Imlifidase for Highly Sensitized Kidney Transplant Recipients With a posItive crossmAtch Against a Deceased Donor: Results of Kidney Transplantations Performed in Accordance to the French Guidelines.

Imlifidase is a recombinant cysteine protease derived from Streptococcus pyogenes and produced in Escherichia coli, which has the ability to cleave and degrade all human IgGs. Four to six hours after imlifidase infusion, the entire IgG pool is degraded into F(ab')2 and Fc fragments. In vitro, imlifidase inhibits HLA antibody-mediated NK cell activation and antibody-dependent cell-mediated cytotoxicity. Imlifidase degrades also the IgG of the B cell Receptor (BCR), inhibiting BCR-mediated cell signal, transiently preventing memory B cell response to antigenic stimulation and their transition into antibody-producing cells.

Two clinical studies have been designed to determine whether imlifidase could inactivate IgG donor-specific antibodies as a desensitization strategy in highly sensitized candidates for kidney transplantation. In the phase I/II study, 25 patients were transplanted in Sweden and United States. Among them, 18 had a positive flow cytometry crossmatch (FCXM) and 2 a positive complement-dependent cytotoxicity crossmatch (CDCXM). In the phase II study (Highdes Trial), 19 patients with an incompatible living or deceased donor from the United States, Sweden, and France were included. Among them, 7, 18, 2, and 8 had respectively a positive T-cell FCXM, positive B-cell FCXM, positive T-cell CDCXM, and positive B-cell CDCCXM. The primary efficacy endpoint was the ability of Imlifidase to convert a positive XM to a negative one. Conversion of baseline positive XM to negative within 24 h after Imlifidase treatment occurred in 89.5% (n=17) of the 19 patients. In the follow-up study including all the patients transplanted after Imlifidase desensitization, the antibody-mediated rejection rate (AMR) was at 39%, most of them occurring during the first month post-transplantation. Three-year death-censored graft survival was 93% in patients with AMR and 77% in the others. Three-year patient survival was 85% in patients with AMR and 94% in the others. No safety signal was reported.

Based on these data, Imlifidase is now indicated as a desensitization agent of highly sensitized adult kidney transplant patients with positive crossmatch against an available ABO-compatible deceased donor. It should be reserved for patients unlikely to be transplanted under the available kidney allocation system including the prioritization program for highly sensitized patients (https://www.ema.europa.eu). Therefore, the French Society of Transplantation (SFT), the French-speaking Society of Nephrology, Dialysis and Transplantation (SFNDT) and the French Society of Histocompatibility and Immunogenetics (SFHI) have proposed French recommendations for patient selection, choice of antibodies characteristics, treatment and follow-up in order to homogenize practices.

Although this new treatment addressed an unmet medical need, its authorization was based on only two small-scale studies. Therefore, additional data on long-term graft function and survival are required in patients treated by imlifidase.