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OBM Transplantation

(ISSN 2577-5820)

OBM Transplantation (ISSN 2577-5820) is an international peer-reviewed Open Access journal published quarterly online by LIDSEN Publishing Inc., which covers all evidence-based scientific studies related to transplantation, including: transplantation procedures and the maintenance of transplanted tissues or organs; assimilation of grafted tissue and the reconstitution of removed organs or parts of organs; transplantation of heart, lung, kidney, liver, pancreatic islets and bone marrow, etc. Areas related to clinical and experimental transplantation are also of interest.

OBM Transplantation is committed to rapid review and publication, and we aim at serving the international transplant community with high accessibility as well as relevant and high quality content.

The journal publishes all types of articles in English. There is no restriction on the length of the papers. We encourage authors to be concise but present their results in as much detail as necessary, as reviewers are expected to emphasize scientific rigor and reproducibility.

 
 

Publication Speed (median values for papers published in 2024): Submission to First Decision: 6.7 weeks; Submission to Acceptance: 14.4 weeks; Acceptance to Publication: 4 days (1-2 days of FREE language polishing included)

 
 
Current Issue: 2026  Archive: 2025 2024 2023 2022 2021 2020 2019 2018 2017
Open Access Review

Novel Therapies for the Treatment of Antibody Mediated Rejection in Solid Organ Transplantation: A Systematic Review

Alisia Chen 1,* ORCID logo, Jeong M. Park 2 ORCID logo

  1. Department of Pharmacy, University of Washington Medical Center, Seattle, WA, USA

  2. Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA

* Correspondence: Alisia Chen ORCID logo

Academic Editor: Maurizio Salvadori

Special Issue: The Role of Antibody Mediated Rejection in Organ Transplantation

Received: October 29, 2025 | Accepted: February 13, 2026 | Published: February 24, 2026

OBM Transplantation 2026, Volume 10, Issue 1, doi:10.21926/obm.transplant.2601267

Recommended citation: Chen A, Park JM. Novel Therapies for the Treatment of Antibody Mediated Rejection in Solid Organ Transplantation: A Systematic Review. OBM Transplantation 2026; 10(1): 267; doi:10.21926/obm.transplant.2601267.

© 2026 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Antibody mediated rejection (AMR) is a considerable cause of late allograft failure in solid organ transplantation. Conventional approaches, using plasmapheresis, intravenous immunoglobulin, rituximab, bortezomib, and eculizumab have been unsuccessful in improving graft survival. This review aims to assess emerging therapies for AMR treatment across all organs. Using a PubMed search, literature published up to July 20, 2025 regarding tocilizumab, clazakizumab, carfilzomib, daratumumab, imlifidase, felzartamab, and obinutuzumab were reviewed. Articles were included if available in English, full-text, and reported clinical efficacy outcomes, and excluded if they discussed non-AMR indications or were review articles, single case reports, opinion pieces, protocols, animal studies, or in vitro studies. A total of 28 studies were included, and grouped by drug, organ, and indication. Quality was rated with the Newcastle-Ottawa Scale. The majority of evidence was with single-center retrospective studies and kidney transplantation. Tocilizumab demonstrated the most promise for stabilizing graft function in kidney chronic active AMR (cAMR). Clazakizumab failed to meet its primary efficacy outcome in its cAMR phase III study despite encouraging findings in earlier trials. Carfilzomib may be considered in acute AMR when toxicities preclude use of bortezomib, but comes with risks of nephrotoxicity. Evidence to support daratumumab’s utility in acute AMR is limited to highly heterogenous case series. Imlifidase, felzartamab, and obinutuzumab are not widely studied but may be potential therapies in the future. Studies comparing these therapies to standard of care are needed to establish the place in therapy of these agents. Additionally, there is a need to identify patient characteristics most predictive of clinical success.

Keywords

Antibody mediated rejection; solid organ transplantation; kidney transplant; liver transplant; lung transplant; heart transplant

1. Introduction

Antibody mediated rejection (AMR) remains a therapeutic challenge in solid organ transplantation and is a major cause for late allograft loss across all organ groups [1,2,3,4,5]. In kidney transplantation, there is a 4.7-fold increased risk of graft loss in patients experiencing AMR in comparison to those who do not [1]. Similarly, C4d positive staining and the presence of donor specific antibodies (DSA) in both pancreas and liver transplantation are associated with a significantly increased risk of graft loss [2,3]. In cardiothoracic transplantation, AMR portends a poor prognosis, with a 5.4-fold increased risk of developing cardiac allograft vasculopathy (CAV) in heart transplantation and an 8.7-fold increased risk of developing chronic lung allograft dysfunction (CLAD) in lung transplantation [6,7,8].

Allograft injury resulting from acute AMR is driven predominantly by production of donor-specific human leukocyte antigen (HLA) antibodies, which results in inflammation and endothelial cell injury, complement activation, and infiltration of innate immune cells into the endothelium. Repeated allograft injury and uncontrolled repair responses can result in transplant vasculopathy and irreversible fibrosis, characteristic of chronic active AMR (cAMR) [9]. Conventional therapy for AMR includes a combination of plasmapheresis (PLEX) and intravenous immunoglobulin (IVIg) for removal and neutralization of DSA. In the past decade, adjunctive therapies such as rituximab targeting B cells, bortezomib targeting plasma cells, and eculizumab targeting the complement system have been used [10,11]. Yet, these approaches have been unsuccessful in improving clinical outcomes and long-term survival in kidney transplantation. In a randomized controlled trial, addition of rituximab to PLEX and IVIg failed to show any differences from placebo in graft loss, renal function, Banff histologic scores, or DSA strength [12]. Additionally, long-term death-censored graft survival at 7 years remained not different from placebo [13]. Given that rituximab targets CD20 without any effect on antibody-producing plasma cells, bortezomib, a 26S proteasome inhibitor has been explored as a potential therapeutic option. However, bortezomib also failed to show benefits in comparison to placebo in estimated glomerular filtration rate (eGFR) slope, graft survival, Banff histology or DSA strength [14]. Eculizumab, which targets the C5 complement protein, preventing formation of the membrane attack complex, has also been studied as a potential treatment option. In a randomized control trial where eculizumab was compared to placebo for cAMR, there was no improvement in kidney function or endothelial cell-associated transcripts [15]. A subsequent case series of 15 kidney transplant recipients found improvements in eGFR in early acute AMR (within 30 days of transplant). However, this study lacked a comparator group, and therefore these findings do not confirm the definitive benefit of eculizumab [16]. With these therapies, the management of acute AMR and attenuating the progression towards chronic, irreversible allograft injury remains challenging.

