We are analyzing https://link.springer.com/article/10.1186/s13045-023-01487-5.

Title:
Synergistic efficacy of simultaneous anti-TGF-β/VEGF bispecific antibody and PD-1 blockade in cancer therapy | Journal of Hematology & Oncology
Description:
Background Recently, therapeutic antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have exerted potent anticancer effect in a variety of tumors. However, blocking the PD-1/PD-L1 axis alone is not sufficient to restore normal immune response. Other negative regulators of antitumor immunity, like TGF-β and VEGFA, are also involved in immune escape of tumor cells and induce immunotherapy resistance. Methods We developed a novel anti-TGF-β/VEGF bispecific antibody Y332D based on the Nano-YBODY™ technology platform. The CCK-8, flow cytometry, SBE4 luciferase reporter assay, western blotting and transwell assays were used to measure the biological activities of the anti-TGF-β moiety. The NFAT luciferase reporter assay, luminescent cell viability assay and tube formation assay were used to measure the biological activities of the anti-VEGF moiety. The in vivo anticancer efficacy of Y332D alone or in combination with PD-1 blockade was evaluated in H22, EMT-6, 4T1, and AKT/Ras-driven murine hepatocellular carcinoma tumor models. Immunofluorescent staining, flow cytometry, RNA-seq and quantitative RT-PCR were adopted to analyze the alterations in the tumor microenvironment. Results Y332D could maintain specific binding affinities for TGF-β and VEGFA. Y332D almost entirely counteracted the in vitro biological functions of TGF-β and VEGFA, including immunosuppression, activated TGF-β signaling, epithelial-mesenchymal transition (EMT), activated VEGF/VEGFR signaling, HUVEC proliferation and tube formation. The in vivo experiment data demonstrated that Y332D was more effective in inhibiting tumor growth and metastasis than anti-TGF-β and anti-VEGF monotherapies. In combination therapies, Y332D plus PD-1 blockade exhibited the most potent and durable anticancer effect. Mechanistically, Y332D plus PD-1 blockade upregulated the density and function of tumor-infiltrating lymphocytes and exerted reinvigorated antitumor immunity. Conclusion Y332D could simultaneously block TGF-β and VEGF signalings. In comparison with the monotherapies, Y332D combined with PD-1 blockade exerts superior antitumor effect through improving immune microenvironment.
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tumor, pubmed, cells, tgfβ, article, cell, google, scholar, cas, assay, fig, central, cancer, antipd, mice, immune, antivegf, therapy, antibodies, antibody, antitgfβ, combination, antitumor, vegf, murine, vegfa, treatment, effect, model, binding, emt, signaling, blockade, expression, performed, αpd, plates, day, bispecific, tumors, data, carcinoma, activity, staining, min, mgkg, pdpdl, hepatocellular, microenvironment, significantly,

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secondary antibodies goat-anti-rabbit-igg-hrp anti-vegf/tgf-β bispecific antibody anti-tgf-β single-domain antibody tgf-β-regulated epithelial-mesenchymal transition reversed tgf-β-induced emt tgf-β/smad signaling pathway anti-tgf-β targeting drugs parent anti-tgf-β antibody tgf-β1-caused cytokine secretion anti-pd-1/pd-l1 monotherapy [57 targeting pd-1/pd-l1 pathway immune-negative signals tgf-β anti-tgf-β significantly decreased nano-body™ platform-based development blocking pd-1/pd-l1 signaling anti-pd-1/pd-l1 therapy emt-related markers e-cadherin /programmed death-ligand 1 including anti-e-cadherin staining anti-vascular targeting drugs anti-vegf termini due oncology meets immunology article download pdf tgf-β-regulated emt controlling vegf/vegfr2 signaling tgf-β signaling pathway immunomodulatory tgf-β signaling real-time rt-pcr tgf-β/smad pathway tgf-β-mediated immunosuppression liquid chromatograph-mass spectrometer tgf-β pathway antagonists bispecific antibody targeting pd-l1 triple blockage antigen–antibody binding ratio plasmid encoding myr-akt1 pro-tumor m2 tumor parent anti-vegf antibody myeloid-derived suppressor cell advanced hepatocellular carcinoma tgf-β1-hampered proliferation biotin labeling kit-nh2 prepare single-cell suspensions pd-1/pd-l1 axis soluble pd-1/pd-l1 anti-pd-1 therapy enhanced unresectable hepatocellular carcinoma transcription factor downstream multiple immune-related genes blocking tgf-β signaling

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Targeting tumor interstitial fluid pressure: Will it yield novel successful therapies for solid tumors?

