Inhibition of B cell activation following in vivo co-engagement of B cell antigen receptor and Fcγ receptor IIb in non-autoimmune-prone and SLE-prone mice

Seung Y. Chu, Erik Pong, Christine Bonzon, Ning Yu, Chaim O. Jacob, Samantha A. Chalmers, Chaim Putterman, David E. Szymkowski, William Stohl

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Engagement of Fcγ receptor IIb (FcγRIIb) suppresses B cell activation and represents a promising target for therapy in autoimmunity. Obexelimab is a non-depleting anti-human CD19 mAb with an Fc region engineered to have high affinity for human FcγRIIb, thereby co-engaging BCR and FcγRIIb. To assess its ability to suppress B cell activation in vivo, we generated non-autoimmune-prone C57BL/6 (B6) and SLE-prone NZM 2328 (NZM) mice in which the human FcγRIIb extracellular domain was knocked into the mouse Fcgr2b locus (B6.hRIIb and NZM.hRIIb mice, respectively, the latter retaining features of SLE). XENP8206, a mAb which bears the same FcγRIIb-enhanced human Fc domain as does obexelimab but which recognizes murine CD19 rather than human CD19, inhibited in vitro BCR-triggered activation of B cells from both B6.hRIIb and NZM.hRIIb mice. Following administration of XENP8206 to B6.hRIIb or NZM.hRIIb mice, B cell numbers in the spleen and lymph nodes remained stable but became hyporesponsive to BCR-triggered activation for at least 14 days. These findings demonstrate proof-of-principle that pharmacologic co-engagement of BCR and human FcγRIIb inhibits B cell activation in non-autoimmune and SLE-prone hosts while preserving B cell numbers. These observations lay a strong foundation for clinical trials in human SLE with agents that co-engage BCR and FcγRIIb. Moreover, B6.hRIIb and NZM.hRIIb should serve as powerful in vivo models in the elucidation of the cellular and molecular underpinnings of the changes induced by BCR/FcγRIIb co-engagement.

Original languageEnglish
Article number100075
JournalJournal of Translational Autoimmunity
Volume4
DOIs
StatePublished - Jan 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 The Author(s)

Keywords

  • B cells
  • FcγRIIb
  • Lupus
  • Murine

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