Thus, there have been recent efforts in identifying new therapeutic targets for the treatment of AMR. The goal of this review is to assess the available data for tocilizumab, clazakizumab, carfilzomib, daratumumab, imlifidase, felzartamab, and obinutuzumab for use in the treatment of AMR across all solid organ transplant types.

2. Methods

2.1 Protocol and Ethics Statement

Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [17]. The protocol was registered with the PROSPERO registry (CRD420251072841). This review was screened for Institutional Review Board criteria, and did not require approval through an ethics committee.

2.2 Search Strategy

Emerging therapeutic agents for AMR were identified from published review articles [18,19,20,21,22,23,24,25,26,27,28]. A PubMed search was conducted to identify studies assessing the use of tocilizumab, clazakizumab, carfilzomib, daratumumab, imlifidase, felzartamab, obinutuzumab, belimumab, ofatumumab, inebilizumab, and isatuximab for the treatment of AMR. Studies published up to July 20, 2025 were assessed for inclusion. The database was searched using the drug name AND (“antibody mediated rejection” OR “antibody-mediated rejection”) AND (kidney transplantation [MeSH Terms] OR “kidney transplant*” OR pancreas transplantation [MeSH Terms] OR “pancreas transplant*” OR liver transplantation [MeSH Terms] OR “liver transplant*” OR lung transplantation [MeSH Terms] OR “lung transplant*” OR heart transplantation [MeSH Terms] OR “heart transplant*” OR organ transplantation [MeSH Terms] OR “organ transplant*”).

2.3 Study Selection

Articles were included if they were available in English, full-text and reported clinical efficacy outcomes of the drug of interest. Articles were excluded if they discussed the drug therapy for non-AMR indications, if they were review articles, single case reports, opinion pieces, study protocols, animal studies, or in vitro studies. The final search results were exported, and an eligibility assessment was independently performed by the authors. Differences were resolved by consensus. Additional articles were included as appropriate if they were identified through the bibliography of articles that came from the PubMed search.

2.4 Data Extraction and Bias Assessment

Data were independently extracted by both authors. Subsequently results were discussed, and inconsistencies in charting were resolved by consensus. The following data were extracted from the studies: organ type, indication, study design (study type, number of centers, country), number of patients, inclusion/exclusion criteria, timing of rejection, baseline graft function [serum creatinine (SCr)/eGFR, liver function tests (LFTs), forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC), left ventricular ejection fraction (LVEF)], baseline histology/AMR classification, baseline DSA, treatment regimen and timing of initiation, follow-up duration, efficacy outcomes (graft survival, patient survival, graft function, histology, and DSA), and safety outcomes [adverse effects (AEs), treatment discontinuations]. Studies were grouped by drug, organ type, and indication.

Both authors independently assessed and rated study quality following the Newcastle-Ottawa Scale (NOS) for cohort studies [29]. The total NOS score ranges from 0-9, with the following criteria: quality of patient selection (S: 0-4 points), comparability of cohorts (C: 0-2 points), and assessment/follow-up of outcomes (O: 0-3 points).

3. Results

3.1 Identified Studies

The search strategy yielded 156 results which were then filtered to exclude 3 non-English articles and 1 non-full text article. After screening titles and abstracts, 126 articles were excluded for non-AMR indications (n = 22) and article types (n = 104). After assessing full-text articles for exclusion criteria and the addition of studies through bibliographies, 28 studies were included in the final review (Figure 1). Belimumab, ofatumumab, inebilizumab, and isatuximab were included in the initial search strategy because they were proposed as potential treatment options for AMR in published review articles [18,19,20,21,22,23,24,25,26,27,28]. However, our literature search yielded five reports for belimumab, but none of them met the inclusion criteria (three review articles and two case reports for non-AMR indications). No studies for ofatumumab, inebilizumab, and isatuximab were found on our literature search.

Click to view original image

Figure 1 PRISMA Flow Diagram.

3.2 Study Characteristics

The included studies are grouped by agent, organ type, and indication. No studies assessed the treatment of AMR in pancreas transplantation. The majority of studies were retrospective case series, with only three studies being prospective studies. Six studies included a comparator group, of which three were retrospective studies and three were randomized controlled trials. Overall, NOS selection scores ranged from 3-4, comparability scores ranged from 0-1, and outcome scores ranged from 2-3, with a total NOS score range of 5-8. In the selection category, all studies received at least 3 points given representativeness of the exposed cohort to the average population, ascertainment of the exposure from secure records, and demonstration that the outcome of interest was not present at the start of the study. The three retrospective comparative studies received an additional point in the selection category for having the non-exposed cohort drawn from the same community as the exposed cohort, and an additional point in the comparability category for including a control for comparison. No studies received the full 2 points in the comparability category due to lack of additional controls. In the outcome category, all studies had at least 2 points given for independent blind assessment of outcomes and >80% of subjects included at follow-up. Seventeen of the studies had an additional point for the outcome category for a follow-up period ≥1 year when considering efficacy outcomes. Table 1 summarizes the study design and baseline characteristics, and Table 2 summarizes the efficacy and safety outcomes.

