GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models
Cachexia is a complicated metabolic syndrome mainly associated with cancers, characterized by extreme weight loss and muscle wasting. It is a debilitating condition that negatively affects prognosis and survival. However, there is currently no effective pharmacological intervention that can reverse...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2416453 |
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| author | Yu Huang Jinyong Wang Xiling Wei Hui Zhang Wei Shang Xiangling Zhang Lanjiao Zhai Xi Chen Huiming Li Suofu Qin |
| author_facet | Yu Huang Jinyong Wang Xiling Wei Hui Zhang Wei Shang Xiangling Zhang Lanjiao Zhai Xi Chen Huiming Li Suofu Qin |
| author_sort | Yu Huang |
| collection | DOAJ |
| description | Cachexia is a complicated metabolic syndrome mainly associated with cancers, characterized by extreme weight loss and muscle wasting. It is a debilitating condition that negatively affects prognosis and survival. However, there is currently no effective pharmacological intervention that can reverse body weight loss and improve physical performance in patients with cachexia. Growth differentiation factor 15 (GDF15) can suppress appetite and regulate energy balance through binding to glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). In order to develop a novel, effective treatment for cachexia, we generated a GDF15-targeting VHH nanobody, GB18–06, that was able to bind GDF15 with high affinity. In vitro, GB18–06 potently inhibited the GDF15-GFRAL signaling pathway, leading to a reduction of downstream ERK and AKT phosphorylation levels; in vivo, GB18–06 alleviated weight loss (>20%) in cancer and chemotherapy-induced cachexia models in mice. Compared with the control (phosphate-buffered saline) group, the ambulatory activity of mice in the GB18–06-treated group also increased 77%. Furthermore, GB18–06 exhibited desirable pharmacokinetic properties and an excellent developability profile. Our study has demonstrated a means of developing targeted treatment for cachexia with high efficacy, potentially leading to improved clinical outcomes and quality of life for patients with cachexia. |
| format | Article |
| id | doaj-art-59be9df8b6f74328b7974b0edc494114 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-59be9df8b6f74328b7974b0edc4941142025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2416453GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia modelsYu Huang0Jinyong Wang1Xiling Wei2Hui Zhang3Wei Shang4Xiangling Zhang5Lanjiao Zhai6Xi Chen7Huiming Li8Suofu Qin9Drug Discovery, Center for Research and Development, Kexing Biopharm Co. Ltd, Shenzhen, ChinaDrug Discovery, Center for Research and Development, Kexing Biopharm Co. Ltd, Shenzhen, ChinaDrug Discovery, Center for Research and Development, Kexing Biopharm Co. Ltd, Shenzhen, ChinaDrug Discovery, Center for Research and Development, Kexing Biopharm Co. Ltd, Shenzhen, ChinaDrug Discovery, Center for Research and Development, Kexing Biopharm Co. Ltd, Shenzhen, ChinaDrug Discovery, Center for Research and Development, Kexing Biopharm Co. Ltd, Shenzhen, ChinaDrug Discovery, Center for Research and Development, Kexing Biopharm Co. Ltd, Shenzhen, ChinaDrug Discovery, Center for Research and Development, Kexing Biopharm Co. Ltd, Shenzhen, ChinaDrug Discovery, Center for Research and Development, Kexing Biopharm Co. Ltd, Shenzhen, ChinaDrug Discovery, Center for Research and Development, Kexing Biopharm Co. Ltd, Shenzhen, ChinaCachexia is a complicated metabolic syndrome mainly associated with cancers, characterized by extreme weight loss and muscle wasting. It is a debilitating condition that negatively affects prognosis and survival. However, there is currently no effective pharmacological intervention that can reverse body weight loss and improve physical performance in patients with cachexia. Growth differentiation factor 15 (GDF15) can suppress appetite and regulate energy balance through binding to glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). In order to develop a novel, effective treatment for cachexia, we generated a GDF15-targeting VHH nanobody, GB18–06, that was able to bind GDF15 with high affinity. In vitro, GB18–06 potently inhibited the GDF15-GFRAL signaling pathway, leading to a reduction of downstream ERK and AKT phosphorylation levels; in vivo, GB18–06 alleviated weight loss (>20%) in cancer and chemotherapy-induced cachexia models in mice. Compared with the control (phosphate-buffered saline) group, the ambulatory activity of mice in the GB18–06-treated group also increased 77%. Furthermore, GB18–06 exhibited desirable pharmacokinetic properties and an excellent developability profile. Our study has demonstrated a means of developing targeted treatment for cachexia with high efficacy, potentially leading to improved clinical outcomes and quality of life for patients with cachexia.https://www.tandfonline.com/doi/10.1080/19420862.2024.2416453CachexiaCancerChemotherapyGDF15Nanobody |
| spellingShingle | Yu Huang Jinyong Wang Xiling Wei Hui Zhang Wei Shang Xiangling Zhang Lanjiao Zhai Xi Chen Huiming Li Suofu Qin GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models mAbs Cachexia Cancer Chemotherapy GDF15 Nanobody |
| title | GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models |
| title_full | GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models |
| title_fullStr | GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models |
| title_full_unstemmed | GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models |
| title_short | GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models |
| title_sort | gb18 06 a nanobody targeting gdf15 effectively alleviates weight loss and restores physical function in cachexia models |
| topic | Cachexia Cancer Chemotherapy GDF15 Nanobody |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2416453 |
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