Potential kidney transplant patients with HLA-specific antibodies have reduced access to transplantation. Their harmful effects are mediated by the Fc portion of IgG, including activation of the complement system and Fc receptor-initiated cytotoxic processes by circulating leucocytes. Avoiding antibody incompatibility is the conventional approach, but for some patients this can mean extended waiting times, or even no chance of a transplant if there are no alternative, compatible donors. For these cases, pretransplant antibody removal may provide access to transplantation. Plasmapheresis is currently used to achieve this, with acceptable outcome results, but the process can take days to reduce the antibody levels to a safe level, so has limited use for deceased donors. There is now an alternative, in the form of an IgG-digesting enzyme, Imlifidase, which can be administered for in vivo IgG inactivation. Imlifidase cleaves human IgG, separating the antigen-binding part, F(ab\')2 from Fc. Typically, within six hours of dosing, most, if not all, of the circulating IgG has been inactivated, allowing safe transplantation from a previously incompatible donor. For deceased donor transplantation, where minimizing cold ischaemia is critical, this six-hour delay before implantation should be manageable, with the compatibility testing processes adjusted to accommodate the treatment. This agent has been used successfully in phase 2 clinical trials, with good short to medium term outcomes. While a donation rate that matches demand may be one essential answer to providing universal access to kidney transplantation, this is currently unrealistic. IgG inactivation, using Imlifidase, is, however, a realistic and proven alternative.

The IgG-degrading enzyme derived from Streptococcus pyogenes is a recombinant cysteine protease of S. pyogenes produced in Escherichia coli that cleaves all four human subclasses of IgG with strict specificity. The proteolytic activity on IgG molecules prevents the occurrence of IgG-mediated antibody-dependent, cellular cytotoxicity and complement-mediated cytotoxicity, two processes that are critical for antibody rejection. The results from phase II studies demonstrated that desensitization with imlifidase represents a therapeutic strategy that can operationalize desensitization, allowing life-saving transplants from deceased donors (DD) and living donors (LD) to proceed in highly sensitized kidney transplant candidates with low risk of hyperacute rejection. Its action onset is rapid, allowing kidney transplantation from a deceased donor. Disadvantages of imlifidase include a quick reappearance of DSAs, which poses a risk of antibody-mediated rejection, the quick development of anti-Ides antibodies, which rules out repeated use of imlifidase and its IgG-degrading potential, limiting the use of therapeutic antibodies. Imlifdase received conditional approval on 26 August 2020 in the EU for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor.

UNASSIGNED: The transplantation of highly sensitized patients remains a major obstacle. Immunized patients wait longer for a transplant if not prioritized, and if transplanted, their transplant outcome is worse.
UNASSIGNED: We report a successful AB0- and HLA-incompatible living donor kidney transplantation in a 35-year-old female patient with systemic lupus erythematosus (SLE) and antiphospholipid syndrome. The patient had a positive T- and B-cell complement-dependent cytotoxicity (CDC) crossmatch and previous graft loss due to renal vein thrombosis. We treated the patient with intravenous immunoglobulins, rituximab, horse anti-thymocyte globulin, daratumumab, and imlifidase, besides standard immunosuppression. All IgG antibodies were sensitive to imlifidase treatment. Besides donor-specific HLA antibodies, anti-dsDNA antibodies and antiphospholipid antibodies were cleaved. The patient initially had delayed graft function. Two kidney biopsies (day 7 and day 14) revealed acute tubular necrosis without signs of HLA antibody-mediated rejection. On posttransplant day 30, hemodialysis was stopped, and creatinine levels declined over the next weeks to a baseline creatinine of about 1.7 mg/dL after 12 months.
UNASSIGNED: In this case, a novel multimodal treatment strategy including daratumumab and imlifidase enabled successful kidney transplantation for a highly immunized patient with antiphospholipid antibodies.

