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Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific antibodies against B-cell acute lymphoblastic leukemia:targeted immunotherapy for acute lymphoblastic leukemia

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Frontiers of Medicine 2022年第1期16卷 139-149页

作者： Sisi Wang Lijun Peng Wenqian Xu Yuebo Zhou Ziyan Zhu Yushan Kong Stewart Leung Jin Wang Xiaoqiang Yan Jian-Qing Mi Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China Pôle Franco-Chinois de Recherche en Sciences du Vivant et Genomique Shanghai 200025China Shanghai Blood Center Shanghai 200051China Generon Biomed Shanghai 201210China

The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic ***,several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight,and thus its clinical use is ***,multiple trials have shown that approximately 30%of blinatumomab-relapsed cases are characterized by CD19 negative leukemic ***,we design and characterize two novel antibodies,A-319 and *** and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures,and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 *** in vitro,ex vivo,and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells,enhancing T-cell function,mediating B-cell depletion,and eventually inhibiting tumor growth in Raji xenograft *** two molecules are complementary in terms of efficacy and specificity *** activity of A-319 demonstrated superior to that of A-2019,whereas A-2019 has an additional capability to target CD20 in cells missing CD19,suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.

关键词： B-cell acute lymphoblastic leukemia bispecific antibody trispecific antibody CD19 CD20

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trispecific killer engager 161519 enhances natural killer cell function and provides anti-tumor activity against CD19-positive cancers

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Cancer Biology & Medicine 2020年第4期17卷 1026-1038页

作者： Ying Cheng Xiaodong Zheng Xuefu Wang Yongyan Chen Haiming Wei Rui Sun Zhigang Tian Haoyu Sun Hefei National Laboratory for Physical Sciences at Microscale The CAS Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Sciences and MedicineInstitute of ImmunologyUniversity of Science and Technology of ChinaHefei 230027China Research Unit of NK Cell Study Chinese Academy of Medical SciencesBeijing 100864China

Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic ***:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and *** TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK ***:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK *** cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 *** use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 ***:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor *** 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.

关键词： trispecific antibody trispecific killer engager(TriKE) NK cell B-cell lymphoma tumor immunotherapy

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trispecific killer engager 161519 enhances natural killer cell function and provides anti-tumor activity against CD19-positive cancers

Trispecific killer engager 161519 enhances natural killer ce...

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第十四届全国免疫学学术大会

作者： Ying Cheng Rui Sun Haoyu Sun Zhigang Tian University of Science and Technology of China

Objective:Natural killer(NK) cells have gained considerable attention due to their potential in treating "cold tumors," and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic ***:We constructed a trispecific killer engager(TriKE) consisting of anti-CD16,IL-1 5,and *** TriKE was designed to attract CD19 tumor cells to CD16 NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK ***:Treatment with 161519 TriKE in the presence of CD19 targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK *** cells "armed" with 161519 TriKE showed stronger cytolysis against CD19 targets compared with that of "unarmed" NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 *** use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 ***:The newly generated 16151 9 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19 tumor *** 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.

关键词： trispecific antibody trispecific killer engager(TriKE) NK cell B-cell lymphoma tumor immunotherapy

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