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

The GDF15–GFRAL–RET neuroendocrine axis is a key regulator of body-weight homeostasis and metabolic control. GFRAL, a hindbrain-restricted receptor for the stress-responsive cytokine GDF15, signals by assembling a ternary complex with GDF15 and the tyrosine kinase RET. Pathological hyperactivation of this axis drives disease-associated weight loss, including cancer-associated cachexia. Here, we report a GFRAL-binding and GDF15–GFRAL pathway-blocking antibody (GB2Ab) and its humanized lead with potent preclinical efficacy. The GB2Ab Fab–GFRAL D3 crystal structure reveals an induced-fit mechanism in which GB2Ab sterically occludes the GFRAL–RET interface and remodels the primary RET CLD1–CLD2 binding site, providing a structural basis for high-affinity binding, slow dissociation, and potent antagonism. Structure-guided humanization preserves high-affinity and cross-reactivity. The humanized antibody reaches the area postrema, attenuates GDF15-evoked neural activation, ameliorates cachectic phenotypes, and suppresses sympathetic preganglionic activity in an orthotopic cancer cachexia model, establishing receptor-centric GDF15–GFRAL–RET antagonism as a promising strategy for cancer-associated cachexia and other GDF15-driven diseases.