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.
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.
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.
Parallel
BiTE (CD19 x CD3 Bispecific Antibody)
DrugBlinatumomab 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 cycle. Following the 7-day interval, Cycle 2 (Days 12-15) is administered with the identical regimen of 9 µg/day for 4 consecutive days.
BiTE (BCMA x CD3 Bispecific Antibody)
DrugTeclistamab 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 is administered on Day 10.
Percentage of participants achieving the predefined composite desensitization response
A composite desensitization response is defined as meeting at least one of the following criteria: 1. cPRA decreases to \<20%; 2. cPRA decreases by ≥50% from baseline; 3. a previously positive HLA antibody becomes negative, defined as an MFI \<1,000; or 4. the MFI of a persistent HLA antibody decreases by ≥50% from baseline or reaches the prespecified threshold. The number and percentage of participants achieving the composite response will be reported at Months 1, 2, 3, 6, and 12 after treatment. (HLA class I and II antibodies and their mean fluorescence intensity will be assessed using a single-antigen bead assay. Calculated panel-reactive antibody levels will be determined based on the unacceptable HLA antigen profile. At each prespecified assessment timepoint, participants will be classified as responders or nonresponders, and the percentage of responders will be reported.)
Percentage reduction from baseline in calculated panel-reactive antibody level
Percentage reduction will be calculated as: (Baseline cPRA - cPRA at the assessment timepoint) / baseline cPRA × 100%. A positive value indicates a reduction, whereas a negative value indicates an increase.HLA antibodies will be assessed using a single-antigen bead assay, and cPRA will be calculated based on unacceptable HLA antigens. The percentage reduction from baseline will be calculated at each assessment timepoint.
Absolute change from baseline in calculated panel-reactive antibody level
Absolute change will be calculated as cPRA at the assessment timepoint minus baseline cPRA. A negative value indicates a reduction from baseline. Results will be reported separately at Months 1, 2, 3, 6, and 12. HLA antibody specificities will be determined using a single-antigen bead assay. cPRA will be calculated based on prespecified unacceptable HLA antigens and the HLA antigen frequencies of the reference donor population. The absolute difference between cPRA at each assessment and baseline cPRA will be calculated.
Change from baseline in the maximum mean fluorescence intensity of unacceptable HLA class I antibodies
The change will be calculated as the maximum MFI at each assessment minus the baseline maximum MFI. A negative value indicates a reduction in HLA class I antibody strength. Maximum MFI will be used as the prespecified participant-level summary when multiple antibody specificities are present. HLA-A, HLA-B, and HLA-C antibodies will be measured using a single-antigen bead assay. For each participant, the highest MFI among all baseline unacceptable HLA class I antibody specificities will be identified, and the MFI of the same antibody specificity will be followed at each assessment.
Change from baseline in the maximum mean fluorescence intensity of unacceptable HLA class II antibodies
Change will be calculated as the maximum MFI at each assessment minus the baseline maximum MFI. A negative value indicates a reduction in antibody strength. HLA-DR, HLA-DQ, and HLA-DP antibodies will be measured using a single-antigen bead assay. The highest MFI among all baseline unacceptable HLA class II antibody specificities will be identified for each participant, and the same antibody specificity will be followed over time.
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