B-cell targeting with anti-CD38 daratumumab: implications for differentiation and memory responses

Dorit Verhoeven*, Lucas Grinwis, T2B Consortium, Casper Marsman, Machiel H. Jansen, Ester M.M. Van Leeuwen, Taco Kuijpers, Annabel Ruiter, Linda van der Weele, Karoline Kielbassa, Mariateresa Coppola, Dorit Verhoeven*, Jyaysi Desai, Mirjam van der Burg, Esther Vletter, Maaike Braham, Matthias Busch, Carlo Bonasia, Elisabeth Raveling, Ruth HuizingaNiels Verstegen, Casper Marsman, Sabrina Pollastro, Koos van Dam, Laurent Paardekooper, Renée Ysermans, Odilia Corneth, Annemarie Buisman, Rob van Binnendijk, Pauline van Schouwenburg, Marvyn Koning, Luuk Wieske, Lisa van Baarsen, Nico Bos, Anja ten Brinke, Eric Eldering, Cecile van Els, Marieke van Ham, Peter Heeringa, Rudi Hendriks, Maartje Huijbers, Ruth Huizinga, Reina Mebius, Filip Eftimov, Casper Franssen, Jaap Groothoff, Bart Jacobs, Barbara Horvath, Arnon Kater, Joep Killestein, Maarten Titulaer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)
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Abstract

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.

Original languageEnglish
Article numbere202302214
JournalLife Science Alliance
Volume6
Issue number9
Early online date7 Jul 2023
DOIs
Publication statusPublished - Sept 2023

Bibliographical note

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.

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