TY - JOUR
T1 - Anti-HLA serologic response to CD38-targeting desensitization therapy is challenged by peripheral memory B cells in highly sensitized kidney transplant candidates
AU - Torija, Alba
AU - Matignon, Marie
AU - Vincenti, Flavio
AU - Casanova-Ferrer, Franc
AU - Pilon, Caroline
AU - Tambur, Anat R.
AU - Donadeu, Laura
AU - Crespo, Elena
AU - Kervella, Delphine
AU - Meneghini, Maria
AU - Torres, Irina B.
AU - Hafkamp, Florianne
AU - Martinez-Lacalle, Anna
AU - Carrera, Claudia
AU - Zúñiga, José
AU - Brar, Amarpali
AU - Cruzado, Josep
AU - Gaber, A. Osama
AU - Lee, Helen
AU - Montgomery, Robert A.
AU - Stegall, Mark
AU - Carmagnat, Maryvonnick
AU - Usureau, Cédric
AU - Moreso, Francesc
AU - Grimbert, Philippe
AU - Bestard, Oriol
N1 - Publisher Copyright:
© 2024 American Society of Transplantation & American Society of Transplant Surgeons
PY - 2025/1
Y1 - 2025/1
N2 - 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.
AB - 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.
KW - CD38-targeting treatments
KW - HLA desensitization therapy
KW - antibody-producing cells
KW - highly sensitized kidney
KW - memory B cells
KW - transplant patients
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U2 - 10.1016/j.ajt.2024.08.004
DO - 10.1016/j.ajt.2024.08.004
M3 - Article
AN - SCOPUS:85203200500
SN - 1600-6135
VL - 25
SP - 88
EP - 101
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 1
ER -