CD38 mAb Induction + Azathioprine Maintenance for Chronic Active AMR in Kidney Transplant Recipients

Official title

A Multicenter Exploratory Clinical Study of Targeted NK Cell Inhibition for Transplant Kidney Chronic Active Antibody-Mediated Rejection (caABMR): Single Induction With CD38 Monoclonal Antibody Followed by Sequential Maintenance With Azathioprine

Overview

This multicenter, prospective, single-arm exploratory study evaluates the efficacy and safety of a novel sequential regimen for chronic active antibody-mediated rejection (caABMR) in kidney transplant recipients: single-dose CD38 monoclonal antibody (1800 mg subcutaneous) induction to deplete plasma cells and NK cells, followed by long-term maintenance with azathioprine (replacing mycophenolate mofetil) plus standard triple immunosuppression (steroid + calcineurin inhibitor). The regimen aims to control DSA-driven injury, stabilize or improve graft function (primary: eGFR decline slope), reduce DSA, improve pathology (Banff 2022), and minimize infection/nephrotoxicity risks associated with intensified or prolonged biologic therapy. Twenty patients across 6 Chinese transplant centers will be enrolled. CD38 mAb, azathioprine, key monitoring tests (HLA antibody, pharmacogenomics, immune profiling) are provided free by the study team (\~40,000 RMB per patient). Ethics approved; informed consent obtained.

Detailed description

Background: caABMR is the leading cause of late kidney allograft loss. Current therapies (plasmapheresis, IVIG, rituximab, bortezomib, long-term CD38 mAb) have limited efficacy, high recurrence, significant side effects, and high cost with no approved standard.

Rationale: CD38 mAb depletes antibody-producing plasma cells and pathogenic NK cells, rapidly lowering DSA and micro vascular inflammation. However, long-term monotherapy is costly and may increase infection risk. This study uses single induction dose + switch to azathioprine (safe, inexpensive, long-used in transplantation, suppresses NK activity) for durable, affordable maintenance. TPMT/NUDT15 genotyping guides personalized AZA dosing; serial NK cell monitoring targets \<20/μL.

Design: Multicenter (6 centers), prospective, open-label, single-arm, exploratory (N=20).

Intervention: Baseline: CD38 mAb 1800 mg SC x1 + immediate switch MMF→AZA (dose per genotype: normal metabolizer 2-3 mg/kg/d; intermediate 0.6-2.4 mg/kg/d). Maintain triple IS (steroid + AZA + Tac target 5-7 ng/mL or CsA 150-250 ng/mL).

Interventions

• Biological CD38
  Single 1800 mg subcutaneous injection at baseline to induce rapid depletion of plasma cells (source of DSA) and NK cells (key effectors of microvascular injury in caABMR). Marketed anti-CD38 mAb (off-label use in this indication).
• Drug Azathioprine (AZA)
  Oral azathioprine maintenance (replaces mycophenolate), individualized starting dose 2.0-3.0 mg/kg/day (normal TPMT/NUDT15 metabolizer) or 30-80% reduced (intermediate metabolizer), titrated per serial NK cell counts and hematologic tolerance. Long-term NK suppression to maintain immune balance and protect graft.
• Other Standard Triple Immunosuppression Maintenance
  Continued per local practice with protocol targets

Primary outcome measures

• Slope of estimated glomerular filtration rate (eGFR) decline [Time frame: Baseline through Week 28, planned assessments at weeks 0, 4, 8, 12, 16, 20, 24, 28]

Secondary outcome measures (11)

• Change in peripheral blood NK cell, T cell and B cell subset counts and percentages measured by flow cytometry [Time frame: Baseline, Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28]
• Absolute and relative percentage change in estimated glomerular filtration rate calculated by CKD-EPI 2021 formula [Time frame: Baseline, Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28]
• Percentage change in urine protein-to-creatinine ratio (UPCR) [Time frame: Baseline and Week 28]
• Relative percentage change in donor-specific antibody (DSA) mean fluorescence intensity (MFI) [Time frame: Baseline, Week 8, Week 28]
• Change in Transplant Kidney Biopsy Pathology Scores (Banff 2022) [Time frame: Baseline, Week 28]
• Incidence of Acute Rejection (TCMR, AMR, or Mixed) [Time frame: Through Week 28]
• Patient overall survival rate [Time frame: Week 28]
• Graft survival rate [Time frame: Week 28]
• Incidence of BK Virus (BKV) Infection [Time frame: Through Week 28]
• Incidence of Cytomegalovirus (CMV) Infection [Time frame: Through Week 28]
• Incidence of Neutropenia [Time frame: Through Week 28]

Eligibility criteria

Inclusion criteria

• Voluntary written informed consent.
• Age ≥18 years.
• Kidney transplant (living or deceased donor) ≥180 days prior.
• eGFR ≥30 mL/min/1.73 m² (CKD-EPI 2021).
• Currently on stable triple immunosuppression (CNI + MMF + steroid) for ≥4 weeks, no severe related adverse effects.
• Positive HLA Class I and/or Class II donor-specific antibodies (DSA).
• Transplant kidney biopsy meeting Banff 2022 criteria for chronic active antibody-mediated rejection (caABMR).
• TPMT/NUDT15 genotyping: non-homozygous mutant (normal or intermediate metabolizer).

