Nanobody-based trispecific T cell engager (Nb-TriTE) enhances therapeutic efficacy by overcoming tumor-mediated immunosuppression

Author:

Ding Ziqiang,Sun Shuyang,Wang Xuan,Yang Xiaomei,Shi Wei,Huang Xianing,Xie Shenxia,Mo Fengzhen,Hou Xiaoqiong,Liu Aiqun,Jiang Xiaobing,Tang Zhuoran,Lu Xiaoling

Abstract

Abstract Background T cell engagers (TCEs) have been established as an emerging modality for hematologic malignancies, but solid tumors remain refractory. However, the upregulation of programmed cell death 1 (PD-1) is correlated with T cell dysfunction that confer tumor-mediated immunosuppression. Developing a novel nanobody-based trispecific T cell engager (Nb-TriTE) would be a potential strategy to improve therapeutic efficacy. Methods Given the therapeutic potential of nanobodies (Nbs), we first screened Nb targeting fibroblast activation protein (FAP) and successfully generated a Nb-based bispecific T cell engager (Nb-BiTE) targeting FAP. Then, we developed a Nb-TriTE by fusing an anti-PD-1 Nb to the Nb-BiTE. The biological activity and antitumor efficacy of the Nb-TriTE were evaluated in vitro and in both cell line-derived and patient-derived xenograft mouse models. Results We had for the first time successfully selected a FAP Nb for the generation of novel Nb-BiTE and Nb-TriTE, which showed good binding ability to their targets. Nb-TriTE not only induced robust tumor antigen-specific killing, potent T cell activation and enhanced T cell function in vitro, but also suppressed tumor growth, improved survival and mediated more T cell infiltration than Nb-BiTE in mouse models of different solid tumors without toxicity. Conclusions This novel Nb-TriTE provides a promising and universal platform to overcome tumor-mediated immunosuppression and improve patient outcomes in the future.

Funder

National Natural Science Foundation of China

Guangxi Key Research and Development Program

National Key Research and Development Program of China

Guangxi Key Laboratory of Nanobody Research

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology,Molecular Biology,Hematology

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