Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney Transplantation

Abstract

Introduction: The safety and benefit of the anti-CD38 monoclonal antibody daratumumab, which induces lysis of antibody-producing plasma cells in sensitized patients prior to kidney transplantation, remain to be determined.

Methods: A 2-phase (1 and 2), monocentric open-label study was conducted to evaluate the month 6 (M6) safety and efficacy of daratumumab in kidney transplant candidates with calculated panel reactive antibody (cPRA) > 95%. In the first (safety) phase, we used 4-weekly escalating doses of daratumumab. Phase 2 tested desensitization with 8 weekly infusions of 16 mg/kg daratumumab. cPRA 10,000 was calculated considering only human leukocyte antigen (HLA) antibodies with mean fluorescence intensity (MFI) of > 10,000.

Results: Nine patients were enrolled in phase 1 and 14 in phase 2. Safety analysis showed 4 serious non-treatment-emergent adverse events (non-TEAEs), 36 mild TEAEs, mostly infusion-related reactions, grade 1 and 2 (causing 2 temporary drug discontinuations), but no serious TEAEs. Significant reductions in anti-HLA antibodies were observed at month 3 (M3), with cPRA 10,000 (P = 0.003), number of anti-HLA (P < 0.001), maximum MFI (MFI max) (P = 0.053), and the sum of MFI (MFI sum) (P < 0.001), with complete return to baseline levels at month 12 (M12). At M6, 46.15% (19.22%-74.87%) and 76.92% (46.19%-94.96%) of patients showed sustained response (1% decrease in cPRA) for cPRA 2000 and 10,000, respectively. At month 1 (M1), immune cells (T-reg, CD8 + TEMRA, CD19 + CD138 + B cells, and NK cells) significantly decreased. At M3, other antibodies decreased significantly, but returned to baseline levels at M12, except for gamma globulins, without any infectious complications.

Conclusion: The first use of daratumumab in desensitization demonstrated infusion-related adverse (AEs) events and rapid, albeit transient, reductions in anti-HLA antibodies, with less than 40% of durable responders, limiting its potential clinical use.

Keywords: lymphocytes; pharmacokinetics; translational; transplantation.

Graphical abstract

Figure 1

(a) Design and (b) flowchart of the study. The study consisted of 2 steps: phase 1 evaluated the safety of daratumumab given at doses that were doubled once every 4 weeks over 3 dose-intervals, from 4 mg/kg to 8 mg/kg and then to 16 mg/kg, in 9 patients (dose escalation phase). Phase 2 evaluated the desensitization effect of 16 mg/kg of daratumumab given for 8 weeks (desensitization step). Follow-up lasted 12 months after the first infusion.

Figure 2

Evolution of anti-HLA characteristics between baseline and month 12 after the first infusion; each curve represents a patient. (a) cPRA 2000 remained stable (P = 0.197); (b) cPRA 10,000 returned to baseline (P = 0.399); (c) total number of anti-HLA antibodies returned to baseline (P = 0.301); (d) global MFI max returned to baseline (P = 0.592); (e) global MFI sum returned to baseline (P = 0.207). cPRA, calculated panel reactive antibody; MFI max, maximum mean fluorescence intensity; MFI sum, sum of mean fluorescence intensity.

Figure 3

Phenotypic analysis of peripheral blood mononuclear cells (PBMCs), kinetics of the indicated population over the 12-month follow-up and box plot comparison for the M0/M1 period. (a) Plasmablast CD138+ cell levels among PBMC. (b) CD8 CD45RA+ CCR7− TEMRA (terminally differentiated effector memory) and CD45RA+ CCR7+ naive cell levels among CD8. (c) Percentage of T-reg cells (CD4+ CD25+ Foxp3+) among CD4 cells. (d) Total NK cells (CD56+) among PBMC. Box plots show the percentage of positive cells with 5% to 95% whiskers. Wilcoxon signed rank test was used to compare results. ∗P < 0.05, ∗∗P < 0.01. M0, month 0; M1, month 1; NK, natural killer; Treg, T-regulator cells.