Principles of antibody-mediated TNF receptor activation

Area of Science:

• Immunology
• Molecular Biology
• Biotechnology

Background:

• Receptors of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) are critical in cellular signaling.
• Agonistic antibodies are widely used to stimulate TNFRSF receptors, with CD95 being an early example.
• Initial in vitro studies highlighted the importance of antibody valency and Fcγ receptor (FcγR) binding for TNFRSF agonistic activity.

Purpose of the Study:

• To review the critical role of antibody oligomerization and Fcγ receptor (FcγR) binding in TNFRSF receptor activation.
• To discuss the implications of these factors for the development of therapeutic antibodies targeting TNFRSF.

Main Methods:

• Review of existing literature on TNFRSF receptor activation by antibodies.
• Analysis of in vitro and in vivo studies investigating antibody valency, oligomerization, and FcγR interactions.
• Discussion of current models of TNFRSF receptor activation.

Main Results:

• Antibodies with higher valency (e.g., IgM) or those prone to aggregation show superior agonistic activity.
• Binding to Fcγ receptors significantly potentiates TNFRSF receptor signaling.
• Recent in vivo studies confirm the importance of oligomerization and FcγR binding for therapeutic antibody efficacy.

Conclusions:

• Antibody oligomerization and FcγR binding are essential for potent TNFRSF receptor stimulation.
• These structural features are critical considerations for the rational design of therapeutic TNFRSF-targeting antibodies.
• Further research into these aspects will advance the development of novel immunotherapies.