Table 1 Study Design and Baseline Characteristics.

Table 2 Efficacy and Safety Outcomes.

3.3 Tocilizumab

3.3.1 Kidney – Acute AMR

Two retrospective case series described tocilizumab primarily for the treatment of acute AMR in 32 kidney transplant recipients. Four patients had mixed acute AMR and acute cellular rejections (ACR), 18 had acute AMR alone, and 10 had cAMR. Tocilizumab 8 mg/kg IV monthly was given for 1-6 months in addition to conventional therapies (which included combinations of steroids, PLEX, IVIg, rituximab, or bortezomib) in Pottebaum, et al., and for a median of 12 months for patients who were refractory to combinations of IVIg, rituximab, steroids, PLEX, or bortezomib in Pearl, et al. 17/32 (53%) of patients discontinued tocilizumab, with nine discontinuing due complications. Patients were followed for a median of 3 months (IQR 3-6) post-tocilizumab in Pottebaum, et al., while follow-up period was not reported in Pearl, et al.; graft survival was 71.4% and 96% respectively. Renal function improved or stabilized during tocilizumab therapy in both studies. For Pottebaum, et al., a ≥50% reduction in immunodominant donor specific antibodies (iDSA) was observed in four patients with DSAs, iDSA stabilized in two patients, and one patient did not have DSAs checked after therapy. Pearl, et al., found a significant decrease in iDSA strength in the subset of patients who had DSAs at tocilizumab initiation. Follow-up histology was not reported in either of the studies. Given the small sample size, inclusion of cAMR patients, lack of a control, and heterogeneity of regimens used with tocilizumab, it is difficult to determine if tocilizumab significantly altered the course of acute AMR in kidney transplant recipients. It is also unclear if the complications observed were associated with tocilizumab [30,31].

3.3.2 Kidney – Chronic Active AMR

Ten studies reported tocilizumab for treatment of cAMR and/or refractory AMR in kidney transplant recipients [32,33,34,35,36,37,38,39,40,41]. Of these studies, two were prospective open-label case series, seven were retrospective case series, and one study was a retrospective cohort study comparing tocilizumab plus standard of care (SOC) to historical SOC. Tocilizumab was added as rescue therapy for refractory cAMR in six studies, two focused on tocilizumab as first line therapy in cAMR, and two discussed tocilizumab in both first line and rescue therapy. The majority of patients were treated with tocilizumab 8 mg/kg IV monthly for 3-25 months. One study also examined subcutaneous dosing with 162 mg every 15 days.

Overall graft survival with tocilizumab therapy was 50-100%, with median follow-up of 5.8-20.7 months. Renal function remained stable in seven studies, worsened in two studies, and was not different between the tocilizumab and the non-tocilizumab groups in the cohort study. The effect of tocilizumab on DSA was variable, with three studies reporting a statistically significant decline in DSA, and the other seven studies reporting either a DSA change of unknown significance or non-significant change in DSA. A reduction in microvascular inflammation (g+ptc score) was reported in four studies, with two studies finding statistical significance. No other trends were seen among other histological parameters. In the studies that reported the following specific safety outcomes, 49/194 (25.3%) experienced infection, 21/53 (39.6%) experienced leukopenia, 12/51 (23.5%) experienced hypogammaglobinemia, and 11/117 (9.4%) experienced asymptomatic liver enzyme elevations, which were potentially secondary to tocilizumab [32,33,34,35,36,37,38,39,40,41].

Both Choi, et al. and Lavacca, et al. found favorable results where renal function was stabilized, microvascular inflammation was significantly reduced, and DSA strength was significantly decreased [32,33]. In contrast, a subsequent study from Kumar, et al. failed to find any improvement in microvascular inflammation or DSA strength but found that renal function remained stable. This finding could be secondary to higher baseline microvascular inflammation in comparison to the two proceeding studies [34]. Massat, et al. evaluated tocilizumab as add-on therapy in comparison to SOC and did not find any differences in graft survival or decline in eGFR between the two groups despite the serological and histological improvements in tocilizumab patients [35]. Noble, et al. (2021) found that patients who lost their allograft had both lower eGFR (mean ± SD: 24.5 ± 16 vs. 46.3 ± 15 mL/min/1.73 m2, p = 0.006) and higher proteinuria (mean ± SD: 1.8 ± 1 vs. 0.8 ± 0.9 g/L, p = 0.022) at the time of AMR diagnosis in comparison to those who did not. As expected, patients who had more severe histology (ct = 3, ci = 3, v =2) were more likely to lose their graft in comparison to those who did not (p < 0.05) [36]. Khairallah, et al. found that tocilizumab stabilized renal function, with significant improvement in interstitial inflammation, and no significant effect on DSA [37]. Similarly, Boonpheng, et al. found stabilization of renal function, numerical improvements in microvascular inflammation, and no significant effect on DSA [38]. Chaumon, et al. and Sangermano et al. found worsened renal function, and no differences in histology [39,40]. A subsequent study from Noble, et al. (2025), examined tocilizumab in both cAMR and those with microvascular inflammation (MVI) without DSA or C4d deposition. Renal function was stabilized with tocilizumab in both patient groups, with significant decreases in the g score in those who had surveillance biopsies at 1 year. In this study, younger age (OR = 0.95, p = 0.02), MVI without DSA or C4d deposition (OR = 5.1, p = 0.01) and lower chronic glomerulopathy score (OR = 4.5, p = 0.02) were associated with treatment response (defined as eGFR stabilization or improvement). Subcutaneous administration was also not associated with a reduced treatment response (p = 0.421) [41]. Synthesizing these findings, tocilizumab in cAMR seemed to generally stabilize renal function, with variable effect on histological parameters and DSA strength. Patients with cAMR were more likely to benefit from tocilizumab if baseline microvascular inflammation was lower. Interestingly, one study’s results suggested that tocilizumab may also have utility in earlier stages of graft inflammation even without the presence of DSA or C4d staining. However, the majority of studies that examined tocilizumab in cAMR in kidney transplantation were case series without a comparator.