Exclusion criteria

• Participating in another clinical trial.
• Age <18 years.
• Pregnant, breastfeeding, or inadequate contraception in females.
• ABO-incompatible transplant.
• TPMT/NUDT15 homozygous mutant genotype.
• Biopsy shows any of: T-cell mediated rejection (TCMR), new/recurrent severe thrombotic microangiopathy, or polyomavirus nephropathy.
• Received anti-rejection therapy in prior 3 months.
• Received other immunomodulatory monoclonal/polyclonal antibodies (anti-CD20, bortezomib, anti-C5, anti-IL-6/IL-6R) in prior 3 months.
• Total bilirubin >2×ULN or ALT/AST >2.5×ULN.
• Hemoglobin <8 g/dL.
• Platelets <100×10\^9/L.
• WBC <3×10\^9/L or neutrophils <1.5×10\^9/L.
• Hypogammaglobulinemia: IgG <400 mg/dL.
• Active bacterial, viral, or fungal infection.
• Active malignancy requiring intensified immunosuppression.
• Latent or active tuberculosis.
• Live vaccine within 6 weeks of screening.
• History of alcohol or illicit drug abuse.
• Severe medical or psychiatric illness likely to impair study participation.
• Active hepatitis B.
• Known hypersensitivity to CD38 mAb, azathioprine, or study drug components, or severe drug allergy history.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• ten Berge RJ, Schellekens PT, Surachno S, The TH, ten Veen JH, Wilmink JM. A longitudinal study on the effects of azathioprine and high doses of prednisone on the immune system of kidney-transplant recipients. Clin Immunol Immunopathol. 1982 Jul;24(1):33-46. doi: 10.1016/0090-1229(82)90086-1. No abstract available. PMID 7049473
• Hoffmann U, Neudorfl C, Daemen K, Keil J, Stevanovic-Meyer M, Lehner F, Haller H, Blume C, Falk CS. NK Cells of Kidney Transplant Recipients Display an Activated Phenotype that Is Influenced by Immunosuppression and Pathological Staging. PLoS One. 2015 Jul 6;10(7):e0132484. doi: 10.1371/journal.pone.0132484. eCollection 2015. PMID 26147651
• Prince HE, Ettenger RB, Dorey FJ, Fine RN, Fahey JL. Azathioprine suppression of natural killer activity and antibody-dependent cellular cytotoxicity in renal transplant recipients. Transplant Proc. 1984 Dec;16(6):1475-7. No abstract available. PMID 6390849
• Reinders ME, Hoogduijn MJ. NK Cells and MSCs: Possible Implications for MSC Therapy in Renal Transplantation. J Stem Cell Res Ther. 2014 Feb 7;4(2):1000166. doi: 10.4172/2157-7633.1000166. No abstract available. PMID 24900946
• Chambon M, Koenig A. NK Cells: Not Just Followers But Also Initiators of Chronic Vascular Rejection. Transpl Int. 2024 Oct 16;37:13318. doi: 10.3389/ti.2024.13318. eCollection 2024. PMID 39479216
• Chocair PR, Neves PDMM, Mohrbacher S, Neto MP, Sato VAH, Oliveira ES, Barbosa LV, Bales AM, da Silva FP, Cuvello-Neto AL, Duley JA. Case Report: Azathioprine: An Old and Wronged Immunosuppressant. Front Immunol. 2022 Jun 10;13:903012. doi: 10.3389/fimmu.2022.903012. eCollection 2022. PMID 35757730
• Bohmig GA, Naesens M, Viklicky O, Thaunat O, Diebold M, Rostaing L, Budde K. Antibody-mediated rejection-treatment standard. Nephrol Dial Transplant. 2025 Aug 1;40(8):1615-1627. doi: 10.1093/ndt/gfaf097. PMID 40440205
• Matignon M, Grimbert P, Moktefi A, Pilon C. Anti-CD38 and Regression of Chronic Active Antibody-Mediated Rejection After Kidney Transplantation - Myth or Reality? Kidney Int Rep. 2025 Sep 2;10(10):3305-3307. doi: 10.1016/j.ekir.2025.08.031. eCollection 2025 Oct. No abstract available. PMID 41141512

Identifiers

NCT: NCT07718308 · IIT20260074C-R1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