could slow progression to kidney failure.
Background
A randomized phase 2 trial showed felzartamab (anti-CD38) suppressed antibody-mediated rejection in kidney transplant patients, but rejection recurred in some after treatment ended. This study examined the molecular effects on the trial's biopsies to understand how the drug works and what happens after it is stopped.
Study design
Genome-wide microarray analysis of biopsies from the trial — pretreatment, end-of-treatment (week 24), and posttreatment (week 52) — comparing 10 felzartamab-treated and 10 placebo patients.
Key findings
Felzartamab reduced molecular ABMR activity scores in all nine patients with baseline activity, selectively suppressing interferon-gamma-inducible and natural-killer-cell transcripts while having minimal effect on endothelial (ABMR-stage) transcripts and none on T-cell transcripts. Suppression was often incomplete when rejection was intense, and molecular recurrence was nearly universal by week 52. Nonetheless, felzartamab slowed the trajectory of molecular injury scores beyond the treatment period, indicating lasting parenchymal recovery.
Clinical implications
CD38-directed therapy works largely by dampening NK-cell- and interferon-gamma-mediated rejection activity, and although its effect on rejection is transient, the durable reduction in tissue injury suggests it could slow progression to kidney failure. These insights support ongoing phase 3 evaluation and may guide whether prolonged or repeated dosing is needed.
Category
Transplant
Source
Nature Medicine
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