Kidney transplantation, the gold-standard therapeutic approach for patients with end-stage kidney disease, offers improvement in patient survival and quality of life. However, broad sensitization against human leukocyte antigens often resulting in a positive crossmatch against the patient\'s living donor or the majority of potential deceased donors in the allocation system represents a major obstacle due to a high risk for antibody-mediated rejection, delayed graft function and allograft loss. Kidney-paired donation and desensitization protocols have been established to overcome this obstacle, with limited success. Imlifidase, a novel immunoglobulin G (IgG)-degrading enzyme derived from Streptococcus pyogenes and recombinantly produced in Escherichia coli, is a promising agent for recipients with a positive crossmatch against their organ donor with high specificity towards IgG, rapid action and high efficacy in early pre-clinical and clinical studies. However, the rebound of IgG after a few days can lead to antibody-mediated rejection, making the administration of potent immunosuppressive regimens in the early post-transplant phase necessary. There is currently no comparative study evaluating the efficiency of imlifidase therapy compared with conventional desensitization protocols along with the lack of randomized control trials, indicating the clear need for future large-scale clinical studies in this field. Besides providing a practical framework for the clinical use of the agent, our aim in this article is to evaluate the underlying mechanism of action, efficiency and safety of imlifidase therapy in immunologically high-risk kidney transplant recipients.

Through a clinical case, we will describe the difficulties associated with providing transplantation opportunities to highly immunized patients. We will therefore focus on new desensitization therapies and their pharmacological effects with the consequent improvement in clinical outcomes. The main desensitization strategies in use and the main future therapeutic prospects will also be discussed.

Imlifidase recently received early access authorization for highly sensitized adult kidney transplant candidates with a positive crossmatch against an ABO-compatible deceased donor. These French consensus guidelines have been generated by an expert working group, in order to homogenize patient selection, associated treatments and follow-up. This initiative is part of an international effort to analyze properly the benefits and tolerance of this new costly treatment in real-life. Eligible patients must meet the following screening criteria: cPRA ≥ 98%, ≤ 65-year of age, ≥ 3 years on the waiting list, and a low risk of biopsy-related complications. The final decision to use Imlifidase will be based on the two following criteria. First, the results of a virtual crossmatch on recent serum, which shall show a MFI for the immunodominant donor-specific antibodies (DSA) > 6,000 but the value of which does not exceed 5,000 after 1:10 dilution. Second, the post-Imlifidase complement-dependent cytotoxicity crossmatch must be negative. Patients treated with Imlifidase will receive an immunosuppressive regimen based on steroids, rATG, high dose IVIg, rituximab, tacrolimus and mycophenolic acid. Frequent post-transplant testing for DSA and systematic surveillance kidney biopsies are highly recommended to monitor post-transplant DSA rebound and subclinical rejection.

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UNASSIGNED: Imlifidase, the IgG-degrading enzyme derived from Streptococcus pyogenes, can cleave all four human IgG subclasses with precise specificity. All IgG molecules can be inactivated for ~1-to-2 weeks, until new IgG synthesis is detected.
UNASSIGNED: Imlifidase was first studied for the desensitization of highly HLA-sensitized patients to enable kidney transplantation. It is currently being evaluated for kidney transplant recipients who have antibody-mediated rejection (AMR), those with acute kidney injury in the setting of anti-glomerular basement membrane disease, and those with Guillain-Barré syndrome. In 2020, imlifidase received conditional approval from the European Medicines Agency for use to desensitize deceased-donor kidney transplant recipients with a positive crossmatch. Literature search through PubMed revealed that so far, 39 crossmatched-positive patients, i.e. in the presence of donor-specific alloantibodies (DSA) on the transplantation day, have received imlifidase prior to kidney transplantation in four single-arm, open-label, phase II studies. Results at 3-year follow-up are good, i.e. allograft survival is 84%, despite 38% of patients presenting with acute AMR. Mean estimated glomerular filtration rate at 3 years was 55 mL/min/1.73 m2.
UNASSIGNED: The major hurdle now is how to prevent/avoid DSA rebound within days 5-15 post-transplantation. Thus, imlifidase represents a major breakthrough for highly HLA-sensitized kidney transplant candidates, particularly those that have calculated panel-reactive alloantibodies of ≥90%.

The discovery of bacterial enzymes with specificity for IgG antibodies has led to breakthroughs in several autoantibody-mediated diseases. Two such enzymes, IdeS and EndoS, degrade IgG by different mechanisms, and have separately shown promise in numerous animal models of autoimmune diseases. Recently, imlifidase (the international nonproprietary name for IdeS) has advanced to clinical trials, where it has performed remarkably well in desensitizing patients to enable kidney transplantation, and in anti-glomerular basement membrane disease. Conversely, it performed poorly in thrombotic thrombocytopenic purpura. This review summarizes the development of antibody-degrading enzymes, with a discussion of key clinical studies involving imlifidase. The future of the field is also discussed, including the use of these enzymes in other diseases, and the potential for re-dosing.

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