The Lancet regional health. Europe · 2026
Prolonged CD38 targeting with felzartamab in antibody-mediated kidney transplant rejection: a biomarker-guided open-label phase 2 extension.
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Mayer Katharina A, Diebold Matthias, Schrezenmeier Eva V, Halloran Philip F, Haindl Susanne, Schatzl Martina, Akifova Aylin, Allmer Daniela M, Schranz Sabine, Kozakowski Nicolas, Kläger Johannes, Amann Kerstin, Beck Julia, Schütz Ekkehard, Naesens Maarten, Loupy Alexandre, Raynaud Marc, Görzer Irene, Vietzen Hannes, Ingle Gordon, Flesher Donna L, Patel Uptal D, Halleck Fabian, Graf Irene, Jilma Bernd, Budde Klemens, Böhmig Georg A
Аннотация
BACKGROUND: 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.
METHODS: 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.
FINDINGS: 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.
INTERPRETATION: 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.
FUNDING: Biogen (unrestricted grant). Insight (in kind dd-cfDNA measurements).
METHODS: 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.
FINDINGS: 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.
INTERPRETATION: 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.
FUNDING: Biogen (unrestricted grant). Insight (in kind dd-cfDNA measurements).