Safety and Efficacy of BiTE in Desensitization Therapy for Highly Sensitized Kidney Transplant Candidates With cPRA ≥ 90%

Overview

This study is a prospective, open-label, two-arm exploratory clinical trial aimed at evaluating the safety and efficacy of Bispecific T-cell Engager (BiTE) therapies in refractory, highly sensitized kidney transplant candidates. Patients with end-stage renal disease (ESRD) who have a calculated panel reactive antibody (cPRA) ≥ 90% and have waited for a transplant for over 5 years, despite receiving standard desensitization therapies (e.g., IVIG, plasmapheresis, rituximab), will be enrolled. A total of 20 participants will be randomized in a 1:1 ratio to receive either Blinatumomab (a CD19×CD3 BiTE) or Teclistamab (a BCMA×CD3 BiTE). The primary objective is to evaluate the desensitization response rate, defined as the reduction of cPRA to \< 20% or by ≥ 50% from baseline, assessed at multiple time points up to 1 year post-treatment. Secondary objectives include assessing the safety profile (such as the incidence of Cytokine Release Syndrome \[CRS\] and neurotoxicity), the extent of CD19+ B cell depletion, and the proportion of participants who successfully undergo kidney transplantation within 1 year.

Detailed description

Background:

Kidney transplantation is the optimal treatment for end-stage renal disease (ESRD). However, highly sensitized patients with a calculated panel reactive antibody (cPRA) ≥ 90% face significant barriers to finding a compatible donor and have a higher risk of antibody-mediated rejection (AMR). Standard desensitization protocols, primarily utilizing intravenous immunoglobulin (IVIG) and plasmapheresis (PLEX), often fail to achieve long-term reductions in human leukocyte antigen (HLA) antibodies because they do not adequately deplete memory B cells and long-lived plasma cells. Bispecific T-cell Engagers (BiTEs) such as Blinatumomab (CD19×CD3) and Teclistamab (BCMA×CD3) directly recruit endogenous T cells to eliminate B cells and plasma cells, respectively. This study investigates whether these targeted therapies can provide a deeper and more sustained desensitization for refractory transplant candidates, bridging them to a successful transplant.

Study Design:

This is a single-center, prospective, non-blinded, two-arm exploratory trial conducted at West China Hospital, Sichuan University. Twenty eligible patients will be enrolled and randomly assigned (1:1) via block randomization (block size of 4) to either the Blinatumomab arm or the Teclistamab arm.

Interventions:

Arm 1 (Blinatumomab): Administered intravenously. Cycle 1 consists of 9 µg/day for 4 consecutive days (Days 1-4). Following a 7-day interval, Cycle 2 consists of 9 µg/day for another 4 consecutive days (Days 12-15).

Arm 2 (Teclistamab): Administered subcutaneously using a step-up dosing schedule to mitigate Cytokine Release Syndrome (CRS) risk. Cycle 1 involves 0.06 mg/kg on Day 1 and 0.3 mg/kg on Day 2. Following a 7-day interval, Cycle 2 involves a target dose of 1.5 mg/kg on Day 10.

Study Objectives \& Endpoints:

Primary Endpoint: Desensitization response rate evaluated at 1, 2, 3, 6, and 12 months post-treatment. A positive response is defined as a reduction of cPRA from \>90% to \<20% (or a ≥50% decrease from baseline), or the conversion of positive HLA antibodies to negative, or a ≥50% reduction in Mean Fluorescence Intensity (MFI) to a predefined threshold.

Secondary Endpoints:

Safety and tolerability, including the incidence and severity of CRS, Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), infections, and neutropenia.

Changes in peripheral blood lymphocyte subsets, with a specific focus on CD19+ B cell depletion and recovery trends.

Duration of sustained low cPRA levels. Proportion of patients receiving a kidney transplant within 1 year.

Safety Monitoring:

Given the mechanism of action of BiTEs, strict monitoring for adverse events like CRS and ICANS is integrated into the protocol, utilizing ASTCT consensus grading standards. Treatment algorithms for managing severe events (e.g., using tocilizumab or corticosteroids) are predefined. An independent Data and Safety Monitoring Board (DSMB) consisting of multidisciplinary experts will oversee the study. The protocol includes strict stopping rules for severe toxicities, such as ≥ Grade 3 CRS/ICANS refractory to standard treatment, severe infections, or treatment-related mortality, to ensure patient safety throughout the trial.

