Bispecific antibody simultaneously targeting PD1 and HER2 inhibits tumor growth via direct tumor cell killing in combination with PD1/PDL1 blockade and HER2 inhibition
Autor: | Zhenping Zhu, Haomin Huang, Gu Changling, Wei Xu, Xiao-Qing Meng, Kai Li, Lan Deng, Hai-Xia Zhu, Le Zhao, Yue-Qin Liu |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Receptor ErbB-2 Programmed Cell Death 1 Receptor Antigen presentation Mice Nude B7-H1 Antigen Mice 03 medical and health sciences 0302 clinical medicine Breast cancer Trastuzumab In vivo Cell Line Tumor Neoplasms Antibodies Bispecific Animals Humans Medicine Pharmacology (medical) Neoplasm Metastasis skin and connective tissue diseases Immune Checkpoint Inhibitors neoplasms Pharmacology Mice Inbred BALB C Cell Death business.industry General Medicine medicine.disease Xenograft Model Antitumor Assays Immunological Synapses In vitro Immune checkpoint Tumor Burden Blockade 030104 developmental biology 030220 oncology & carcinogenesis Cancer research Female business medicine.drug |
Zdroj: | Acta Pharmacologica Sinica. 43:672-680 |
ISSN: | 1745-7254 1671-4083 |
Popis: | Immune checkpoint blockade has shown significant clinical benefit in multiple cancer indications, but many patients are either refractory or become resistant to the treatment over time. HER2/neu oncogene overexpressed in invasive breast cancer patients associates with more aggressive diseases and poor prognosis. Anti-HER2 mAbs, such as trastuzumab, are currently the standard of care for HER2-overexpressing cancers, but the response rates are below 30% and patients generally suffer relapse within a year. In this study we developed a bispecific antibody (BsAb) simultaneously targeting both PD1 and HER2 in an attempt to combine HER2-targeted therapy with immune checkpoint blockade for treating HER2-positive solid tumors. The BsAb was constructed by fusing scFvs (anti-PD1) with the effector-functional Fc of an IgG (trastuzumab) via a flexible peptide linker. We showed that the BsAb bound to human HER2 and PD1 with high affinities (EC50 values were 0.2 and 0.14 nM, respectively), and exhibited potent antitumor activities in vitro and in vivo. Furthermore, we demonstrated that the BsAb exhibited both HER2 and PD1 blockade activities and was effective in killing HER2-positive tumor cells via antibody-dependent cellular cytotoxicity. In addition, the BsAb could crosslink HER2-positive tumor cells with T cells to form PD1 immunological synapses that directed tumor cell killing without the need of antigen presentation. Thus, the BsAb is a new promising approach for treating late-stage metastatic HER2-positive cancers. |
Databáze: | OpenAIRE |
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