VEGFR2-targeted antibody fused with IFNαmut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity
Although interferon α (IFNα) and anti-angiogenesis antibodies have shown appropriate clinical benefit in the treatment of malignant cancer, they are deficient in clinical applications. Previously, we described an anti-vascular endothelial growth factor receptor 2 (VEGFR2)-IFNα fusion protein named J...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-02-01
|
| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221138352030719X |
| _version_ | 1818615210617864192 |
|---|---|
| author | Pengzhao Shang Rui Gao Yijia Zhu Xiaorui Zhang Yang Wang Minji Guo Hui Peng Min Wang Juan Zhang |
| author_facet | Pengzhao Shang Rui Gao Yijia Zhu Xiaorui Zhang Yang Wang Minji Guo Hui Peng Min Wang Juan Zhang |
| author_sort | Pengzhao Shang |
| collection | DOAJ |
| description | Although interferon α (IFNα) and anti-angiogenesis antibodies have shown appropriate clinical benefit in the treatment of malignant cancer, they are deficient in clinical applications. Previously, we described an anti-vascular endothelial growth factor receptor 2 (VEGFR2)-IFNα fusion protein named JZA01, which showed increased in vivo half-life and reduced side effects compared with IFNα, and it was more effective than the anti-VEGFR2 antibody against tumors. However, the affinity of the IFNα component of the fusion protein for its receptor-IFNAR1 was decreased. To address this problem, an IFNα-mutant fused with anti-VEGFR2 was designed to produce anti-VEGFR2-IFNαmut, which was used to target VEGFR2 with enhanced anti-tumor and anti-metastasis efficacy. Anti-VEGFR2-IFNαmut specifically inhibited proliferation of tumor cells and promoted apoptosis. In addition, anti-VEGFR2-IFNαmut inhibited migration of colorectal cancer cells and invasion by regulating the PI3K–AKT–GSK3β–snail signal pathway. Anti-VEGFR2-IFNαmut showed superior anti-tumor efficacy with improved tumor microenvironment (TME) by enhancing dendritic cell maturation, dendritic cell activity, and increasing tumor-infiltrating CD8+ T cells. Thus, this study provides a novel approach for the treatment of metastatic colorectal cancer, and this design may become a new approach to cancer immunotherapy. |
| first_indexed | 2024-12-16T16:30:17Z |
| format | Article |
| id | doaj.art-4f0ae32b98654f878f7a2dd3cb3e52bb |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-16T16:30:17Z |
| publishDate | 2021-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-4f0ae32b98654f878f7a2dd3cb3e52bb2022-12-21T22:24:37ZengElsevierActa Pharmaceutica Sinica B2211-38352021-02-01112420433VEGFR2-targeted antibody fused with IFNαmut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activityPengzhao Shang0Rui Gao1Yijia Zhu2Xiaorui Zhang3Yang Wang4Minji Guo5Hui Peng6Min Wang7Juan Zhang8Antibody Engineering Laboratory, School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, ChinaAntibody Engineering Laboratory, School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, ChinaAntibody Engineering Laboratory, School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, ChinaAntibody Engineering Laboratory, School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, ChinaAntibody Engineering Laboratory, School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, ChinaAntibody Engineering Laboratory, School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, ChinaDepartment of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin 300050, ChinaAntibody Engineering Laboratory, School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, ChinaAntibody Engineering Laboratory, School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, China; Corresponding author.Although interferon α (IFNα) and anti-angiogenesis antibodies have shown appropriate clinical benefit in the treatment of malignant cancer, they are deficient in clinical applications. Previously, we described an anti-vascular endothelial growth