3.3.3 Lung – Acute AMR

One single-center cohort study assessed tocilizumab in the treatment of acute AMR in lung transplant recipients. Patients who received combination therapy containing tocilizumab (n = 9) were compared to patients who received a non-tocilizumab regimen (n = 18). Therapies that were used in combination regimens included rituximab, carfilzomib, bortezomib, rabbit anti-thymocyte globulin (rATG), IVIg, extracorporeal photopheresis, and PLEX. Mean duration of tocilizumab therapy was 6 months (range 2-12). At an average follow up of 211 days (tocilizumab group) and 261 days (non-tocilizumab group), improved graft survival was observed with tocilizumab therapy in comparison to non-tocilizumab regimens (88.9% vs. 50%, p = 0.049). Non-statistically significant improvements in average FEV1 and FVC were also observed with tocilizumab therapy. Tocilizumab resulted in more clearance of DSA, lower recurrence of DSA, and lower development of de novo DSA, but none of these findings were statistically significant. Post-treatment infection rate was similar between the tocilizumab and non-tocilizumab groups (56% vs. 61%). Of note, at this institution, no patients who received tocilizumab received PLEX vs. 38.9% of patients who received non-tocilizumab regimens received PLEX, and in general more therapies were given to non-tocilizumab treated patients. However, given that there was a favorable change in DSA strength in the tocilizumab treated patients, this was less likely to be a significant confounder. Tocilizumab may be considered as an adjunctive therapy in lung acute AMR due to its favorable impact on graft survival in comparison to non-tocilizumab regimens, but given the wide range of therapies that were given in conjunction to tocilizumab, the treatment effect of tocilizumab cannot be definitively ascertained from the findings of this study [42].

3.3.4 Heart – Acute AMR

One single-center case series assessed tocilizumab for acute AMR in heart transplantation. Of the seven patients included, four patients had refractory AMR, who all received PLEX, IVIg and rituximab prior to initiation of tocilizumab, and the other three patients received tocilizumab in conjunction with PLEX and IVIg for first line therapy. Median duration of tocilizumab therapy was 15 months (IQR 10-21), and patients were followed up at a range of 5-54 months after tocilizumab therapy initiation, at which graft survival was 85.7%. The one patient who expired had an autopsy that showed severe CAV. LVEF improved in all patients post-tocilizumab therapy with a median change of +17% (IQR 11-18), and all patients reported an improvement in functional capacity as measured by the New York Heart Association Functional Classification. Median change in LVEF for those who received tocilizumab for rescue therapy was similar to that of those who received tocilizumab as first line therapy (+17% vs. +15%). Three patients that had follow-up biopsy results showed an improvement from pre-tocilizumab biopsy findings. International Society for Heart and Lung Transplantation (ISHLT) CAV grade generally worsened with two patients having CAV grade 2-3 at baseline, to five patients having CAV grade 2-3 at follow-up. No consistent effect was observed on DSA. Tocilizumab as both first line and rescue therapy in this case series improved both echocardiographic measurements and functional capacity but failed to decrease risk of progression of CAV, demonstrating the difficulties with preventing the progression and development of CAV in patients who experience AMR [43].

3.4 Clazakizumab

3.4.1 Kidney – Late AMR

Two phase II studies to date have been published examining the use of clazakizumab for AMR in solid organ transplantation [44,45]. Doberer, et al. conducted a randomized, double-blind, placebo-controlled pilot trial, where kidney transplant recipients with late acute or cAMR were randomized 1:1 to receive clazakizumab 25 mg SQ every 4 weeks (n = 10) or placebo (n = 10) for 12 weeks (part A), followed by a 40-week open-label extension during which all patients received clazakizumab (part B) with the last trial visit conducted at week 52 [44]. Jordan, et al. conducted an open-label single-arm trial of kidney transplant recipients with cAMR who received clazakizumab 25 mg SQ every 4 weeks for 12 months (n = 10). At 12 months, patients were provided the option to enter a long-term extension where they received clazakizumab 25 mg SQ every other month [45]. In the two studies, patients were enrolled at a median range of 8.2-10.6 years post-transplant, with 2/30 (6.7%) patients having acute AMR, and 28/30 (93.3%) patients having cAMR. In Doberer, et al., prior treatments for patients who had cAMR were not reported, but patients who had acute rejection treatment <3 months prior to screening were excluded from the trial [44]. In Jordan, et al., 8/10 (80%) patients had received previous therapies, all with a combination of either ritixumab and/or obinutuzumab with IVIg; additionally, 3/8 of these patients also received tocilizumab for 6 months [45]. Graft survival was not explicitly reported in Doberer, et al., and was 80% in Jordan, et al. Both studies demonstrated either stabilization or improvement of renal function and DSA, with the improvements reaching statistical significance in Doberer, et al. With extension of clazakizumab therapy beyond 12 weeks in Doberer, et al., and beyond 12 months with Jordan, et al., DSA was reduced further. In terms of histology, the 51-week biopsies demonstrated a significant decrease in molecular AMR (p = 0.020) and all rejection scores (p = 0.037) in Doberer, et al., and the 6 months biopsies demonstrated significant decreases in g+ptc score in Jordan, et al. In terms of safety, 9/20 (45%) of patients developed diverticulitis in Doberer, et al., with no patients experiencing this complication in Jordan, et al. Overall, 19/30 (63.3%) of patients experienced an infection under clazakizumab therapy. Given that clazakizumab demonstrated beneficial effects on DSA, histology, and eGFR decline, it showed some promise in altering the course of patients experiencing late AMR, meeting an unmet need [44,45].