Interventions

• Drug BiTE (CD19 x CD3 Bispecific Antibody)
  Blinatumomab is a CD19×CD3 bispecific T-cell engager (BiTE) administered via intravenous infusion. This intervention utilizes a specific low-dose, short-course exploratory regimen tailored for non-oncology kidney transplant candidates to safely deplete B cells and reduce HLA antibodies. The treatment consists of two cycles separated by a 7-day interval. In Cycle 1 (Days 1-4), patients receive a continuous infusion of 9 µg/day for 4 consecutive days, with a total target dose of 35 µg for the cycl
• Drug BiTE (BCMA x CD3 Bispecific Antibody)
  Teclistamab is a BCMA×CD3 bispecific T-cell engager (BiTE) administered via subcutaneous injection. To mitigate the early risk of cytokine release syndrome (CRS), this intervention employs a strictly defined step-up dosing schedule. The treatment involves two cycles separated by a 7-day interval. Cycle 1 (Days 1-2) begins with a step-up dose of 0.06 mg/kg on Day 1, followed by 0.3 mg/kg on Day 2. After the 7-day interval, Cycle 2 (Days 10-11) is initiated, during which a target dose of 1.5 mg/kg

Primary outcome measures

• Percentage of participants achieving the predefined composite desensitization response [Time frame: At baseline and at 1, 2, 3, 6, and 12 months after treatment]

Secondary outcome measures (12)

• Percentage reduction from baseline in calculated panel-reactive antibody level [Time frame: At baseline and at 1, 2, 3, 6, and 12 months after treatment]
• Absolute change from baseline in calculated panel-reactive antibody level [Time frame: At baseline and at 1, 2, 3, 6, and 12 months after treatment]
• Change from baseline in the maximum mean fluorescence intensity of unacceptable HLA class I antibodies [Time frame: At baseline and at 1, 2, 3, 6, and 12 months after treatment]
• Change from baseline in the maximum mean fluorescence intensity of unacceptable HLA class II antibodies [Time frame: At baseline and at 1, 2, 3, 6, and 12 months after treatment]
• Number of participants receiving kidney transplantation within 12 months after treatment [Time frame: Within 12 months after the first administration of study treatment]
• Change from baseline in peripheral blood CD19-positive B-cell absolute count [Time frame: At baseline, at protocol-specified assessments during treatment, and at 1, 2, 3, 6, and 12 months after treatment]
• Number of participants achieving peripheral blood CD19-positive B-cell depletion [Time frame: During treatment and at 1, 2, 3, 6, and 12 months after treatment]
• Change from baseline in peripheral blood CD3-positive T-cell absolute count [Time frame: At baseline, during treatment, and at 1, 2, 3, 6, and 12 months after treatment]
• Change from baseline in peripheral blood CD4-positive T-cell absolute count [Time frame: At baseline, during treatment, and at 1, 2, 3, 6, and 12 months after treatment]
• Change from baseline in peripheral blood CD8-positive T-cell absolute count [Time frame: At baseline, during treatment, and at 1, 2, 3, 6, and 12 months after treatment]
• Change from baseline in peripheral blood CD3-negative CD16-positive and/or CD56-positive natural killer cell absolute count [Time frame: At baseline, during treatment, and at 1, 2, 3, 6, and 12 months after treatment]
• Number of participants with cytokine release syndrome as assessed by the ASTCT consensus grading criteria [Time frame: From the first dose through 30 days after the last dose]

Eligibility criteria

Inclusion criteria

• Male or female participants aged 18 to 65 years.
• Diagnosis of end-stage kidney disease and being evaluated for or awaiting kidney transplantation.
• Calculated panel-reactive antibody level (cPRA) ≥90% and a kidney transplant waiting time of ≥5 years.
• Previous treatment with a conventional desensitization regimen based on intravenous immunoglobulin and/or plasma exchange, with or without rituximab, with traceable medical records.
• Persistent cPRA ≥90% or unacceptable HLA antibodies after conventional desensitization, resulting in failure to meet the immunological criteria for kidney transplantation.
• Adequate nonrenal organ function to tolerate the study treatment, including left ventricular ejection fraction >50%, resting oxygen saturation >94%, AST and ALT <3 times the upper limit of normal, total bilirubin <34.2 μmol/L, and no active infection.
• Ability to understand the study procedures, provide written informed consent, and comply with study treatment and follow-up requirements.

