{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:34:25Z","timestamp":1790678065896,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T00:00:00Z","timestamp":1680652800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Patients with cancer undergoing chemotherapy experience cachexia with anorexia, body weight loss, and the depletion of skeletal muscles and adipose tissues. Effective treatment strategies for chemotherapy\u2010induced cachexia are scarce. The growth differentiation factor 15 (GDF15)\/GDNF family receptor alpha\u2010like (GFRAL)\/rearranged during transfection (RET) axis is a critical signalling pathway in chemotherapy\u2010induced cachexia. In this study, we developed a fully human GFRAL antagonist antibody and investigated whether it inhibits the GDF15\/GFRAL\/RET axis, thereby alleviating chemotherapy\u2010induced cachexia in tumour\u2010bearing mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Anti\u2010GFRAL antibodies were selected via biopanning, using a human combinatorial antibody phage library. The potent GFRAL antagonist antibody A11 was selected via a reporter cell assay and its inhibitory activity of GDF15\u2010induced signalling was evaluated using western blotting. To investigate the <jats:italic>in vivo<\/jats:italic> function of A11, a tumour\u2010bearing mouse model was established by inoculating 8\u2010week\u2010old male C57BL\/6 mice with B16F10 cells (<jats:italic>n<\/jats:italic>\u00a0=\u00a010\u201316 mice per group). A11 was administered subcutaneously (10\u00a0mg\/kg) 1\u00a0day before intraperitoneal treatment with cisplatin (10\u00a0mg\/kg). Animals were assessed for changes in food intake, body weight, and tumour volume. Plasma and key metabolic tissues such as skeletal muscles and adipose tissues were collected for protein and mRNA expression analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A11 reduced serum response element\u2010luciferase reporter activity up to 74% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.005) in a dose\u2010dependent manner and blocked RET phosphorylation up to 87% (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0593), AKT phosphorylation up to 28% (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0593) and extracellular signal regulatory kinase phosphorylation up to 75% (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0636). A11 inhibited the action of cisplatin\u2010induced GDF15 on the brainstem and decreased GFRAL\u2010positive neuron population expressing c\u2010Fos in the area postrema and nucleus of the solitary tract by 62% <jats:italic>in vivo<\/jats:italic> (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). In a melanoma mouse model treated with cisplatin, A11 recovered anorexia by 21% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and tumour\u2010free body weight loss by 13% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). A11 significantly improved the cisplatin\u2010induced loss of skeletal muscles (quadriceps: 21%, gastrocnemius: 9%, soleus: 13%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and adipose tissues (epididymal white adipose tissue: 37%, inguinal white adipose tissue: 51%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study suggests that GFRAL antagonist antibody may alleviate chemotherapy\u2010induced cachexia, providing a novel therapeutic approach for patients with cancer experiencing chemotherapy\u2010induced cachexia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13219","type":"journal-article","created":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T12:18:34Z","timestamp":1680697114000},"page":"1441-1453","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["GDNF family receptor alpha\u2010like antagonist antibody alleviates chemotherapy\u2010induced cachexia in melanoma\u2010bearing mice"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-952X","authenticated-orcid":false,"given":"Beom Yong","family":"Lee","sequence":"first","affiliation":[{"name":"Department of New Biology Daegu Gyeongbuk Institute of Science and Technology (DGIST)  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0391-1929","authenticated-orcid":false,"given":"Jongwon","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of New Biology Daegu Gyeongbuk Institute of Science and Technology (DGIST)  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inseong","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of New Biology Daegu Gyeongbuk Institute of Science and Technology (DGIST)  Daegu Republic of 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