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

作者：Shravan Madireddi, So-Young Eun, Seung‐Woo Lee, Ivana Nemčovičová, Amit Kumar Mehta, Dirk M. Zajonc, Nozomu Nishi, Toshiro Niki, Mitsuomi Hirashima, Michael Croft · 发表于：The Journal of Experimental Medicine · 年份：2014 · DOI：10.1084/jem.20132687 · 被引用次数：131 · 研究领域：Galectins and Cancer Biology、Toxin Mechanisms and Immunotoxins、Signaling Pathways in Disease

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.