Anti-HLA serological response to CD38-targeting desensitization therapy is challenged by peripheral memory B-cells in highly sensitized kidney transplant candidates
In highly sensitized kidney transplant candidates, serologic response to CD38-targeting desensitization varied widely, and the pretreatment abundance of specific circulating memory B-cell phenotypes accurately distinguished responders from non-responders.
Background
High HLA sensitization limits access to compatible transplantation. CD38-targeting agents can reduce anti-HLA antibodies but with important interpatient variability, creating a need to identify responders and non-responders before treatment to guide decision-making.
Study design
The study analyzed 26 highly sensitized patients from two desensitization trials using anti-CD38 monoclonal antibodies. Spectral flow cytometry and functional HLA-specific memory B-cell assessment were performed on peripheral blood and bone marrow samples from 16 patients treated with isatuximab, and a phenotypic signature was validated in an external cohort of 10 patients receiving daratumumab. Hierarchical clustering identified high responders, low responders, and non-responders.
Key findings
Isatuximab depleted bone marrow plasma cells, peripheral CD38-expressing plasmablasts, plasma cells, transitional B cells, and class-switched memory B cells, ultimately reducing HLA-specific IgG-producing memory B cells. Pretreatment abundance of specific circulating memory B-cell phenotypes, especially CD38-negative class-switched memory B cells, distinguished high responders from low responders or non-responders (AUC 0.958), the latter also showing significantly lower frequencies of HLA-specific IgG-producing memory B cells.
Clinical implications
Peripheral memory B-cell phenotyping may serve as a biomarker to predict serologic response to CD38-targeting desensitization, potentially guiding treatment decisions in highly sensitized transplant candidates. Persistent memory B-cell populations appear to challenge the durability of the anti-HLA serologic response.
Category
Transplant
Source
American Journal of Transplantation
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