The subsequent phase III trial examining clazakizumab for kidney transplant recipients experiencing cAMR aimed to recruit approximately 350 kidney transplant recipients, randomized 1:1 to clazakizumab or placebo [58]. Unfortunately, in the interim analysis of 100 participants who completed 1-year of the study, investigators found that the study was unlikely to meet the primary efficacy outcome (time to composite of all-cause allograft loss or irreversible loss of allograft function), and the data and safety monitoring board recommended discontinuation of the study. The final analysis after the 1-year interim analysis of eGFR found no difference in Least Squares mean change from baseline eGFR at week 52 for clazakizumab in comparison with placebo, confirming that clazakizumab does not seem to attenuate renal function decline in cAMR [59].

Timing of rejection/therapy initiation was approximately 8-10 years post-transplant for the phase II trials but not reported in the phase III trial. Outcomes examined were similar among all three studies. In terms of follow-up, all studies utilized a follow-up period of 52 weeks or 12 months. Notably, baseline microvascular inflammation and chronicity scores were only reported in one of the studies. Therefore, baseline degree of cAMR progression cannot be compared among the studies, which would have had an important factor in interpretation of findings. Additionally, the number of participants included in the phase III study was significantly greater than that of the phase II studies, which may point to the possibility of a type II error found in the phase II studies.

3.5 Carfilzomib

3.5.1 Kidney – Acute AMR

In a case series of two pediatric kidney transplant recipients with AMR, carfilzomib was used in the setting of bortezomib intolerance. Patient 1 underwent treatment with rituximab, IVIg, and then PLEX and bortezomib, which was limited by thrombocytopenia and peripheral neuropathy. Patient 2 underwent treatment with PLEX and bortezomib, which was limited by peripheral neuropathy. Both were switched to carfilzomib, which resulted in a decrease in DSA MFI (Patient 1 cleared all three class II DSA; patient 2 cleared one class I DSA but continued to have low levels of two class II DSA). Patient 1 already had histological improvements prior to carfilzomib treatment, while patient 2 experienced improvements after carfilzomib treatment. Both patients experienced acute kidney injury (AKI) under carfilzomib, which was treated with N-acetylcysteine and IV fluids pre- and post-therapy. Patient 1 finished six doses of carfilzomib 20 mg/m2 (days 1, 2, 8, 9, 15, and 16), whereas patient 2 discontinued after four doses of carfilzomib given that SCr remained elevated even with IV fluid administration. After a follow-up period of approximately 1 year, SCr returned to pre-AMR baseline in patient 1, and SCr in patient 2 decreased but not back to the pre-AMR baseline. Since both patients underwent prior proteasome inhibition with bortezomib, it is difficult to differentiate if the improvement in DSA and SCr at the follow-up was due to carfilzomib vs. bortezomib. Additionally, carfilzomib is known to be associated with AKI, and there were differing effects of IV fluids and N-acetylcysteine in preventing AKI. Thus, carfilzomib should be used with caution in the solid organ transplant population [46].

3.5.2 Liver – Acute AMR

In a case series of two liver transplant recipients, carfilzomib 20 mg/m2 (days 1, 2, 8, 9, 15, and 16) with PLEX for 2 cycles was utilized in patients with acute AMR refractory to steroids, IVIg and rituximab. Patient 1 presented with AMR features on biopsy at 10 days post-transplant, whereas patient 2 presented with ACR on biopsy and no evidence of AMR, but positive DSAs at 158 days post-transplant. Only patient 1 had demonstrated clinically significant normalization of LFTs and DSAs. Patient 2 later required repeat liver transplantation. Patient 1 discontinued carfilzomib early given a mild pneumonia that later resolved. Patient 2 discontinued treatment at the time of referral for retransplantation. Other specific adverse effects were not reported in this study. This case series shows that carfilzomib may be a potential therapy option used in acute AMR in liver transplantation, and treatment response may be improved with earlier recognition and treatment of AMR. Given that AMR occurs infrequently in liver transplantation, there are difficulties in timely diagnosis, and treatment strategies remain unclear in this population [47].

3.5.3 Lung – Acute AMR

Three single-center retrospective case series reported the use of carfilzomib for treatment of acute AMR in lung transplant recipients, with one of the three studies comparing carfilzomib therapy to rituximab therapy [48,49,50]. Number of carfilzomib cycles administered was not reported in any of the studies. Carfilzomib was administered in addition to PLEX and IVIg in Ensor, et al. and Pham, et al., and in addition to IVIg ± PLEX in Razia, et al. In Ensor, et al. and Razia, et al., carfilzomib was utilized as initial therapy, whereas in Pham, et al., 6/28 (21.4%) patients were given rituximab prior to carfilzomib, and 7/28 (25%) patients were given rATG prior to carfilzomib. As expected, AKI was associated with carfilzomib, occurring in 12/44 (27.2%) patients. FEV1 or % predicted FEV1 rose after carfilzomib therapy in one study and was unchanged in two studies [48,49,50]. The study that compared rituximab to carfilzomib found that % predicted ΔFEV1 at 6 months after treatment was significantly higher in the rituximab group than in the carfilzomib group (12% vs. 2%, p = 0.002) [50]. Carfilzomib significantly decreased DSA in all three studies, and in the two studies that looked at C1q fixing ability, carfilzomib also had significant effects in suppressing C1q fixing ability of DSAs [48,49,50]. The study that compared rituximab to carfilzomib found that median change in MFI was comparable, but carfilzomib had a shorter median interval to DSA rebound in comparison to rituximab (4.8 vs. 15.6 months, p = 0.015) [50]. Ensor, et al. found that patients who had loss of C1q fixing ability of iDSA were less likely to develop CLAD or have progression of CLAD in comparison to those who did not (25% vs. 83%, p = 0.04) [48]. Razia, et al. found that cumulative CLAD free survival was similar between those who received carfilzomib in comparison to those who received rituximab (75% vs. 86.2%, p = 0.339) [50]. Follow-up histology was not reported in any of the studies.

