Enhanced anti-angiogenetic effect of transferrin receptor-mediated delivery of VEGF-trap in a glioblastoma mouse model
Glioblastoma (GBM) is a common and aggressive brain cancer that accounts for 60% of adult brain tumors. Anti-angiogenesis therapy is an attractive option due to the high vasculature density of GBM. However, the best-known anti-angiogenic therapeutics, bevacizumab, and aflibercept, have failed to sho...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2022-12-01
|
| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2022.2057269 |
| _version_ | 1828291164896231424 |
|---|---|
| author | Peng Zhao Yasuaki Anami Peng Gao Xuejun Fan Leike Li Kyoji Tsuchikama Ningyan Zhang Zhiqiang an |
| author_facet | Peng Zhao Yasuaki Anami Peng Gao Xuejun Fan Leike Li Kyoji Tsuchikama Ningyan Zhang Zhiqiang an |
| author_sort | Peng Zhao |
| collection | DOAJ |
| description | Glioblastoma (GBM) is a common and aggressive brain cancer that accounts for 60% of adult brain tumors. Anti-angiogenesis therapy is an attractive option due to the high vasculature density of GBM. However, the best-known anti-angiogenic therapeutics, bevacizumab, and aflibercept, have failed to show significant benefits in GBM patients. One of the reasons is the limited brain penetration of antibody-based therapies due to existence of the blood–brain barrier (BBB), which is further strengthened by the blood vessel normalization effects induced by anti-angiogenic therapies. To investigate if increased drug concentration in the brain by transferrin receptor (TfR)-mediated delivery across the BBB can enhance efficacy of anti-angiogenic antibody therapies, we first identified an antibody that binds to the apical domain of the mouse TfR and does not compete with the natural ligand transferrin (Tf) binding to TfR. Then, we engineered two bispecific antibodies fusing a vascular endothelial growth factor (VEGF)-Trap with the TfR-targeting antibody. Characterization of the two bispecific formats using multiple in vitro assays, which include endocytosis, cell surface and whole-cell TfR levels, human umbilical vein endothelial cell growth inhibition, and binding affinity, demonstrated that the VEGF-Trap fused with a monovalent αTfR (VEGF-Trap/moAb4) has desirable endocytosis without the induction of TfR degradation. Peripherally administered VEGF-Trap/moAb4 improved the brain concentration of VEGF-Trap by more than 10-fold in mice. The distribution of VEGF-Trap/moAb4 was validated to be in the brain parenchyma, indicating the molecule was not trapped inside the vasculature. Moreover, improved VEGF-Trap brain distribution significantly inhibited the angiogenesis of U-87 MG GBM tumors in a mouse model. |
| first_indexed | 2024-04-13T10:47:56Z |
| format | Article |
| id | doaj.art-605dbefac98a4efba2de6c9aa8c56cc8 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-04-13T10:47:56Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-605dbefac98a4efba2de6c9aa8c56cc82022-12-22T02:49:44ZengTaylor & Francis GroupmAbs1942-08621942-08702022-12-0114110.1080/19420862.2022.2057269Enhanced anti-angiogenetic effect of transferrin receptor-mediated delivery of VEGF-trap in a glioblastoma mouse modelPeng Zhao0Yasuaki Anami1Peng Gao2Xuejun Fan3Leike Li4Kyoji Tsuchikama5Ningyan Zhang6Zhiqiang an7Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USATexas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USATexas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USATexas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USATexas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USATexas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USATexas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USATexas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, Texas, USAGlioblastoma (GBM) is a common and aggressive brain cancer that accounts for 60% of adult brain tumors. Anti-angiogenesis therapy is an attractive option due to the high vasculature density