Everestmab, a novel long-acting GLP-1/anti GLP-1R nanobody fusion protein, exerts potent anti-diabetic effects
In the present study, a novel single domain antibody (sdAb) fusion protein, named everestmab, composing of a mutated GLP-1(A8G) fused to the tandem bispecific humanized GLP-1R-targeting and albumin-binding nanobodies was designed and characterized for the therapies for type 2 diabetes mellitus (T2DM...
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Taylor & Francis Group
2020-01-01
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| Series: | Artificial Cells, Nanomedicine, and Biotechnology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/21691401.2020.1770268 |
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| author | Hongchao Pan Yunnan Su Yini Xie Weiyong Wang Wanli Qiu Wei Chen Wenying Lu Zhao Lu Weiwei Wang Anquan Shang |
| author_facet | Hongchao Pan Yunnan Su Yini Xie Weiyong Wang Wanli Qiu Wei Chen Wenying Lu Zhao Lu Weiwei Wang Anquan Shang |
| author_sort | Hongchao Pan |
| collection | DOAJ |
| description | In the present study, a novel single domain antibody (sdAb) fusion protein, named everestmab, composing of a mutated GLP-1(A8G) fused to the tandem bispecific humanized GLP-1R-targeting and albumin-binding nanobodies was designed and characterized for the therapies for type 2 diabetes mellitus (T2DM). Surface plasmon resonance (SPR) measurements demonstrated everestmab associates with serum albumins of rat and monkey species with high affinity, and tends to be cross-reactive with rat and monkey species. In vitro GLP-1R binding and activation assays revealed that everestmab can specifically activate the GLP-1R, and the antagonist exendin-4 (9–39) did not inhibit the activation yet. In vivo multiple oral glucose tolerance tests (OGTTs) and hypoglycaemic efficacy tests proved that a single injection of everestmab reduced the blood glucose for at least 144 h in Goto-Kakizaki (GK) rats. The plasma half-lives of 4.1 and 7.8 days were observed after a single s.c. administration of everestmab in SD rats and cynomolgus monkeys, respectively. Chronic treatment of everestmab to GK and diet induced obese (DIO) rats achieved beneficial effects on weight reducing, HbA1c lowering, glucose tolerance, liver and pancreas islet function impairment. In summary, everestmab is a unique G-protein-coupled receptor-targeted nanobody fusion protein and exerts potential as a therapeutic treatment for T2DM. |
| format | Article |
| id | doaj-art-b15626c8fedc430fb2c7f39a5caa309b |
| institution | Kabale University |
| issn | 2169-1401 2169-141X |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Artificial Cells, Nanomedicine, and Biotechnology |
| spelling | doaj-art-b15626c8fedc430fb2c7f39a5caa309b2025-08-20T03:41:30ZengTaylor & Francis GroupArtificial Cells, Nanomedicine, and Biotechnology2169-14012169-141X2020-01-0148185486610.1080/21691401.2020.1770268Everestmab, a novel long-acting GLP-1/anti GLP-1R nanobody fusion protein, exerts potent anti-diabetic effectsHongchao Pan0Yunnan Su1Yini Xie2Weiyong Wang3Wanli Qiu4Wei Chen5Wenying Lu6Zhao Lu7Weiwei Wang8Anquan Shang9Department of Laboratory Medicine, Shanghai SimpleGene Medical Laboratory, Shanghai, P. R. ChinaDepartment of Neurology, Baoshan Branch, Shanghai General Hospital, Shanghai, P. R. ChinaDepartment of Laboratory Medicine, The People’s Hospital of Jiedong, Jieyang, P. R. ChinaDepartment of Medical Center, Yandong Hospital of Yancheng City, Yancheng, P. R. ChinaDepartment of Medical Center, Yandong Hospital of Yancheng City, Yancheng, P. R. ChinaDepartment of Experimental Medicine Center, The Sixth People’s Hospital of Yancheng City, Yancheng, P. R. ChinaDepartment of Experimental Medicine Center, The Sixth People’s Hospital of Yancheng City, Yancheng, P. R. ChinaDepartment of Laboratory Medicine, Key Laboratory of Pharmaceutical Chemistry, China Pharmaceutical University, NanJing, P. R. ChinaDepartment of Experimental Medicine Center, The Sixth People’s Hospital of Yancheng City, Yancheng, P. R. ChinaDepartment of Laboratory Medicine, Tongji Hospital of Tongji University, Shanghai, P. R. ChinaIn the present study, a novel single domain antibody (sdAb) fusion protein, named everestmab, composing of a mutated GLP-1(A8G) fused to the tandem bispecific humanized GLP-1R-targeting and albumin-binding nanobodies was designed and characterized for the therapies for type 2 diabetes mellitus (T2DM). Surface plasmon resonance (SPR) measurements demonstrated everestmab associates with serum albumins of rat and monkey species with high affinity, and tends to be cross-reactive with rat and monkey species. In vitro GLP-1R binding and activation assays revealed that everestmab can specifically activate the GLP-1R, and the antagonist exendin-4 (9–39) did not inhibit the activation yet. In vivo multiple oral glucose tolerance tests (OGTTs) and hypoglycaemic efficacy tests proved that a single injection of everestmab reduced the blood glucose for at least 144 h in Goto-Kakizaki (GK) rats. The plasma half-lives of 4.1 and 7.8 days were observed after a single s.c. administration of everestmab in SD rats and cynomolgus monkeys, respectively. Chronic treatment of everestmab to GK and diet induced obese (DIO) rats achieved beneficial effects on weight reducing, HbA1c lowering, glucose tolerance, liver and pancreas islet function impairment. In summary, everestmab is a unique G-protein-coupled receptor-targeted nanobody fusion protein and exerts potential as a therapeutic treatment for T2DM.https://www.tandfonline.com/doi/10.1080/21691401.2020.1770268Long-acting GLP-1glucose metabolismsingle domain antibodyhuman serum albuminanti-diabetic properties |
| spellingShingle | Hongchao Pan Yunnan Su Yini Xie Weiyong Wang Wanli Qiu Wei Chen Wenying Lu Zhao Lu Weiwei Wang Anquan Shang Everestmab, a novel long-acting GLP-1/anti GLP-1R nanobody fusion protein, exerts potent anti-diabetic effects Artificial Cells, Nanomedicine, and Biotechnology Long-acting GLP-1 glucose metabolism single domain antibody human serum albumin anti-diabetic properties |
| title | Everestmab, a novel long-acting GLP-1/anti GLP-1R nanobody fusion protein, exerts potent anti-diabetic effects |
| title_full | Everestmab, a novel long-acting GLP-1/anti GLP-1R nanobody fusion protein, exerts potent anti-diabetic effects |
| title_fullStr | Everestmab, a novel long-acting GLP-1/anti GLP-1R nanobody fusion protein, exerts potent anti-diabetic effects |
| title_full_unstemmed | Everestmab, a novel long-acting GLP-1/anti GLP-1R nanobody fusion protein, exerts potent anti-diabetic effects |
| title_short | Everestmab, a novel long-acting GLP-1/anti GLP-1R nanobody fusion protein, exerts potent anti-diabetic effects |
| title_sort | everestmab a novel long acting glp 1 anti glp 1r nanobody fusion protein exerts potent anti diabetic effects |
| topic | Long-acting GLP-1 glucose metabolism single domain antibody human serum albumin anti-diabetic properties |
| url | https://www.tandfonline.com/doi/10.1080/21691401.2020.1770268 |
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