factor receptor 2 (VEGFR2)-IFNα fusion protein named JZA01, which showed increased in vivo half-life and reduced side effects compared with IFNα, and it was more effective than the anti-VEGFR2 antibody against tumors. However, the affinity of the IFNα component of the fusion protein for its receptor-IFNAR1 was decreased. To address this problem, an IFNα-mutant fused with anti-VEGFR2 was designed to produce anti-VEGFR2-IFNαmut, which was used to target VEGFR2 with enhanced anti-tumor and anti-metastasis efficacy. Anti-VEGFR2-IFNαmut specifically inhibited proliferation of tumor cells and promoted apoptosis. In addition, anti-VEGFR2-IFNαmut inhibited migration of colorectal cancer cells and invasion by regulating the PI3K–AKT–GSK3β–snail signal pathway. Anti-VEGFR2-IFNαmut showed superior anti-tumor efficacy with improved tumor microenvironment (TME) by enhancing dendritic cell maturation, dendritic cell activity, and increasing tumor-infiltrating CD8+ T cells. Thus, this study provides a novel approach for the treatment of metastatic colorectal cancer, and this design may become a new approach to cancer immunotherapy.http://www.sciencedirect.com/science/article/pii/S221138352030719XAnti-VEGFR2IFNαmutTumor microenvironmentColorectal cancerLiver metastasisCancer immunotherapy |
| spellingShingle | Pengzhao Shang Rui Gao Yijia Zhu Xiaorui Zhang Yang Wang Minji Guo Hui Peng Min Wang Juan Zhang VEGFR2-targeted antibody fused with IFNαmut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity Acta Pharmaceutica Sinica B Anti-VEGFR2 IFNαmut Tumor microenvironment Colorectal cancer Liver metastasis Cancer immunotherapy |
| title | VEGFR2-targeted antibody fused with IFNαmut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity |
| title_full | VEGFR2-targeted antibody fused with IFNαmut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity |
| title_fullStr | VEGFR2-targeted antibody fused with IFNαmut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity |
| title_full_unstemmed | VEGFR2-targeted antibody fused with IFNαmut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity |
| title_short | VEGFR2-targeted antibody fused with IFNαmut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity |
| title_sort | vegfr2 targeted antibody fused with ifnαmut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti tumor and anti metastasis activity |
| topic | Anti-VEGFR2 IFNαmut Tumor microenvironment Colorectal cancer Liver metastasis Cancer immunotherapy |
| url | http://www.sciencedirect.com/science/article/pii/S221138352030719X |
| work_keys_str_mv | AT pengzhaoshang vegfr2targetedantibodyfusedwithifnamutregulatesthetumormicroenvironmentofcolorectalcancerandexhibitspotentantitumorandantimetastasisactivity AT ruigao vegfr2targetedantibodyfusedwithifnamutregulatesthetumormicroenvironmentofcolorectalcancerandexhibitspotentantitumorandantimetastasisactivity AT yijiazhu vegfr2targetedantibodyfusedwithifnamutregulatesthetumormicroenvironmentofcolorectalcancerandexhibitspotentantitumorandantimetastasisactivity AT xiaoruizhang vegfr2targetedantibodyfusedwithifnamutregulatesthetumormicroenvironmentofcolorectalcancerandexhibitspotentantitumorandantimetastasisactivity AT yangwang vegfr2targetedantibodyfusedwithifnamutregulatesthetumormicroenvironmentofcolorectalcancerandexhibitspotentantitumorandantimetastasisactivity AT minjiguo vegfr2targetedantibodyfusedwithifnamutregulatesthetumormicroenvironmentofcolorectalcancerandexhibitspotentantitumorandantimetastasisactivity AT huipeng vegfr2targetedantibodyfusedwithifnamutregulatesthetumormicroenvironmentofcolorectalcancerandexhibitspotentantitumorandantimetastasisactivity AT minwang vegfr2targetedantibodyfusedwithifnamutregulatesthetumormicroenvironmentofcolorectalcancerandexhibitspotentantitumorandantimetastasisactivity AT juanzhang vegfr2targetedantibodyfusedwithifnamutregulatesthetumormicroenvironmentofcolorectalcancerandexhibitspotentantitumorandantimetastasisactivity |