Graft survival at last follow-up in Ensor, et al. and Pham, et al. were similar at 50% (post- carfilzomib therapy, follow-up period not reported) and 42.9% (median time to death was 0.8 years, IQR 0.4-2.0), respectively. Razia, et al. reported higher graft survival rates with carfilzomib: 87.5% at 1 year and 75% at 3 years. In terms of ISHLT AMR classification, the majority of patients had probable AMR in Ensor, et al. (50%) and Pham, et al. (64.3%), whereas the majority of patients had possible AMR in Razia, et al. (84.1%), suggesting that the former two studies had included more patients who had a higher likelihood of true AMR, which could have contributed to these findings. Baseline pulmonary function testing among the three studies did not demonstrate any association with outcomes.

Across all studies, DSA MFI significantly decreased with carfilzomib therapy, confirming the efficacy of carfilzomib in reduction of DSAs in acute AMR. Ensor, et al. found that non-responders had significantly more high-titer DSA pre-carfilzomib and longer time from DSA detection to therapy, showing that early initiation of carfilzomib may result in improved reduction of DSA. However, despite significant reductions in DSAs found with carfilzomib, altering the course of AMR and improving long term graft survival remains a challenge [48,49,50].

3.5.4 Heart – Acute AMR

In a single-center retrospective case series of heart transplant recipients treated with PLEX and proteasome inhibitors (n = 8 carfilzomib, and n = 2 bortezomib) for initial treatment of acute AMR, graft survival was 90% at 1 year after AMR diagnosis. Of the ten patients included, six presented with graft dysfunction at the time of AMR diagnosis. With proteasome inhibition, 4/6 (66.7%) patients had a recovered EF to >40% after treatment, with five of these patients being treated with carfilzomib. Pathologic AMR resolved in 5/7 (71.4%) patients within 1 year after treatment. Proteasome inhibition also resulted in reductions in MFI of strong DSAs in both undiluted serum and at a 1:16 dilution, with a median reduction of 56% (IQR 13-39), and 92% (IQR 53-95) respectively. All non-responders (patients who did not have an MFI reduction in the strong DSA) had DSA with MFI of >8,000 at 1:16 dilution. Increased number of proteasome inhibitor cycles, and earlier treatment was associated with treatment responsiveness, as some DSA with MFI >8,000 at a 1:16 dilution responded to early and multiple treatment cycles. In summary, this retrospective case series shows that proteasome inhibition as initial therapy can effectively reduce DSAs in heart transplant recipients presenting with acute AMR, but given that both bortezomib and carfilzomib were included, and the lack of a sub-group analysis examining the differences in efficacy, the preferred therapy for AMR cannot be clearly identified [51].

3.6 Daratumumab

3.6.1 Kidney – Acute AMR and Chronic Active AMR

Three single-center retrospective case series have been published reporting the use of daratumumab for treatment of seven acute AMR cases and one cAMR case. Zhu, et al. used an intensive dosing phase where daratumumab 400-500 mg IV once a weekly was given until DSA MFI fell <5000, after which daratumumab 400-500 mg IV once weekly was given until DSA disappeared [52]. Lemal, et al. administered daratumumab 16 mg/kg IV as a one-time dose, and Osmanodja, et al. administered daratumumab 16 mg/kg IV monthly for 9 months [53,54]. Daratumumab was utilized as rescue therapy after a combination of rituximab and/or carfilzomib + PLEX/IVIg in Zhu et al., after PLEX in Lemal, et al., and after PLEX/IVIg in Osmanodja, et al. Follow up ranged from 1-35 months, with a graft survival of 100%. Renal function remained stable or improved in all patients, histological parameters improved in 5/6 (83.3%) patients who had follow-up biopsies, and DSA MFI decreased or stabilized in all patients. Baseline Banff histology scores were worse in Osmanodja, et al. in comparison to Zhu, et al., but were not reported by Lemal, et al. Given the wide heterogeneity of patients included, and the variability in both daratumumab dosing regimens used and duration of therapy, it is difficult to draw conclusions regarding the efficacy of daratumumab for the indications of both acute AMR and cAMR, and the patients who would benefit most from daratumumab therapy [52,53,54]. Additionally, there have been concerns for increased risk of ACR with daratumumab, as seen in a few case reports, given its effect on enhancing effector T-cell functions [60,61,62]. One patient in the published case series did present with ACR after daratumumab therapy, although tacrolimus levels were also subtherapeutic at time of presentation [52]. Thus, if utilizing daratumumab in AMR, managing treatment of AMR, while balancing the risk of ACR is an important consideration.

