Dual Targeting of B Cell Compartments Using Belatacept and Daratumumab in Highly Sensitized Kidney Transplant Candidates: A Mechanistic Proof-of-Concept Desensitization Trial
In a small phase 1b/2 proof-of-concept desensitization trial, combining belatacept (costimulation blockade) with daratumumab (anti-CD38 plasma-cell depletion) was well tolerated and produced serologic responses in 3 of 4 evaluable highly sensitized kidney transplant candidates, with depletion of HLA-specific memory B cells and bone-marrow plasma cells.
Background
Highly sensitized candidates (calculated panel-reactive antibody >99%) have very limited access to compatible donor kidneys because persistent anti-HLA antibodies and memory B-cell responses are not adequately targeted by current desensitization regimens. The trial tested whether simultaneously hitting two arms of the humoral response — T/B-cell costimulation and antibody-producing plasma cells — could improve desensitization.
Study design
This was a single-arm phase 1b/2 trial (NCT05145296) enrolling 5 highly sensitized kidney transplant candidates with cPRA >99%, treated with belatacept plus daratumumab. Serum anti-HLA antibody levels, HLA-specific memory B cells, and bone-marrow long-lived plasma cells were profiled using single-antigen beads, functional B-cell assays, and spectral flow cytometry.
Key findings
The regimen was well tolerated, with no serious adverse events attributed to the study drugs. Three of 4 evaluable patients showed a substantial serologic response through elimination and reductions in antibody mean fluorescence intensity and titers, predominantly against anti-HLA class I. In responders, HLA-specific memory B cells and CD38+ plasma cells were significantly depleted in both peripheral blood and bone marrow, accompanied by reductions in cPRA driven mainly by class I antibodies.
Clinical implications
Dual targeting of B-cell compartments with belatacept and daratumumab appears to be a safe and mechanistically effective desensitization strategy for highly sensitized candidates. Given the very small sample size and proof-of-concept design, the findings support — but do not yet establish — efficacy, and larger trials are needed before clinical adoption.
Category
Transplant
Source
American Journal of Transplantation
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