Coactivation of Tie2 and Wnt signaling using an antibody–R-spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemia
Therapeutic angiogenesis by intentional formation of blood vessels is essential for treating various ischemic diseases, including limb ischemia. Because Wnt/β-catenin and angiopoietin-1/Tie2 signaling play important roles in endothelial survival and vascular stability, coactivation of these signalin...
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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/10.1080/19420862.2024.2435478 |
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| author | Byungtae Hwang Min-Young Jeon Ju-Hong Jang Young-Lai Cho Dong Gwang Lee Jeong-Ki Min Jangwook Lee Jong-Gil Park Ji-Hun Noh Wonjun Yang Nam-Kyung Lee |
| author_facet | Byungtae Hwang Min-Young Jeon Ju-Hong Jang Young-Lai Cho Dong Gwang Lee Jeong-Ki Min Jangwook Lee Jong-Gil Park Ji-Hun Noh Wonjun Yang Nam-Kyung Lee |
| author_sort | Byungtae Hwang |
| collection | DOAJ |
| description | Therapeutic angiogenesis by intentional formation of blood vessels is essential for treating various ischemic diseases, including limb ischemia. Because Wnt/β-catenin and angiopoietin-1/Tie2 signaling play important roles in endothelial survival and vascular stability, coactivation of these signaling pathways can potentially achieve therapeutic angiogenesis. In this study, we developed a bifunctional antibody fusion, consisting of a Tie2-agonistic antibody and the Furin domains of R-spondin 3 (RSPO3), to simultaneously activate Tie2 and Wnt/β-catenin signaling. We identified a Tie2-agonistic antibody T11 that cross-reacted with the extracellular domain of human and mouse Tie2, and evaluated its ability to increase endothelial cell survival and tube formation. We generated a bifunctional T11–RF12 by fusing T11 with the Furin-1 and −2 domains of RSPO3. T11–RF12 could bind not only to Tie2, but also to LGR5 and ZNRF3, which are counterparts of the Furin-1 and −2 domains. T11–RF12 significantly increased Wnt/β-catenin signaling, as well as the formation of capillary-like endothelial tubes, regardless of the presence of Wnt ligands. Coactivation of Tie2 and Wnt/β-catenin signaling by T11–RF12 increased the blood flow, and thereby reduced foot necrosis in a mouse hindlimb ischemia model. In particular, T11–RF12 induced therapeutic angiogenesis by promoting vessel stabilization through pericyte coverage and retaining endothelial expression of Frizzled 10 and active β-catenin. These results indicate that the agonistic synergism of Tie2 and Wnt/β-catenin signaling achieved using T11–RF12 is a novel therapeutic option with potential for treating limb ischemia and other ischemic diseases. |
| format | Article |
| id | doaj-art-c9a1c77ade8348988dd97d428588e83e |
| 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-c9a1c77ade8348988dd97d428588e83e2025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2435478Coactivation of Tie2 and Wnt signaling using an antibody–R-spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemiaByungtae Hwang0Min-Young Jeon1Ju-Hong Jang2Young-Lai Cho3Dong Gwang Lee4Jeong-Ki Min5Jangwook Lee6Jong-Gil Park7Ji-Hun Noh8Wonjun Yang9Nam-Kyung Lee10Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of KoreaBiotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of KoreaBiotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of KoreaEnvironmental Diseases Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of KoreaBiotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of KoreaBiotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of KoreaBiotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of KoreaBiotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of KoreaDepartment of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, Republic of KoreaBiotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of KoreaBiotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of KoreaTherapeutic angiogenesis by intentional formation of blood vessels is essential for treating various ischemic diseases, including limb ischemia. Because Wnt/β-catenin and angiopoietin-1/Tie2 signaling play important roles in endothelial survival and vascular stability, coactivation of these signaling pathways can potentially achieve therapeutic angiogenesis. In this study, we developed a bifunctional antibody fusion, consisting of a Tie2-agonistic antibody and the Furin domains of R-spondin 3 (RSPO3), to simultaneously activate Tie2 and Wnt/β-catenin signaling. We identified a Tie2-agonistic antibody T11 that cross-reacted with the extracellular domain of human and mouse Tie2, and evaluated its ability to increase endothelial cell survival and tube formation. We generated a bifunctional T11–RF12 by fusing T11 with the Furin-1 and −2 domains of RSPO3. T11–RF12 could bind not only to Tie2, but also to LGR5 and ZNRF3, which are counterparts of the Furin-1 and −2 domains. T11–RF12 significantly increased Wnt/β-catenin signaling, as well as the formation of capillary-like endothelial tubes, regardless of the presence of Wnt ligands. Coactivation of Tie2 and Wnt/β-catenin signaling by T11–RF12 increased the blood flow, and thereby reduced foot necrosis in a mouse hindlimb ischemia model. In particular, T11–RF12 induced therapeutic angiogenesis by promoting vessel stabilization through pericyte coverage and retaining endothelial expression of Frizzled 10 and active β-catenin. These results indicate that the agonistic synergism of Tie2 and Wnt/β-catenin signaling achieved using T11–RF12 is a novel therapeutic option with potential for treating limb ischemia and other ischemic diseases.https://www.tandfonline.com/doi/10.1080/19420862.2024.2435478Bifunctional antibodyhindlimb ischemiaR-spondintherapeutic angiogenesisTie2vessel stabilization |
| spellingShingle | Byungtae Hwang Min-Young Jeon Ju-Hong Jang Young-Lai Cho Dong Gwang Lee Jeong-Ki Min Jangwook Lee Jong-Gil Park Ji-Hun Noh Wonjun Yang Nam-Kyung Lee Coactivation of Tie2 and Wnt signaling using an antibody–R-spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemia mAbs Bifunctional antibody hindlimb ischemia R-spondin therapeutic angiogenesis Tie2 vessel stabilization |
| title | Coactivation of Tie2 and Wnt signaling using an antibody–R-spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemia |
| title_full | Coactivation of Tie2 and Wnt signaling using an antibody–R-spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemia |
| title_fullStr | Coactivation of Tie2 and Wnt signaling using an antibody–R-spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemia |
| title_full_unstemmed | Coactivation of Tie2 and Wnt signaling using an antibody–R-spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemia |
| title_short | Coactivation of Tie2 and Wnt signaling using an antibody–R-spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemia |
| title_sort | coactivation of tie2 and wnt signaling using an antibody r spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemia |
| topic | Bifunctional antibody hindlimb ischemia R-spondin therapeutic angiogenesis Tie2 vessel stabilization |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2435478 |
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