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An investigational monoclonal antibody appeared to have therapeutic benefits among kidney transplant patients with antibody-mediated rejection, a randomized phase II trial showed.

After 24 weeks, resolution of morphologic antibody-mediated rejection occurred in nine of the 11 participants who received infusions of the CD38 monoclonal antibody felzartamab compared with two of 10 placebo-treated participants (risk ratio 0.23, 95% CI 0.06-0.83), reported Georg Böhmig, MD, of the Medical University of Vienna, and colleagues in the .

Originally developed for multiple myeloma, felzartamab is a fully human IgG1 monoclonal CD38 antibody that depletes target cells through antibody-dependent cellular cytotoxicity and phagocytosis.

"The results of our study could represent a breakthrough in the treatment of kidney transplant rejection," said co-author Katharina Mayer, MD, also of the Medical University of Vienna, in a . Mayer presented the findings over the weekend at the in Stockholm.

In a statement, Böhmig noted that "there is a large unmet need for a therapy that resolves disease by the Banff classification and preserves kidney function in patients with antibody-mediated rejection. The data presented in this study are very compelling and represent the potential for significant progress to be made in this high-burden disease."

The resolution of morphologic antibody-mediated rejection observed in the trial was mainly driven by a reduction in microvascular inflammation. Participants in the felzartamab group had a median microvascular inflammation score of 0 compared with 2.5 in the placebo group.

The felzartamab group also had lower molecular scores at 24 weeks, representative of the probability of antibody-mediated rejection, compared with the placebo group (median score 0.17 vs 0.77), as well as lower median levels of donor-derived cell-free DNA (0.31% vs 0.82%, respectively), which is used to diagnose graft injury. Median CD16^bright natural killer cell count in peripheral blood was also lower in the felzartamab group than the placebo group (16 cells/µL vs 54 cells/µL).

"Although this trial was not powered for clinical outcomes, the results suggest a potential stabilization of the eGFR [estimated glomerular filtration rate] slope, which is a surrogate for long-term allograft survival," the researchers wrote. The 1-year eGFR slope was -0.39 mL/min/1.73 m² in the felzartamab group and -4.53 mL/min/1.73 m² in the placebo group.

However, treatment effects were not durable after discontinuation, with three of nine patients responsive to felzartamab having a recurrence of antibody-mediated rejection by week 52, along with an increase in molecular activity and biomarker levels toward baseline levels. Of the felzartamab-treated patients who experienced resolution, biopsy results showed that 67% maintained resolution at 52 weeks with no additional drug administered.

This suggests that "continuing treatment would be required for long-term prevention of rejection-related graft loss," Böhmig and colleagues wrote.

The small trial recruited 22 kidney transplant recipients with antibody-mediated rejection -- 11 randomized to each group. One placebo patient didn't finish the study following graft loss caused by rejection at week 14. The median time from kidney transplantation to trial inclusion was 9 years. Median age was 39, 50% were women, 91% were white, and 9% were Asian. Only 27% received their kidney from a living donor.

Most had chronic active antibody-mediated rejection (68%), followed by active antibody-mediated rejection (32%) and additional borderline lesion antibody-mediated rejection (14%). The majority had human leukocyte antigen (HLA) class II-only donor-specific antibody (59%), followed by HLA class I only (32%); few had HLA class I and II (9%).

Nine felzartamab infusions were administered over the course of 6 months at a dose of 16 mg/kg of body weight, which was followed by a 6-month observation period.

Eight felzartamab-treated patients experienced mild or moderate infusion reactions with the first infusion. Treatment-related adverse events occurred in 91% and 64% of the felzartamab and placebo groups, respectively, and were mostly comprised of infections. Nasopharyngitis, COVID-19, and cytomegalovirus viremia occurred more frequently in the felzartamab group.

No fatal adverse events occurred, and no patients discontinued treatment because of adverse events.

"Our findings also raise the hope that felzartamab could counteract the rejection of other donor organs, such as heart or lung transplants," said Böhmig. "Xenotransplants using genetically modified pig organs could perhaps also move further into the realm of possibility."

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