NDLI: Construction of CD19 targeted dual- and enhanced dual-antibodies and their efficiency in the treatment of B cell malignancy

Content Provider	Springer Nature : BioMed Central
Author	Chen, Manling Liu, Xiaoyu Peng, Nan Zhang, Ting Mou, Junli He, Huizhen Wang, Ying Xu, Yingxi Xing, Haiyan Tang, Kejing Tian, Zheng Rao, Qing Gu, Runxia Qiu, Shaowei Wang, Min Wang, Jianxiang
Abstract	Background T cell-redirecting bispecific antibodies establish a connection between endogenous T cells and tumor cells, activating T cells function to eliminate tumor cells without ex vivo genetic alteration or manipulation. Here, we developed a novel dual-specific antibody (DuAb) and an enhanced DuAb (EDuAb) with different stimulation signal to activate T cells, and evaluated their impact on the treatment of acute lymphoblastic leukemia (ALL). Methods The expression plasmids of the DuAb and EDuAb containing CD80 molecule were constructed by cloning heavy chain and light chain variable fragments from anti-human CD19 (HI19a) and CD3 (HIT3a) monoclonal antibody hybridomas, respectively. The activation and the anti-tumor efficacy of human T cells mediated by DuAb and EDuAb were evaluated in vitro. B-cell ALL xenograft NSG mouse model was established to investigate the therapeutic effect in vivo. Results EDuAb promoted the optimal expansion of primary human T cells with low expression of inhibitory markers in vitro than DuAb did. Both DuAb and EDuAb showed a similar capability in inducing healthy donor T cells to specifically eliminate B-ALL cell lines and primary blasts from patients. The similar ability was also observed in the patient-derived T cells. In vivo study showed that both DuAb and EDuAb significantly alleviated tumor burden and extended survival of B-ALL xenograft NSG mice. The median survival of PBS, DuAb and EDuAb treatment groups were 27, 38 and 45 days, respectively. The phenotype of T cells and cytokine release in peripheral blood (PB) of B-ALL xenograft NSG mice on day 24 were analyzed as well. The results showed that the proportion of CD8+ T cells and cytokine levels, including IL-2, IFN-γ and TNF-α, were higher in the EDuAb group than that of DuAb. Moreover, both DuAb and EDuAb significantly decreased the residual leukemia cells in PB of B-ALL xenograft NSG mice. Conclusions Both DuAb and EDuAb showed great potential as novel treatments for B-ALL in clinical applications. However, compared to DuAb, EDuAb showed a significant advantage in promoting the proliferation and survival of T cells. Furthermore, EDuAb showed a better promising effect on eliminating tumor cells and extending survival in vivo, which provides new insights for the development of new multi-specific antibodies.
Related Links	https://ehoonline.biomedcentral.com/counter/pdf/10.1186/s40164-023-00423-0.pdf
Ending Page	15
Page Count	15
Starting Page	1
File Format	HTM / HTML
ISSN	21623619
DOI	10.1186/s40164-023-00423-0
Journal	Experimental Hematology & Oncology
Issue Number	1
Volume Number	12
Language	English
Publisher	BioMed Central
Publisher Date	2023-07-24
Access Restriction	Open
Subject Keyword	Hematology Oncology Cancer Research CD19 B-ALL Dual-specific antibody Immunotherapy
Content Type	Text
Resource Type	Article
Subject	Hematology Oncology Cancer Research
Journal Impact Factor	9.4/2023
5-Year Journal Impact Factor	8.3/2023

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