Induced-fit anti-GFRAL antibody ameliorates cancer cachexia and attenuates sympathetic outflow in tumor-bearing mice.

A GFRAL-binding, pathway-blocking antibody (GB2Ab) shows induced-fit structural antagonism that sterically occludes the GFRAL-RET interface and ameliorates cancer cachexia in tumor-bearing mice.

• Why it matters: Hyperactivation of the GDF15-GFRAL-RET neuroendocrine axis is linked to disease-associated weight loss, including cancer-associated cachexia, creating a need for receptor-centric blockade.
• What they did: GB2Ab Fab–GFRAL D3 crystal structure was solved to define induced-fit occlusion and RET CLD1-CLD2 remodeling; a structure-guided humanized lead was tested in an orthotopic cancer cachexia model.
• The result: The humanized antibody reaches the area postrema, attenuates GDF15-evoked neural activation, ameliorates cachectic phenotypes, and suppresses sympathetic preganglionic activity, supporting GDF15-GFRAL-RET antagonism as a strategy for cancer cachexia.