Imlifidase Desensitization in Crossmatch-positive, Highly Sensitized Kidney Transplant Recipients: Results of an International Phase 2 Trial (Highdes)
In the international phase 2 Highdes trial, a single dose of imlifidase converted a positive crossmatch to negative within 24 hours in the large majority of highly sensitized kidney transplant candidates, enabling transplantation with good 6-month graft survival despite a high rate of early antibody-mediated rejection.
Background
Highly HLA-sensitized patients have limited access to transplantation because few immunologically suitable donors exist, and a positive crossmatch has traditionally been a contraindication owing to the risk of antibody-mediated rejection. Imlifidase is a cysteine protease that cleaves IgG, producing a rapid fall in antibody levels and inhibition of IgG-mediated graft injury.
Study design
Highdes was an open-label, single-arm, phase 2 trial conducted at five transplant centres that evaluated whether imlifidase could create a negative crossmatch within 24 hours. Secondary endpoints included post-dose donor-specific antibody levels, renal function, and pharmacokinetic and pharmacodynamic profiles, with safety assessed through adverse events and immunogenicity.
Key findings
Among transplanted patients, 89.5% showed conversion of a baseline positive crossmatch to negative within 24 hours of imlifidase. Donor-specific antibodies most often rebounded 3 to 14 days after dosing, with substantial inter-patient variability. Patient survival was 100% and graft survival was 88.9% at 6 months, while 38.9% developed early biopsy-proven antibody-mediated rejection with onset 2 to 19 days post-transplant. Treatment was well tolerated, with seven treatment-related adverse events in six patients, all mild to moderate.
Clinical implications
Imlifidase enabled patients with a median calculated panel-reactive antibody of about 99.8% to undergo transplantation with good early kidney function and graft survival. The main challenge highlighted is managing the donor-specific antibody rebound and associated early antibody-mediated rejection, which requires potent post-transplant immunosuppression and close DSA monitoring.
Category
Transplant
Source
Transplantation
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