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

Area of Science:

• Immunology
• Cell Biology
• Pharmacology

Background:

• Current B cell therapies like anti-CD20 mAbs do not target antibody-producing plasma cells.
• CD38-targeting therapies, such as daratumumab, are promising for plasma cell-mediated diseases.
• The effects of CD38 targeting on human B cell differentiation outside of cancer are largely unknown.

Purpose of the Study:

• To investigate the impact of CD38 targeting with daratumumab on B cell differentiation and function in vitro.
• To analyze the effects on key signaling pathways, including NF-κB.
• To identify which B cell subsets are most affected by daratumumab.

Main Methods:

• In vitro B cell differentiation assays.
• Signaling pathway analysis, including NF-κB activation.
• Culture of sorted human B cell subsets with daratumumab.
• Assessment of T cell activation and proliferation.

Main Results:

• Daratumumab significantly decreased B cell proliferation, differentiation, and IgG production during T cell-dependent stimulation.
• No significant effects were observed on T cell activation or proliferation.
• Daratumumab attenuated NF-κB activation and the transcription of NF-κB-targeted genes in B cells.
• Switched memory B cells were the primary B cell subset affected.

Conclusions:

• CD38 targeting with daratumumab inhibits T cell-dependent B cell responses through non-depleting mechanisms.
• Daratumumab impacts B cell differentiation and antibody production by affecting NF-κB signaling.
• These findings suggest daratumumab could be a therapeutic option for B cell-mediated diseases beyond malignancies by targeting memory B cells.