3.7 Imlifidase

Imlifidase, which has been used for desensitization for kidney transplantation, has also been studied in the context of AMR in kidney transplant recipients. In a randomized, open-label, multicenter, multinational trial, patients were randomized 2:1 to receive either a single IV infusion of imlifidase 0.25 mg/kg (n = 18) or 5-10 sessions of PLEX (n = 10). All patients in the study received methylprednisolone 500 mg IV for 3 days prior to the first treatment, IVIg 2 g/kg 3 days after imlifidase or directly after the last PLEX session, and a single dose of rituximab 375 mg/m2 IV 5 days after IVIg infusion. 4/18 (22%) patients in the imlifidase arm and 1/10 (10%) patients in the PLEX arm had previous AMR. 19/28 (68%) had cAMR or mixed rejection and only 9/28 (32%) had active AMR. Imlifidase demonstrated superiority in both magnitude and time to reduction of DSA in comparison to PLEX. Reduction in DSA 5 days following start of treatment was 97% (range 85-98) for imlifidase vs. 42% (range 5-82) for PLEX (95% CI 37-66), and median time to maximum DSA reduction was 15 hours (range 2-72) in the imlifidase arm vs. 9 days (range 2-180) in the PLEX arm. After antibody rebound in the imlifidase arm (approximately 6-12 days), both arms had similar reductions in DSA. Despite this, imlifidase did not demonstrate any meaningful clinical benefits at the 6-month follow-up, given that graft survival was 77.8% and 90% in the imlifidase and PLEX arms respectively. All graft losses within the imlifidase arm were with concurrent ACR which brings the question of determining if imlifidase or mixed rejection was the greater contributing factor to graft loss. Approximately 50% of all patients had cAMR, thus antibody elimination through imlifidase may not be effective in preventing graft loss once patients have developed significant histopathological changes on biopsy as seen in cAMR. Additionally, median time since transplantation in the imlifidase arm was numerically greater than that of the PLEX arm (4 vs. 1.1 years) [55]. A chronicity score of ≥4 has been associated with graft loss in kidney transplant recipients with AMR; median chronicity score in this trial was 4-5 overall (n = 25), suggesting that all patients, regardless of indication, had more advanced disease at the time of inclusion [63]. Mechanistically, imlifidase may have greater benefit in early acute AMR where prompt DSA removal can serve as a bridge to initiation of other combination therapies. The authors comment on this, stating that if imlifidase is to be explored for AMR in future trials, defining maximum time from transplantation, maximum degree of chronic damage, the clear presence of DSA, and excluding mixed rejection should be considered [55].

3.8 Felzartamab

Recently, a phase II trial examined felzartamab in late acute AMR and late cAMR (n = 22). Patients were randomized 1:1 to receive felzartamab or placebo for 6 months, followed by an observational period of 6 months. Patients who had previous treatment with anti-CD38 monoclonal antibodies at any point, or previous treatment with other immunomodulatory monoclonal/polyclonal antibodies within 3 months of study treatment were excluded from this trial. The trial met its primary outcome of safety as felzartamab showed an acceptable safety profile. At 1 year, one graft loss occurred in the placebo group due to persistent cAMR, and patient survival was 100% in both trial groups. Biopsies were performed at 24 weeks and 52 weeks per study protocol. At 24 weeks, resolution of morphologic AMR was more frequent with felzartamab (9/11) than with placebo (2/10) with a difference of 62% (95% CI 91-100), and a risk ratio of 0.23 (95% CI 0.06-0.83). Median microvascular inflammation score was lower in the felzartamab group than in the placebo group (0 vs. 2.5) for a mean difference of -1.95 (95% CI -0.97 to -0.92). Of note, the effect of felzartamab did not persist after treatment discontinuation, as recurrence of AMR was reported in 3/9 (33.3%) patients who had a response to felzartamab at week 52, suggesting that continuation of therapy may be necessary to stabilize graft function in the setting of late AMR. However, at week 52, median scores for microvascular inflammation remained lower in the felzartamab group (1, IQR 0-2) than in the placebo group (2, IQR 2-3.5) for a median difference between groups of -1.58 (95% CI -2.70 to -0.45). eGFR slope at 1 year was -0.39 mL/min/1.73 m2 (95% CI -5.47 to 4.69) in the felzartamab group and -4.53 mL/min/1.73 m2 (95% CI -9.83 to 0.77) in the placebo group with a difference of 4.14 mL/min/1.73 m2 (95% CI -3.20 to 11.48), indicating that felzartamab may potentially stabilize graft function. There were modestly lower values for iDSA with felzartamab treatment (not reported numerically) [56]. These results show promise for utilization of felzartamab in the setting of late AMR, thus the two phase III trials for felzartamab in cAMR with and without DSA are planned [64,65].

3.9 Obinutuzumab

Obinutuzumab, an anti-CD20 monoclonal antibody, has been used in a case series of two kidney transplant recipients with AMR on biopsy at post-operative day (POD) 6 and POD 13. Both patients had persistent histological features of active AMR refractory to PLEX, IVIg, and eculizumab prior to receiving obinutuzumab. Patient 1 received eculizumab on POD 37, followed by obinutuzumab on POD 41, and patient 2 received eculizumab on POD 18 followed by obinutuzumab on POD 21. SCr in both patients decreased from time of AMR to last follow-up at 3 years, from 4.4 mg/dL to 1.3 mg/dL for patient 1, and from 2.2 mg/dL to 1.9 mg/dL for patient 2. Histological improvements were also seen on follow-up biopsies for both patients, but no consistent effect on specific Banff scores was seen. DSA overall decreased in both patients. At 3 years, no signs of active AMR or rebound DSA were detected. This case series suggests that obinutuzumab may be a viable treatment option; however, these findings need to be confirmed in larger studies [57].

4. Discussion

Evidence regarding emerging therapies for AMR is limited mostly to smaller retrospective case series lacking a comparator arm, which introduces selection bias, and limits both generalizability and the ability to control for confounding factors. Additionally, there was wide heterogeneity in prior and concomitant therapies used for the treatment of AMR and substantial variation in duration of treatment and dosing regimens used which confounds interpretation of efficacy outcomes. Given the need for effective therapies in AMR, publication bias may have also played a role in the available reports in literature. Although 17/25 studies had a follow-up period of more than 1 year, long-term graft function cannot be assessed with the available data as only three of these studies reported an actual or median follow-up period of >3 years. As expected, the majority of literature was in kidney transplantation. In kidney AMR, there are clear criteria for active and cAMR, and more granularity with histological scoring, which is not found in diagnostic criteria of AMR in other solid organs [66,67,68,69,70,71]. Given notable differences in AMR definitions and diagnostic criteria across organs, histological and graft function outcomes found in kidney transplantation data cannot be effectively generalized to other organ types.

