TY - JOUR
T1 - B-cell targeting with anti-CD38 daratumumab
T2 - implications for differentiation and memory responses
AU - Verhoeven, Dorit
AU - Grinwis, Lucas
AU - T2B Consortium
AU - Marsman, Casper
AU - Jansen, Machiel H.
AU - Van Leeuwen, Ester M.M.
AU - Kuijpers, Taco
AU - Ruiter, Annabel
AU - van der Weele, Linda
AU - Kielbassa, Karoline
AU - Coppola, Mariateresa
AU - Verhoeven, Dorit
AU - Desai, Jyaysi
AU - van der Burg, Mirjam
AU - Vletter, Esther
AU - Braham, Maaike
AU - Busch, Matthias
AU - Bonasia, Carlo
AU - Raveling, Elisabeth
AU - Huizinga, Ruth
AU - Verstegen, Niels
AU - Marsman, Casper
AU - Pollastro, Sabrina
AU - van Dam, Koos
AU - Paardekooper, Laurent
AU - Ysermans, Renée
AU - Corneth, Odilia
AU - Buisman, Annemarie
AU - van Binnendijk, Rob
AU - van Schouwenburg, Pauline
AU - Koning, Marvyn
AU - Wieske, Luuk
AU - van Baarsen, Lisa
AU - Bos, Nico
AU - ten Brinke, Anja
AU - Eldering, Eric
AU - van Els, Cecile
AU - van Ham, Marieke
AU - Heeringa, Peter
AU - Hendriks, Rudi
AU - Huijbers, Maartje
AU - Huizinga, Ruth
AU - Mebius, Reina
AU - Eftimov, Filip
AU - Franssen, Casper
AU - Groothoff, Jaap
AU - Jacobs, Bart
AU - Horvath, Barbara
AU - Kater, Arnon
AU - Killestein, Joep
AU - Titulaer, Maarten
N1 - Acknowledgements:
We are thankful to the healthy donors that donated blood. We thank the Amsterdam UMC Pharmacy for the provision of left-over Darzalex and Xolair. We acknowledge the support of patient partners, private partners, and active colleagues of the T2B consortium (see website: www.target-tob.nl). We thank the Sanquin Central Facility and the Laboratory Medical Immunology Amsterdam UMC for the maintenance and calibration of the FACS machines. This collaboration project is financed by the PPP Allowance made available by Top Sector Life Sciences and Health to Samen-werkende Gezondheidsfondsen (SGF) under project number LSHM18055-SGF to stimulate public–private partnerships and co-financing by health foundations that are part of the SGF.
Publisher Copyright:
© 2023 Verhoeven et al.
PY - 2023/9
Y1 - 2023/9
N2 - B cell–targeted therapies, such as CD20-targeting mAbs, deplete B cells but do not target the autoantibody-producing plasma cells (PCs). PC-targeting therapies such as daratumumab (anti-CD38) form an attractive approach to treat PC-mediated diseases. CD38 possesses enzymatic and receptor capabilities, which may impact a range of cellular processes including proliferation and differentiation. However, very little is known whether and how CD38 targeting affects B-cell differentiation, in particular for humans beyond cancer settings. Using in-depth in vitro B-cell differentiation assays and signaling pathway analysis, we show that CD38 targeting with daratumumab demonstrated a significant decrease in proliferation, differentiation, and IgG production upon T cell–dependent B-cell stimulation. We found no effect on T-cell activation or proliferation. Furthermore, we demonstrate that daratumumab attenuated the activation of NF-κB in B cells and the transcription of NF-κB–targeted genes. When culturing sorted B-cell subsets with daratumumab, the switched memory B-cell subset was primarily affected. Overall, these in vitro data elucidate novel non-depleting mechanisms by which daratumumab can disturb humoral immune responses. Affecting memory B cells, daratumumab may be used as a therapeutic approach in B cell–mediated diseases other than the currently targeted malignancies.
AB - B cell–targeted therapies, such as CD20-targeting mAbs, deplete B cells but do not target the autoantibody-producing plasma cells (PCs). PC-targeting therapies such as daratumumab (anti-CD38) form an attractive approach to treat PC-mediated diseases. CD38 possesses enzymatic and receptor capabilities, which may impact a range of cellular processes including proliferation and differentiation. However, very little is known whether and how CD38 targeting affects B-cell differentiation, in particular for humans beyond cancer settings. Using in-depth in vitro B-cell differentiation assays and signaling pathway analysis, we show that CD38 targeting with daratumumab demonstrated a significant decrease in proliferation, differentiation, and IgG production upon T cell–dependent B-cell stimulation. We found no effect on T-cell activation or proliferation. Furthermore, we demonstrate that daratumumab attenuated the activation of NF-κB in B cells and the transcription of NF-κB–targeted genes. When culturing sorted B-cell subsets with daratumumab, the switched memory B-cell subset was primarily affected. Overall, these in vitro data elucidate novel non-depleting mechanisms by which daratumumab can disturb humoral immune responses. Affecting memory B cells, daratumumab may be used as a therapeutic approach in B cell–mediated diseases other than the currently targeted malignancies.
UR - http://www.scopus.com/inward/record.url?scp=85164259824&partnerID=8YFLogxK
U2 - 10.26508/lsa.202302214
DO - 10.26508/lsa.202302214
M3 - Article
C2 - 37419630
AN - SCOPUS:85164259824
SN - 2575-1077
VL - 6
JO - Life Science Alliance
JF - Life Science Alliance
IS - 9
M1 - e202302214
ER -
