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A novel bispecific T-cell engager using the ligand-target csGRP78 against acute myeloid leukemia

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机构： [1]Department of Targeting Therapy & Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Diseaserelated Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China [2]Department of Hematology, Institute of Hematology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China

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关键词： Bispecific T-cell engagers csGRP78 AML Pep42

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Current medical therapies for treating acute myeloid leukemia (AML) remain unmet, and AML patients may benefit from targeted immunotherapy approaches that focus on specific tumor antigens. GRP78, which is upregulated in various malignant tumors such as AML, is partially expressed as cell surface GRP78 (csGRP78) on the cell membrane, making it an ideal target for redirecting T cells, including T-cell engagers. However, considering the conventional approach of using two scFv segments to construct a bispecific T-cell engager (BiTE), we have undertaken the development of a novel BiTE that utilizes a cyclic peptide ligand to specifically target csGRP78, which we refer to as GRP78-CD3/BiTE. We studied the effects of GRP78-CD3/BiTE on treatments for AML in vitro and in vivo and assessed the pharmacokinetics of this engager. Our findings demonstrated that GRP78-CD3/BiTE could not only effectively mediate the cytotoxicity of T cells against csGRP78-expressing AML cells but also specifically eliminate primary AML tumor cells in vitro. Furthermore, GRP78-CD3/BiTE exhibited a longer half-life despite having a lower molecular weight than CD19-CD3/BiTE. In a xenograft mouse model of AML, treatment with GRP78-CD3/BiTE prolonged the survival time of the mice. Our findings demonstrate that GRP78-CD3/BiTE is effective and selective for eliminating csGRP78-expressing AML cells and suggest that this approach to targeted immunotherapy could lead to effective new treatments for AML.© 2024. The Author(s).

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出版当年[2023]版：

大类 | 2 区

生物学

小类 | 2 区生化与分子生物学 2 区细胞生物学

最新[2023]版：

大类 | 2 区

生物学

小类 | 2 区生化与分子生物学 2 区细胞生物学

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第一作者机构： [1]Department of Targeting Therapy & Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Diseaserelated Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China

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A novel bispecific T-cell engager using the ligand-target csGRP78 against acute myeloid leukemia

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