Anti-HLA serologic response to CD38-targeting desensitization therapy is challenged by peripheral memory B cells in highly sensitized kidney transplant candidates

Alba Torija, Marie Matignon, Flavio Vincenti, Franc Casanova-Ferrer, Caroline Pilon, Anat R. Tambur, Laura Donadeu, Elena Crespo, Delphine Kervella, Maria Meneghini, Irina B. Torres, Florianne Hafkamp, Anna Martinez-Lacalle, Claudia Carrera, José Zúñiga, Amarpali Brar, Josep Cruzado, A. Osama Gaber, Helen Lee, Robert A. MontgomeryMark Stegall, Maryvonnick Carmagnat, Cédric Usureau, Francesc Moreso, Philippe Grimbert, Oriol Bestard

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

High human leukocyte antigen (HLA) sensitization limits access to compatible transplantation. New CD38-targeting agents have been shown to reduce anti-HLA antibodies, although with important interpatient variability. Thus, pretreatment identification of responder and nonresponder (NR) patients is needed for treatment decision-making. We analyzed 26 highly sensitized (HS) patients from 2 desensitization trials using anti-CD38 monoclonal antibodies. Hierarchical clustering identified 3 serologic responder groups: high responders, low responders, and NR. Spectral flow cytometry and functional HLA-specific memory B cell (mBC) assessment were first conducted on peripheral blood mononuclear cells and bone marrow samples from 16 patients treated with isatuximab (NCT04294459). Isatuximab effectively depleted bone marrow plasma cells, peripheral CD38-expressing plasmablasts, plasma cells, transitional B cells, and class-switch mBCs, ultimately reducing frequencies of HLA-specific immunoglobulin G (IgG)-producing mBCs. Multidimensional spectral flow cytometry with partial least squares discriminant analysis revealed that pretreatment abundance of specific circulating mBC phenotypes, especially CD38neg class-switch mBCs, accurately distinguished between high serologic responders and low responders or NR (AUC 0.958, 0.860-1.000, P = .009), who also displayed significantly lower frequencies of HLA-specific IgG-producing mBCs (P < .0001). This phenotypical mBC signature predicting response to therapy was validated in an external HS patient cohort (n = 10) receiving daratumumab (NCT04204980). This study identifies critical circulating mBC subset phenotypes that distinguish HS patients with successful serologic responses to CD38-targeting desensitization therapies, potentially guiding treatment decision-making.

Original languageEnglish (US)
Pages (from-to)88-101
Number of pages14
JournalAmerican Journal of Transplantation
Volume25
Issue number1
DOIs
StatePublished - Jan 2025

Keywords

  • CD38-targeting treatments
  • HLA desensitization therapy
  • antibody-producing cells
  • highly sensitized kidney
  • memory B cells
  • transplant patients

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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