Desensitization in Crossmatch-positive Kidney Transplant Candidates

Noble, Johan; Jouve, Thomas; Malvezzi, Paolo; Rostaing, Lionel

doi:10.1097/tp.0000000000004279

Cited by 7 publications

(7 citation statements)

References 94 publications

(112 reference statements)

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“…A significant decrease in NK cells was observed at C3D1 compared with BL (P , 0.001 and adjusted P value 5 0.005), which is mainly driven by the depletion of CD38 1 NK cells as no significant change was detected in the CD38 2 NK cell population at all time points. No notable decreases in the total Treg population were observed, as a decrease in CD38 1 Tregs was compensated by an increase of the CD38 2 Treg compartments (Figure 4, E-G).…”

Section: Pharmacodynamics and Immune Modulation Of Isatuximabmentioning

confidence: 92%

“…Patients may become sensitized to HLAs through pregnancy, after a blood product transfusion, or after solid organ transplantation. 1 Although there is no standardized definition, highly sensitized patients can be regarded as patients with a calculated panel reactive antibody (cPRA) $80.00%. 2,3 Only 6.5% of highly sensitized patients with cPRA $80.00% receive a compatible kidney transplant each year, and almost none of these patients have a cPRA $99.90%.…”

Section: Introductionmentioning

confidence: 99%

“…4 Other trials have also investigated IL-6 targeting therapies, such as tocilizumab and clazakizumab, or proteasome inhibitors, such as bortezomib and carfilzomib. 1 Imlifidase, a cysteine protease that cleaves all IgG subclasses, was recently approved by the European Medicines Agency for desensitization treatment of highly sensitized adult kidney transplant recipients with positive crossmatch against an available deceased donor. 7,8 However, imlifidase lacks durability of effect, requires repeated dosing that would not be feasible due to antidrug antibody (ADA) response, and leaves patients still susceptible to antibody-mediated rejection (ABMR) due to antibody rebound.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant

Vincenti,

Bestard,

Brar

et al. 2023

JASN

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Background Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. Methods This was an open-label single-arm Phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, Cohorts A and B, which enrolled cPRA ≥99.90% and 80.00%–<99.90%, respectively. Results 23 patients (12 Cohort A, 11 Cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38+ plasmablasts, plasma cells, and NK cells; and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, based on a pre-defined composite desensitization end-point, was 83.3% and 81.8% in Cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall cPRA values were minimally impacted, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cut-off (median follow-up 68 weeks), 6 patients received transplant offers, of which 4 were accepted. Conclusions In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity.

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Section: Pharmacodynamics and Immune Modulation Of Isatuximabmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant

Vincenti,

Bestard,

Brar

et al. 2023

JASN

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“…Desensitization and desensitization drugs were recently extensively discussed in a review by Noble et al 34 Plasmapheresis, IVIG, and anti-CD20 therapy are the most commonly used desensitization tools. 27 A combination of these desensitization methods is generally used to prevent ABMRABMR because the higher rejection rates remain challenging and impact allograft survival for crossmatch positive patients.…”

Section: Desensitization Toolsmentioning

confidence: 99%

Imlifidase Desensitization in HLA-incompatible Kidney Transplantation: Finding the Sweet Spot

et al. 2024

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Imlifidase, derived from a Streptococcus pyogenes enzyme, cleaves the entire immunoglobulin G pool within hours after administration in fully cleaved antigen-binding and crystallizable fragments. These cleaved fragments can no longer exert their antibody-dependent cytotoxic functions, thereby creating a window to permit HLA-incompatible kidney transplantation. Imlifidase is labeled, in Europe only, for deceased donor kidney transplantation in highly sensitized patients, whose chances for an HLA-compatible transplant are negligible. This review discusses outcomes of preclinical and clinical studies on imlifidase and describes the phase III desensitization trials that are currently enrolling patients. A comparison is made with other desensitization methods. The review discusses the immunological work-up of imlifidase candidates and especially the "delisting strategy" of antigens that shift from unacceptable to acceptable with imlifidase desensitization. Other considerations for clinical implementation, such as adaptation of induction protocols, are also discussed. Imlifidase cleaves most of the currently used induction agents except for horse antithymocyte globulin, and rebound of donor-specific antibodies should be managed. Another consideration is the timing and interpretation of (virtual) crossmatches when bringing this novel desensitization agent into the clinic.

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“…Our desensitization protocols have included anti-CD20 (rituximab or biosimilar equivalents) as a fundamental component, acting as potent B-cell depleting agents and likely beneficial to prevent primary sensitization and recall antibody responses by memory B-cell depletion [18,[20][21][22]24,25]. Comprehensive reviews of the applications of IVIG and anti-CD20 agents for desensitization have been published [26][27][28][29][30]. Anti-CD20 therapeutics have also advanced, including the development of, Obinutuzumab (type II anti-CD20), which demonstrated clinical superiority to rituximab in treatment of B-cell lymphoma and systemic lupus erythematosus [31].…”

Section: Targeting B-cellsmentioning

confidence: 99%

Advances in desensitization for human leukocyte antigen incompatible kidney transplantation

Vo,

Ammerman,

Jordan

2023

Current Opinion in Organ Transplantation

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Purpose of review Human leukocyte antigen (HLA) sensitization is a major barrier to kidney transplantation induced by exposure to alloantigens through pregnancy, blood product exposure and previous transplantations. Desensitization strategies are undertaken to improve the chances of finding compatible organ offers. Standard approaches to desensitization include the use of plasmapheresis/low dose intravenous immunoglobulin (IVIG) or high dose IVIG plus anti-CD20. However, current methods to reduce HLA antibodies are not always successful, especially in those with calculated panel reactive antibody 99–100%. Recent findings Newer desensitization strategies such as imlifidase [immunoglobulin G (IgG) endopeptidase] rapidly inactivates IgG molecules and creates an “antibody-free zone”, representing an important advancement in desensitization. However, pathogenic antibodies rebound, increasing allograft injury that is not addressed by imlifidase. Here, use of anti-IL-6R (tocilizumab) or anti-interleukin-6 (clazakizumab) could offer long-term control of B-memory and plasma cell DSA responses to limit graft injury. Agents aimed at long-lived plasma cells (anti-CD38 and anti-BCMAxCD3) could reduce or eliminate HLA-producing plasma cells from marrow niches. Other agents such as complement inhibitors and novel agents inhibiting the Fc neonatal receptor (FcRn) mediated IgG recycling will likely find important roles in desensitization. Summary Use of these agents alone or in combination will likely improve the efficacy and durability of desensitization therapies, improving access to kidney transplantation for immunologically disadvantaged patients.

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Desensitization in Crossmatch-positive Kidney Transplant Candidates

Cited by 7 publications

References 94 publications

Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant

Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant

Imlifidase Desensitization in HLA-incompatible Kidney Transplantation: Finding the Sweet Spot

Advances in desensitization for human leukocyte antigen incompatible kidney transplantation

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