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         headline:Synergistic efficacy of simultaneous anti-TGF-β/VEGF bispecific antibody and PD-1 blockade in cancer therapy
         description:Recently, therapeutic antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have exerted potent anticancer effect in a variety of tumors. However, blocking the PD-1/PD-L1 axis alone is not sufficient to restore normal immune response. Other negative regulators of antitumor immunity, like TGF-β and VEGFA, are also involved in immune escape of tumor cells and induce immunotherapy resistance. We developed a novel anti-TGF-β/VEGF bispecific antibody Y332D based on the Nano-YBODY™ technology platform. The CCK-8, flow cytometry, SBE4 luciferase reporter assay, western blotting and transwell assays were used to measure the biological activities of the anti-TGF-β moiety. The NFAT luciferase reporter assay, luminescent cell viability assay and tube formation assay were used to measure the biological activities of the anti-VEGF moiety. The in vivo anticancer efficacy of Y332D alone or in combination with PD-1 blockade was evaluated in H22, EMT-6, 4T1, and AKT/Ras-driven murine hepatocellular carcinoma tumor models. Immunofluorescent staining, flow cytometry, RNA-seq and quantitative RT-PCR were adopted to analyze the alterations in the tumor microenvironment. Y332D could maintain specific binding affinities for TGF-β and VEGFA. Y332D almost entirely counteracted the in vitro biological functions of TGF-β and VEGFA, including immunosuppression, activated TGF-β signaling, epithelial-mesenchymal transition (EMT), activated VEGF/VEGFR signaling, HUVEC proliferation and tube formation. The in vivo experiment data demonstrated that Y332D was more effective in inhibiting tumor growth and metastasis than anti-TGF-β and anti-VEGF monotherapies. In combination therapies, Y332D plus PD-1 blockade exhibited the most potent and durable anticancer effect. Mechanistically, Y332D plus PD-1 blockade upregulated the density and function of tumor-infiltrating lymphocytes and exerted reinvigorated antitumor immunity. Y332D could simultaneously block TGF-β and VEGF signalings. In comparison with the monotherapies, Y332D combined with PD-1 blockade exerts superior antitumor effect through improving immune microenvironment.
         datePublished:2023-08-12T00:00:00Z
         dateModified:2023-08-12T00:00:00Z
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            VEGF
            Bispecific antibody
            PD-1
            Cancer immunotherapy
            The tumor microenvironment
            Oncology
            Hematology
            Cancer Research
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      description:Recently, therapeutic antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have exerted potent anticancer effect in a variety of tumors. However, blocking the PD-1/PD-L1 axis alone is not sufficient to restore normal immune response. Other negative regulators of antitumor immunity, like TGF-β and VEGFA, are also involved in immune escape of tumor cells and induce immunotherapy resistance. We developed a novel anti-TGF-β/VEGF bispecific antibody Y332D based on the Nano-YBODY™ technology platform. The CCK-8, flow cytometry, SBE4 luciferase reporter assay, western blotting and transwell assays were used to measure the biological activities of the anti-TGF-β moiety. The NFAT luciferase reporter assay, luminescent cell viability assay and tube formation assay were used to measure the biological activities of the anti-VEGF moiety. The in vivo anticancer efficacy of Y332D alone or in combination with PD-1 blockade was evaluated in H22, EMT-6, 4T1, and AKT/Ras-driven murine hepatocellular carcinoma tumor models. Immunofluorescent staining, flow cytometry, RNA-seq and quantitative RT-PCR were adopted to analyze the alterations in the tumor microenvironment. Y332D could maintain specific binding affinities for TGF-β and VEGFA. Y332D almost entirely counteracted the in vitro biological functions of TGF-β and VEGFA, including immunosuppression, activated TGF-β signaling, epithelial-mesenchymal transition (EMT), activated VEGF/VEGFR signaling, HUVEC proliferation and tube formation. The in vivo experiment data demonstrated that Y332D was more effective in inhibiting tumor growth and metastasis than anti-TGF-β and anti-VEGF monotherapies. In combination therapies, Y332D plus PD-1 blockade exhibited the most potent and durable anticancer effect. Mechanistically, Y332D plus PD-1 blockade upregulated the density and function of tumor-infiltrating lymphocytes and exerted reinvigorated antitumor immunity. Y332D could simultaneously block TGF-β and VEGF signalings. In comparison with the monotherapies, Y332D combined with PD-1 blockade exerts superior antitumor effect through improving immune microenvironment.