of GBM. However, the best-known anti-angiogenic therapeutics, bevacizumab, and aflibercept, have failed to show significant benefits in GBM patients. One of the reasons is the limited brain penetration of antibody-based therapies due to existence of the blood–brain barrier (BBB), which is further strengthened by the blood vessel normalization effects induced by anti-angiogenic therapies. To investigate if increased drug concentration in the brain by transferrin receptor (TfR)-mediated delivery across the BBB can enhance efficacy of anti-angiogenic antibody therapies, we first identified an antibody that binds to the apical domain of the mouse TfR and does not compete with the natural ligand transferrin (Tf) binding to TfR. Then, we engineered two bispecific antibodies fusing a vascular endothelial growth factor (VEGF)-Trap with the TfR-targeting antibody. Characterization of the two bispecific formats using multiple in vitro assays, which include endocytosis, cell surface and whole-cell TfR levels, human umbilical vein endothelial cell growth inhibition, and binding affinity, demonstrated that the VEGF-Trap fused with a monovalent αTfR (VEGF-Trap/moAb4) has desirable endocytosis without the induction of TfR degradation. Peripherally administered VEGF-Trap/moAb4 improved the brain concentration of VEGF-Trap by more than 10-fold in mice. The distribution of VEGF-Trap/moAb4 was validated to be in the brain parenchyma, indicating the molecule was not trapped inside the vasculature. Moreover, improved VEGF-Trap brain distribution significantly inhibited the angiogenesis of U-87 MG GBM tumors in a mouse model.https://www.tandfonline.com/doi/10.1080/19420862.2022.2057269Bispecific antibodytransferrin receptorBBBGBMangiogenesis |
| spellingShingle | Peng Zhao Yasuaki Anami Peng Gao Xuejun Fan Leike Li Kyoji Tsuchikama Ningyan Zhang Zhiqiang an Enhanced anti-angiogenetic effect of transferrin receptor-mediated delivery of VEGF-trap in a glioblastoma mouse model mAbs Bispecific antibody transferrin receptor BBB GBM angiogenesis |
| title | Enhanced anti-angiogenetic effect of transferrin receptor-mediated delivery of VEGF-trap in a glioblastoma mouse model |
| title_full | Enhanced anti-angiogenetic effect of transferrin receptor-mediated delivery of VEGF-trap in a glioblastoma mouse model |
| title_fullStr | Enhanced anti-angiogenetic effect of transferrin receptor-mediated delivery of VEGF-trap in a glioblastoma mouse model |
| title_full_unstemmed | Enhanced anti-angiogenetic effect of transferrin receptor-mediated delivery of VEGF-trap in a glioblastoma mouse model |
| title_short | Enhanced anti-angiogenetic effect of transferrin receptor-mediated delivery of VEGF-trap in a glioblastoma mouse model |
| title_sort | enhanced anti angiogenetic effect of transferrin receptor mediated delivery of vegf trap in a glioblastoma mouse model |
| topic | Bispecific antibody transferrin receptor BBB GBM angiogenesis |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2022.2057269 |
| work_keys_str_mv | AT pengzhao enhancedantiangiogeneticeffectoftransferrinreceptormediateddeliveryofvegftrapinaglioblastomamousemodel AT yasuakianami enhancedantiangiogeneticeffectoftransferrinreceptormediateddeliveryofvegftrapinaglioblastomamousemodel AT penggao enhancedantiangiogeneticeffectoftransferrinreceptormediateddeliveryofvegftrapinaglioblastomamousemodel AT xuejunfan enhancedantiangiogeneticeffectoftransferrinreceptormediateddeliveryofvegftrapinaglioblastomamousemodel AT leikeli enhancedantiangiogeneticeffectoftransferrinreceptormediateddeliveryofvegftrapinaglioblastomamousemodel AT kyojitsuchikama enhancedantiangiogeneticeffectoftransferrinreceptormediateddeliveryofvegftrapinaglioblastomamousemodel AT ningyanzhang enhancedantiangiogeneticeffectoftransferrinreceptormediateddeliveryofvegftrapinaglioblastomamousemodel AT zhiqiangan enhancedantiangiogeneticeffectoftransferrinreceptormediateddeliveryofvegftrapinaglioblastomamousemodel |