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Commentary

Imlifidase Shows Promise for the Most Disadvantaged Sensitized Transplant Candidates

Schinstock, Carrie A. MD1

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doi: 10.1097/TP.0000000000003497
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Imlifidase (IdeS) is a novel therapeutic with tremendous potential with applications for desensitization and antibody-mediated rejection (AMR) treatment. This endopeptidase rapidly cleaves all IgG into F(ab’) and Fc fragments and essentially impairs effector function from all circulating IgG subclasses. In this issue of Transplantation, Jordan et al1 present their findings from an international multicenter open-label single-arm phase 2 trial of IdeS combined with intravenous immunoglobulin (IVIG) and rituximab for desensitization. Similar to results from the initial phase 1–2 single-center study,2 IdeS led a rapid and impressive donor-specific antibody (DSA) reduction, thereby making even deceased donor transplantation possible with a reduced risk of hyperacute rejection. HLA antibodies levels predictably rebounded at 3–7 d posttransplant, leading to early acute AMR among 38.9% of patients, yet 6-month patient and graft survival were acceptable. We commend the authors on their innovative approaches for desensitization, and we look forward to learning about the safety and effectiveness of IdeS used for other indications.

Certainly, there is debate about the role of desensitization in the current era. Critics of aggressive desensitization approaches argue that there is no need to invest in desensitization. Updated allocation policies have substantially increased the transplantation rate among sensitized individuals, and positive crossmatch kidney transplantation can be expensive and associated with reduced allograft survival. While these points are valid, a close examination of transplantation rates following the implementation of the new kidney allocation system in the United States has revealed a population of candidates with a detailed calculated panel reactive antibody (cPRA) of 99.9% who remain disadvantaged with prolonged waiting times and disproportionately high waiting list mortality.3 Unfortunately, this group makes up the largest proportion of 100% cPRA candidates. Nearly 70% of 100% cPRA candidates have a precise cPRA of >99.9%, and thousands of patients in the United States alone are in this group.4 Additionally, living donor transplantation rates are disproportionately low even among patients with lower degrees of sensitization,4 and large national kidney paired donation programs are saturated with the highly sensitized.5 Outcomes after positive crossmatch transplantation are also acceptable,6 especially when compared with remaining on dialysis. Long-term follow-up studies have shown that 7-y posttransplant death-censored allograft survival is ~75%.7 The key point is that desensitization approaches should not be used indiscriminately. Thoughtful patient selection is essential; factors such as detailed cPRA, living donor options, potential time in kidney paired donation, and transplant center expertise in positive crossmatch transplantation must be considered.

Regardless of the debate on desensitization, there is tremendous value in evaluating the efficacy and safety of novel therapeutics with other potential applications in transplantation. The rapid reduction in DSA achieved with only 1 dose of IdeS is remarkable and negates the need for multiple expensive plasmapheresis sessions that are associated with a host of complications. This rapid means of desensitization is particularly attractive for deceased donor candidates without living donor options, and prompt reduction in DSA is advantageous to avoid graft loss in the context of aggressive early acute AMR associated with the anamnestic response. IdeS has been mainly studied in kidney transplantation, but one can envision applications in ABO-incompatible transplantation or in thoracic solid organ transplantation. Furthermore, there is value in studying combination therapy. In this study, patients received rituximab and IVIG as part of their desensitization regimen to reduce memory responses and DSA rebound. Complex pathologic processes such as AMR can likely only be managed with a multifaceted approach targeting multiple mechanisms.

Despite the success in achieving a negative crossmatch and subsequent kidney transplantation with IdeS, there remain many important unanswered questions about long-term outcomes and reasons to tamper one’s enthusiasm with this desensitization approach. This study was small, did not include a control group, and only 6-month follow-up was reported. The study protocol and patients studied were more uniform than the initial IdeS study, but there were important center differences in surveillance and AMR treatments. The use of IdeS, in general, necessitates careful timing of induction therapy, and currently, IdeS can only be used once because anti-IdeS antibodies almost universally form abrogating their effectiveness. Furthermore, the time needed for coordinating IdeS therapy and ensuring negative crossmatches in the deceased donor setting leads to prolonged cold ischemia times (>30 h in some cases).

Receiving a transplant is only the beginning. AMR is the Achilles heel of positive crossmatch kidney transplant. In this cohort, nearly 40% of patients experienced early acute AMR even with rituximab and IVIG. This rate is comparable with what has been reported among control groups in other desensitization studies.8 Surveillance biopsies were not consistently performed, and thus it is truly unknown how many patients developed AMR.

Conducting studies with new therapeutics like IdeS are exciting opportunities to learn as much as possible about sensitization and AMR. Detailed surveillance histological data among all study participants is extremely valuable and can be used to evaluate the long-term efficacy of varied desensitization approaches. Similarly, long-term DSA data including quantitative studies with antibody titers are informative to understand the kinetics of DSA with this approach, particularly because rituximab was added to this desensitization protocol. Importantly, this study and most other desensitization studies have lacked parallel mechanistic studies. Parallel memory B-cell and plasma-cell studies could aid in our understanding of baseline patient characteristics that are predictive of antibody rebound and long-term AMR and help with patient selection and personalize approaches. Finally, randomized, controlled phase 3 trials are needed to obtain possible regulatory approval for novel agents such as IdeS. At this time, no prior approval pathway exists in desensitization; thus, innovative study designs are needed to demonstrate safety and efficacy.

In conclusion, the authors validate the efficacy of rapid HLA antibody depletion with IdeS allowing transplantation in a group with few if any other options for transplantation. Outcomes beyond 6 months are largely unknown. However, we support gaining as many insights as possible into the potential applications for novel therapeutic agents and the use of combination therapies in a highly relevant field.

REFERENCES

1. Jordan SC, Legendre C, Desai NM, et al. Imlifidase desensitization in crossmatch-positive, highly-sensitized kidney transplant recipients: results of an international phase 2 trial (Highdes) [published online ahead of print, 2020 Oct 21]. Transplantation. 2020. doi:10.1097/TP.0000000000003496.
2. Jordan SC, Lorant T, Choi J. IgG endopeptidase in highly sensitized patients undergoing transplantation. N Engl J Med. 2017;377:1693–1694.
3. Jackson KR, Covarrubias K, Holscher CM, et al. The national landscape of deceased donor kidney transplantation for the highly sensitized: transplant rates, waitlist mortality, and posttransplant survival under KAS. Am J Transplant. 2019;19:1129–1138.
4. Schinstock CA, Smith BH, Montgomery RA, et al. Managing highly sensitized renal transplant candidates in the era of kidney paired donation and the new kidney allocation system: is there still a role for desensitization? Clin Transplant. 2019;33:e13751.
5. Flechner SM, Thomas AG, Ronin M, et al. The first 9 years of kidney paired donation through the National Kidney Registry: characteristics of donors and recipients compared with National Live Donor Transplant Registries. Am J Transplant. 2018;18:2730–2738.
6. Schinstock CA, Gandhi M, Cheungpasitporn W, et al. Kidney transplant with low levels of DSA or low positive B-flow crossmatch: an underappreciated option for highly sensitized transplant candidates. Transplantation. 2017;101:2429–2439.
7. Schinstock CA, Bentall AJ, Smith BH, et al. Long-term outcomes of eculizumab-treated positive crossmatch recipients: allograft survival, histologic findings, and natural history of the donor-specific antibodies. Am J Transplant. 2019;19:1671–1683.
8. Stegall MD, Diwan T, Raghavaiah S, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant. 2011;11:2405–2413.
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