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Peer-reviewedCC BY-NCScience Advances

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

  • Sohyun Kim1,2
  • Min Hee Lee3
  • Jinsook Ahn4
  • Sang-Hyeon Ju5
  • Dong Sun Lee4
  • Seohyun Choi1
  • Kwang Wook Min6
  • Minho Shong1,5
  • Ho Min Kim4,5
6 affiliations
  1. 1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST); Daejeon, 34141, Republic of Korea.
  2. 2Life Science Research Institute, Korea Advanced Institute of Science and Technology (KAIST); Daejeon, 34141, Republic of Korea.
  3. 3THOR Therapeutics Inc; Daejeon 34134, Republic of Korea.
  4. 4Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST); Daejeon, 34141, Republic of Korea.
  5. 5InnoCORE AI-CRED Institute, Korea Advanced Institute of Science and Technology (KAIST); Daejeon, 34141, Republic of Korea.
  6. 6Department of Pathology, Division of Molecular and Cellular Pathology, The University of Alabama at Birmingham; Birmingham, AL, USA.
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{kim2026inducedfit,
  title = {{Induced-fit anti-GFRAL antibody ameliorates cancer cachexia and attenuates sympathetic outflow in tumor-bearing mice}},
  author = {Sohyun Kim and Min Hee Lee and Jinsook Ahn and Sang-Hyeon Ju and Dong Sun Lee and Seohyun Choi and Kwang Wook Min and Minho Shong and Ho Min Kim},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aee5992},
  url = {https://www.science.org/doi/abs/10.1126/sciadv.aee5992},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Induced-fit anti-GFRAL antibody ameliorates cancer cachexia and attenuates sympathetic outflow in tumor-bearing mice
AU  - Sohyun Kim
AU  - Min Hee Lee
AU  - Jinsook Ahn
AU  - Sang-Hyeon Ju
AU  - Dong Sun Lee
AU  - Seohyun Choi
AU  - Kwang Wook Min
AU  - Minho Shong
AU  - Ho Min Kim
PY  - 2026
DA  - 2026/10/28
JO  - Science Advances
DO  - 10.1126/sciadv.aee5992
UR  - https://www.science.org/doi/abs/10.1126/sciadv.aee5992
AB  - 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.
SN  - 2375-2548
ER  -