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      dateModified:2023-08-12T00:00:00Z
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      keywords:
         TGF-β
         VEGF
         Bispecific antibody
         PD-1
         Cancer immunotherapy
         The tumor microenvironment
         Oncology
         Hematology
         Cancer Research
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      name:Mengke Niu
      affiliation:
            name:Huazhong University of Science and Technology
            address:
               name:Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
               type:PostalAddress
            type:Organization
      name:Ming Yi
      affiliation:
            name:Huazhong University of Science and Technology
            address:
               name:Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
               type:PostalAddress
            type:Organization
            name:Zhejiang University
            address:
               name:Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
               type:PostalAddress
            type:Organization
      name:Yuze Wu
      affiliation:
            name:Huazhong University of Science and Technology
            address:
               name:Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
               type:PostalAddress
            type:Organization
      name:Lijuan Lyu
      affiliation:
            name:The Second Affiliated Hospital of Xi’an Jiaotong University
            address:
               name:Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
               type:PostalAddress
            type:Organization
      name:Qing He
      affiliation:
            name:Wuhan YZY Biopharma Co., Ltd
            address:
               name:Wuhan YZY Biopharma Co., Ltd, Wuhan, People’s Republic of China
               type:PostalAddress
            type:Organization
      name:Rui Yang
      affiliation:
            name:Wuhan YZY Biopharma Co., Ltd
            address:
               name:Wuhan YZY Biopharma Co., Ltd, Wuhan, People’s Republic of China
               type:PostalAddress
            type:Organization
      name:Liang Zeng
      affiliation:
            name:Wuhan YZY Biopharma Co., Ltd
            address:
               name:Wuhan YZY Biopharma Co., Ltd, Wuhan, People’s Republic of China
               type:PostalAddress
            type:Organization
      name:Jian Shi
      affiliation:
            name:Wuhan YZY Biopharma Co., Ltd
            address:
               name:Wuhan YZY Biopharma Co., Ltd, Wuhan, People’s Republic of China
               type:PostalAddress
            type:Organization
      name:Jing Zhang
      affiliation:
            name:Wuhan YZY Biopharma Co., Ltd
            address:
               name:Wuhan YZY Biopharma Co., Ltd, Wuhan, People’s Republic of China
               type:PostalAddress
            type:Organization
      name:Pengfei Zhou
      affiliation:
            name:Wuhan YZY Biopharma Co., Ltd
            address:
               name:Wuhan YZY Biopharma Co., Ltd, Wuhan, People’s Republic of China
               type:PostalAddress
            type:Organization
      name:Tingting Zhang
      affiliation:
            name:Third Hospital of Shanxi Medical University
            address:
               name:Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
               type:PostalAddress
            type:Organization
      name:Qi Mei
      affiliation:
            name:Huazhong University of Science and Technology
            address:
               name:Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
               type:PostalAddress
            type:Organization
            name:Third Hospital of Shanxi Medical University
            address:
               name:Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Qian Chu
      affiliation:
            name:Huazhong University of Science and Technology
            address:
               name:Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Kongming Wu
      affiliation:
            name:Third Hospital of Shanxi Medical University
            address:
               name:Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
               type:PostalAddress
            type:Organization
            name:Huazhong University of Science and Technology
            address:
               name:Cancer Center, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
      name:Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
      name:Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
      name:Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
      name:Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
      name:Wuhan YZY Biopharma Co., Ltd, Wuhan, People’s Republic of China
      name:Wuhan YZY Biopharma Co., Ltd, Wuhan, People’s Republic of China
      name:Wuhan YZY Biopharma Co., Ltd, Wuhan, People’s Republic of China
      name:Wuhan YZY Biopharma Co., Ltd, Wuhan, People’s Republic of China
      name:Wuhan YZY Biopharma Co., Ltd, Wuhan, People’s Republic of China
      name:Wuhan YZY Biopharma Co., Ltd, Wuhan, People’s Republic of China
      name:Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
      name:Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
      name:Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
      name:Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
      name:Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
      name:Cancer Center, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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