Exclusion criteria

• Inability to understand or comply with the study protocol or follow-up schedule.
• Known or suspected hereditary complement deficiency.
• Clinically significant central nervous system disease, including epilepsy, psychotic disorder, organic brain syndrome, cerebrovascular accident, encephalitis, central nervous system vasculitis, or cranial neuropathy requiring intervention.
• AST, ALT, or GGT >3 times the upper limit of normal, or alkaline phosphatase or total bilirubin >1.5 times the upper limit of normal.
• Acute myocardial infarction or unstable angina within 6 months before screening, severe cardiac arrhythmia, or New York Heart Association class III or IV heart failure.
• Uncontrolled acute or chronic disease unrelated to end-stage kidney disease that may impair tolerance to study treatment.
• Active or uncontrolled infection requiring systemic treatment.
• Human immunodeficiency virus infection or uncontrolled active hepatitis B or hepatitis C infection.
• Participation in another interventional clinical study within 3 months before screening or planned concurrent participation in another interventional study.
• Previous treatment with another T-cell engager or bispecific T-cell-redirecting therapy.
• Known severe hypersensitivity to blinatumomab, teclistamab, or any of their excipients.
• Active malignancy.
• Pregnancy, breastfeeding, or planned pregnancy during the study period.
• Previous bone marrow transplantation, hematopoietic stem cell transplantation, or solid-organ transplantation other than kidney transplantation.
• Receipt of a live vaccine within 30 days before screening or planned receipt of a live vaccine during study treatment.
• Any other clinically significant condition that, in the investigator's judgment, may increase participant risk, interfere with study procedures, or affect safety or efficacy assessments.

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

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Chandramohan D, Adisa O, Patel D, Ware E, Eleti N, Agarwal G. Outcomes of Kidney Transplantation in Highly HLA-Sensitized Patients Treated with Intravenous Immuno-Globulin, Plasmapheresis and Rituximab: A Meta-Analysis. Life (Basel). 2024 Aug 10;14(8):998. doi: 10.3390/life14080998. PMID 39202740
• Anwar IJ, DeLaura IF, Gao Q, Ladowski J, Jackson AM, Kwun J, Knechtle SJ. Harnessing the B Cell Response in Kidney Transplantation - Current State and Future Directions. Front Immunol. 2022 Jun 9;13:903068. doi: 10.3389/fimmu.2022.903068. eCollection 2022. PMID 35757745
• Subklewe M, Magno G, Gebhardt C, Bucklein V, Szelinski F, Arevalo HJR, Hanel G, Dorner T, Zugmaier G, von Bergwelt-Baildon M, Skapenko A, Schulze-Koops H. Application of blinatumomab, a bispecific anti-CD3/CD19 T-cell engager, in treating severe systemic sclerosis: A case study. Eur J Cancer. 2024 Jun;204:114071. doi: 10.1016/j.ejca.2024.114071. Epub 2024 Apr 22. PMID 38691878
• Bucci L, Hagen M, Rothe T, Raimondo MG, Fagni F, Tur C, Wirsching A, Wacker J, Wilhelm A, Auger JP, Pachowsky M, Eckstein M, Alivernini S, Zoli A, Kronke G, Uderhardt S, Bozec A, D'Agostino MA, Schett G, Grieshaber-Bouyer R. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat Med. 2024 Jun;30(6):1593-1601. doi: 10.1038/s41591-024-02964-1. Epub 2024 Apr 26. PMID 38671240
• Leon J, Aubert O, Devriese M, Alameda F, Charbonnier S, Fourgeaud J, Blein T, Nguyen TN, Troger A, Chhun S, Roelens M, Usureau C, Gons C, Roger C, Burger C, Le Stang MB, Cotteret C, Timsit MO, Fillatreau S, Rabant M, Taupin JL, Talbot A, Suarez F, Anglicheau D, Zuber J. B-cell maturation antigen-Targeted T-cell Engager Therapy Combined with B-cell Depletion for Treatment of Refractory HLA Sensitiz PMID 41692345
• Bhoj VG, Kaminski M, Zhao H, Jackson K, Wang W, Liu C, Montgomery RA, Ali N, Mangiola M, Spitzer TR, Safa K, Pattanayak V, Taj R, Chiu J, Bui TM, Sonnenberg EM, Markmann JF, Milone MC, June CH, Siegel DL, Fraietta JA, Gonzalez V, Locci M, Palmer M, Monos D, Hwang WT, Sledge T, Bridges ND, Goldstein JS, Odim J, Sweet SC, Besharatian BD, Hussain SM, Brown NK, Kamoun M, Garfall AL, Naji A. Kidney Tra PMID 42235014

Identifiers

NCT: NCT07689149 · WestChina-BITE-KT

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