title: Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies.
abstract: Biologics to TNF family receptors are prime candidates for therapy of immune disease. Whereas recent studies have highlighted a requirement for Fcγ receptors in enabling the activity of CD40, TRAILR, and GITR when engaged by antibodies, other TNFR molecules may be controlled by additional mechanisms. Antibodies to 4-1BB (CD137) are currently in clinical trials and can both augment immunity in cancer and promote regulatory T cells that inhibit autoimmune disease. We found that the action of agonist anti-4-1BB in suppressing autoimmune and allergic inflammation was completely dependent on Galectin-9 (Gal-9). Gal-9 directly bound to 4-1BB, in a site distinct from the binding site of antibodies and the natural ligand of 4-1BB, and Gal-9 facilitated 4-1BB aggregation, signaling, and functional activity in T cells, dendritic cells, and natural killer cells. Conservation of the Gal-9 interaction in humans has important implications for effective clinical targeting of 4-1BB and possibly other TNFR superfamily molecules.
authors: Division of Immune Regulation and Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors: Shravan
authors: S
authors: Madireddi
authors: Division of Immune Regulation and Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors: So-Young
authors: SY
authors: Eun
authors: Division of Immune Regulation and Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors: Seung-Woo
authors: SW
authors: Lee
authors: Division of Immune Regulation and Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors: Ivana
authors: I
authors: Nemčovičová
authors: Division of Immune Regulation and Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors: Amit Kumar
authors: AK
authors: Mehta
authors: Division of Immune Regulation and Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors: Dirk M
authors: DM
authors: Zajonc
authors: Life Science Research Center; and Department of Immunology and Immunopathology, Faculty of Medicine; Kagawa University, Kagawa 761-0793, Japan.
authors: Nozomu
authors: N
authors: Nishi
authors: Life Science Research Center; and Department of Immunology and Immunopathology, Faculty of Medicine; Kagawa University, Kagawa 761-0793, Japan GalPharma Co., Ltd., Kagawa 760-0301, Japan.
authors: Toshiro
authors: T
authors: Niki
authors: Life Science Research Center; and Department of Immunology and Immunopathology, Faculty of Medicine; Kagawa University, Kagawa 761-0793, Japan GalPharma Co., Ltd., Kagawa 760-0301, Japan.
authors: Mitsuomi
authors: M
authors: Hirashima
authors: Division of Immune Regulation and Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037 mick@liai.org.
authors: Michael
authors: M
authors: Croft
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D037161:Galectins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology
chemical_list: D000906:Antibodies; D037161:Galectins; C105032:LGALS9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C508186:galectin 9, mouse