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Tocilizumab in chronic active antibody-mediated rejection: rationale and protocol of an in-progress randomized
Lillian Streichart1, Marie Felldin1, Jana Ekberg1
1Transplant Institute, Sahlgrenska University Hospital, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, 413 45, Gothenburg, Sweden.
Background:
Chronic active antibody-mediated rejection (caAMR) in kidney transplants is associated with irreversible tissue damage and a leading cause of graft loss in the long-term. However, the treatment for caAMR remains a challenge to date. Recently, tocilizumab, a recombinant humanized monoclonal antibody directed against the human interleukin-6 (IL-6) receptor, has shown promise in the treatment of caAMR. However, it has not been systematically investigated so far underscoring the need for randomized controlled studies in this area.
Methods:
The INTERCEPT study is an investigator-driven randomized controlled open-label multi-center trial in kidney transplant recipients to assess the efficacy of tocilizumab in the treatment of biopsy-proven caAMR. A total of 50 recipients with biopsy-proven caAMR at least 12 months after transplantation will be randomized to receive either tocilizumab (n = 25) added to our standard of care (SOC) maintenance treatment or SOC alone (n = 25) for a period of 24 months. Patients will be followed for an additional 12 months after cessation of study medication. After the inclusion biopsies at baseline, protocol kidney graft biopsies will be performed at 12 and 24 months. The sample size calculation assumed a difference of 5 ml/year in slope of estimated glomerular filtration rate (eGFR) between the two groups for 80% power at an alpha of 0.05. The primary endpoint is the slope of eGFR at 24 months after start of treatment. The secondary endpoints include assessment of the following at 12, 24, and 36 months: composite risk score iBox, safety, evolution and characteristics of donor-specific antibodies (DSA), graft histology, proteinuria, kidney function assessed by measured GFR (mGFR), patient- and death-censored graft survival, and patient-reported outcomes that include transplant-specific well-being, adherence to immunosuppressive medications and perceived threat of the risk of graft rejection.
Discussion:
No effective treatment exists for caAMR at present. Based on the hypothesis that inhibition of IL-6 receptor by tocilizumab will reduce antibody production and reduce antibody-mediated damage, our randomized trial has a potential to provide evidence for a novel treatment strategy for caAMR, therewith slowing the decline in graft function in the long-term.
Trial Registration:
ClinicalTrials.gov NCT04561986. Registered on September 24, 2020.
Insights
Tocilizumab may offer a new treatment for chronic active antibody-mediated rejection (caAMR) in kidney transplants. This study investigates its efficacy in preserving long-term graft function and reducing damage.
Area of Science:
- Nephrology
- Immunology
- Transplantation Medicine
Background:
- Chronic active antibody-mediated rejection (caAMR) is a major cause of long-term kidney transplant failure.
- Current treatments for caAMR are limited, necessitating novel therapeutic strategies.
- Tocilizumab, an IL-6 receptor inhibitor, shows potential for treating caAMR.
Purpose of the Study:
- To evaluate the efficacy of tocilizumab in treating biopsy-proven caAMR in kidney transplant recipients.
- To assess the impact of tocilizumab on slowing the decline of estimated glomerular filtration rate (eGFR).
- To investigate tocilizumab's effects on graft histology, antibody levels, and patient-reported outcomes.
Main Methods:
- The INTERCEPT study is a randomized, open-label, multi-center trial involving 50 kidney transplant recipients with caAMR.
- Participants are randomized to receive either tocilizumab plus standard of care (SOC) or SOC alone for 24 months.
- Primary endpoint is the slope of eGFR at 24 months; secondary endpoints include iBox score, DSA, histology, proteinuria, mGFR, survival, and patient-reported outcomes.
Main Results:
- This section is not yet available as the study is ongoing.
- Further data collection and analysis are required to determine the main results.
- The study is designed to provide robust evidence on tocilizumab's efficacy and safety.
Conclusions:
- No definitive treatment currently exists for caAMR.
- This trial aims to provide evidence for tocilizumab as a novel treatment for caAMR.
- Tocilizumab may offer a strategy to slow long-term graft function decline in kidney transplant recipients.
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