4.1 Tocilizumab

Tocilizumab is a humanized monoclonal antibody that competitively inhibits the binding of interleukin-6 (IL-6) to the IL-6 receptor. IL-6 is a proinflammatory cytokine involved in activation of T-helper 17 cells, inhibition of regulatory T cells, and differentiation of plasma cells [72]. Elevated levels of IL-6 have been associated with both AMR and chronic allograft dysfunction, thus tocilizumab may potentially have utility in both acute AMR and cAMR [45,73]. The majority of published literature for tocilizumab is in cAMR of the kidney, where use of tocilizumab was generally associated with stabilization of renal function, and variable effects on graft survival, DSA MFI reduction, and histological changes [32,33,34,35,36,37,38,39,40,41]. In terms of histology, reduction in microvascular inflammation was most commonly seen with tocilizumab; however, tocilizumab failed to prevent progression of chronicity. This suggests that tocilizumab stabilizes graft function through reduction of inflammation, without significant effect on disease progression. Baseline chronicity and degree of renal dysfunction may possibly be associated with the benefit patients would experience with tocilizumab therapy, but optimal timing of initiation cannot yet be inferred from the literature available.

4.2 Clazakizumab

Clazakizumab is another humanized monoclonal antibody against IL-6, which exhibits increased potency and duration of action in comparison to tocilizumab [74,75]. It is thought that clazakizumab is not associated with the rebound phenomenon as seen with IL-6 accumulation in tocilizumab, thus there was interest in its use in late AMR [32,76]. Despite encouraging results in two phase II studies published in its use in late acute or cAMR, where clazakizumab resulted in a stabilization or improvement of renal function, DSA MFI, and histology, the subsequent phase III study in cAMR was terminated early given failure to find benefit in its primary efficacy outcome [44,45,59]. Thus, at present, there are no known further efforts in exploring clazakizumab as a therapy in AMR.

4.3 Carfilzomib

Carfilzomib is a tetrapeptide epoxyketone that irreversibly binds to the 26S proteasome, resulting in accumulation of ubiquinated proteins and plasma cell apoptosis. Its effective half-life is greater than that of bortezomib, which demonstrates reversible inhibition [77,78]. Carfilzomib also demonstrates specificity of the NH2-terminal threonine residue, which decreases potential for off-target activity with cellular proteases, which may result in improved tolerability in comparison to bortezomib [79]. Carfilzomib was found to decrease DSA MFI in a case series of kidney transplant recipients, with no consistent effect on histology [46]. There has been one published report to date of carfilzomib use in liver transplant recipients, with variable effect on DSA and graft function, showing the complexity of liver transplant AMR [47]. In lung transplant recipients, carfilzomib either improved or stabilized FEV1, and decreased DSA in all studies. Despite these findings, graft survival remained poor at 42.9-50% with carfilzomib use in lung transplant AMR [48,49,50]. In heart transplant, the majority of patients treated with carfilzomib had recovered LVEF, and most patients had resolved pathologic AMR 1-year post-transplant [51]. In both the lung and heart transplant data, longer time from DSA detection and higher DSA MFI was associated with non-response, suggesting earlier initiation of therapy would predict treatment success. As expected, patients across all organ groups experienced AKI with carfilzomib, with the majority of patients recovering. Thus, carfilzomib may be considered in cases where bortezomib use is precluded by thrombocytopenia and peripheral neuropathy; however, caution must be exercised given the known risk of AKI, especially in kidney transplant population. Currently, reported use of carfilzomib outside lung transplant population is limited.

4.4 Daratumumab

Daratumumab is a humanized monoclonal antibody against CD38, which results in apoptosis of plasma cells through Fc mediated crosslinking, leading to complement dependent cytotoxicity, antibody dependent cell mediated cytotoxicity, and antibody dependent cellular phagocytosis [80]. Despite the earlier single case reports in pediatric heart transplantation, the studies that met inclusion criteria were in kidney transplantation for both acute AMR and cAMR [81,82]. Renal function and DSA MFI stabilized or improved in all patients, and histology improved in the majority of patients [52,53,54]. Given the wide variability in dosing regimens used and the heterogeneity of patients included, the utility of daratumumab for AMR cannot be confirmed with the available evidence. Furthermore, the potential for increased effector T-cell functions and risk of subsequent ACR is an important concern when utilizing daratumumab in solid organ transplantation.

4.5 Imlifidase, Felzartamab, Obinutuzumab

Data for imlifidase, felzartamab, and obinutuzumab are limited to single studies, thus no definitive conclusions can be drawn in terms of their place in therapy in AMR [55,56,57].

5. Conclusions and Future Directions

AMR is a significant contributor to late allograft loss in solid organ transplantation. Optimizing treatment of AMR remains difficult given the various mechanisms for DSA-mediated allograft injury. Although there are several potential targets with novel drug therapies on the market, long-term efficacy and safety is not yet known. Optimal timing of therapy, and identification of patients who are likely to benefit most from initiation of therapy also needs to be defined. The majority of studies were case series without a comparator. Prospective, randomized controlled studies with comparisons to standard of care and endpoints predictive of long-term graft survival are needed to better identify the place in therapy of these novel agents.

Author Contributions

Alisia Chen: conceptualization, methodology, writing – original draft, writing – review and editing. Jeong M. Park: conceptualization, methodology, writing – review and editing. All authors have read and approved the published version of the manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Competing Interests

The authors have declared that no competing interests exist.

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