Prolonged CD38 targeting with felzartamab in antibody-mediated kidney transplant rejection: a biomarker-guided...

Antibody-mediated rejection (AMR) is a major cause of kidney transplant failure. The CD38 antibody felzartamab has been shown to reduce AMR activity, but recurrence after stopping treatment suggested a need for sustained therapy. We extended a placebo-controlled phase 2 trial (NCT05021484) to assess the feasibility and durability of prolonged, biomarker-guided treatment.

Of the 21 patients who completed the primary study, eleven patients with recurrent or persistent AMR after treatment discontinuation received felzartamab for an additional 12 months (16 mg/kg IV): 6 months of fixed dosing followed by 6 months of donor-derived cell-free DNA (dd-cfDNA)-guided dosing. Endpoints included biopsy findings, dd-cfDNA, donor-specific antibodies (DSA), natural killer (NK) cell dynamics, urinary chemokines, kidney function, and safety.

Felzartamab (median of two doses during the biomarker-guided phase) was associated with changes in rejection activity and stable kidney function. Median microvascular inflammation decreased from 2 (IQR 2-2) to 0 (0-2) at week 52, with 7 of 11 patients (64%) showing a score of 0; one developed low-grade intimal arteritis. Molecular AMR probability declined from 0.77 (0.58-0.87) to 0.12 (0.08-0.35). Overall, dd-cfDNA, NK cells and chemokines decreased, whereas DSA remained largely unchanged. Treatment was well tolerated, with mild-to-moderate infusion reactions and no treatment discontinuations.

Re-dosing and prolonged CD38 targeting was associated with lower AMR activity in most patients despite heterogeneity, supporting AMR as a chronic process that may benefit from ongoing immunomodulation. dd-cfDNA-guided dosing was feasible, with variable dose requirements and effects. Larger and longer trials are required to determine optimal dosing and long-term benefit.

Biogen (unrestricted grant). Insight (in kind dd-cfDNA measurements).