Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies

Area of Science:

• Immunology
• Molecular Biology
• Pharmacology

Background:

• Biologics targeting TNF family receptors are key for immune disease therapies.
• Fcγ receptors are known to mediate antibody activity for CD40, TRAILR, and GITR.
• Other TNF receptor superfamily (TNFRSF) molecules may utilize different regulatory mechanisms.

Purpose of the Study:

• To investigate the mechanisms underlying the activity of agonist anti-4-1BB antibodies.
• To identify novel factors involved in the function of 4-1BB (CD137) signaling.
• To explore the therapeutic potential of targeting 4-1BB in immune-mediated diseases.

Main Methods:

• Utilized in vitro assays to study the interaction between Galectin-9 (Gal-9) and 4-1BB.
• Investigated the functional consequences of Gal-9 binding on 4-1BB aggregation and signaling.
• Assessed the role of Gal-9 in the therapeutic efficacy of anti-4-1BB antibodies in preclinical models of autoimmune and allergic inflammation.

Main Results:

• The suppressive effects of agonist anti-4-1BB antibodies on autoimmune and allergic inflammation were entirely dependent on Galectin-9 (Gal-9).
• Gal-9 directly binds to 4-1BB at a unique site, separate from antibody and natural ligand binding sites.
• Gal-9 promotes 4-1BB aggregation, signaling, and functional activity across T cells, dendritic cells, and natural killer cells.

Conclusions:

• Galectin-9 is a critical mediator of agonist anti-4-1BB antibody function.
• The distinct binding site of Gal-9 on 4-1BB offers a novel target for therapeutic modulation.
• The conserved interaction between Gal-9 and 4-1BB in humans has significant implications for the clinical development of 4-1BB-targeting therapies and potentially other TNFRSF molecules.