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A novel tetravalent bispecific antibody targeting programmed death 1 and tyrosine-protein kinase Met for treatment of gastric cancer

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Background Redirecting T cells to tumor cells using bispecific antibodies (BsAbs) is emerging as a potent cancer therapy. The main concept of this strategy is to cross-link tumor cells and T cells by simultaneously binding to cell surface tumor-associated antigen (TAA) and the CD3ƹ chain. However, immune checkpoint programmed cell death ligand-1 (PD-L1) on tumor cells or other myeloid cells upreglulated remarkablely after the treatment of CD3-binding BsAbs, leads to the generation of suppressed microenvironment for immune evasion and tumor progression. Although this resistance could be partially reversed by anti-PD-L1 treatment, targeting two pathways through one antibody-based molecule may provide a strategic advantage over the combination of BsAbs and immune checkpoint inhibitors. Methods We developed two novel BsAbs PD-1/c-Met DVD-Ig and IgG-scFv both targeting PD-1 to restore the immune effector function of T cells and engaging them to tumor cells via binding to cellular-mesenchymal to epithelial transition factor (c-Met). Binding activities, T cell activation and proliferation were analyzed by flow cytometry. Cell Cytotoxicity and cytokine release were measured using LDH release assay and ELISA, respectively. Anti-tumor response in vivo was evaluated by generate xenograft models in NOD-SCID mice. Results These bispecific antibodies exhibited effective antitumor activity against high- and low- c-Met-expressing gastric cancer cell lines in vitro and mediated strong tumor growth inhibition in human gastric cancer xenograft models. Conclusion The engagement of the PD-1/PD-L1 blockade to c-Met-overexpressing cancer cells is a promising strategy for the treatment of gastric cancer and potentially other malignancies.

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Funding

This work was supported financially by the National Key Research Project Bio-safety Key Technology Development Program 2016YFC1201501.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Fudan University, P.O. Box #238 No. 138 Yi Xue Yuan Road, Shanghai, China

    Weihua Hou, Qingyun Yuan, Xingxing Yuan, Yuxiong Wang, Wei Mo & Min Yu

  2. Department of Medical Oncology, Shanghai Cancer Center, School of Basic Medicine, Fudan University, P.O. Box #238 No. 138 Yi Xue Yuan Road, Shanghai, China

    Huijie Wang

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  1. Weihua Hou
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  2. Qingyun Yuan
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Correspondence to Huijie Wang or Min Yu.

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All procedures involving human blood products were in accordance with the 1964 Helsinki declaration and its later amendments. Study involving mice use was carried out according to the protocols approved by Institutional Animal Care and Use Committee of Fudan University.

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Hou, W., Yuan, Q., Yuan, X. et al. A novel tetravalent bispecific antibody targeting programmed death 1 and tyrosine-protein kinase Met for treatment of gastric cancer. Invest New Drugs 37, 876–889 (2019). https://doi.org/10.1007/s10637-018-0689-3

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