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

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.

• Authors: Ziqiang Ding, Shuyang Sun, Xuan Wang, Xiaomei Yang, Wei Shi, Xianing Huang, Shenxia Xie, Fengzhen Mo, Xiaoqiong Hou, Aiqun Liu, Xiaobing Jiang, Zhuoran Tang, Xiaoling Lu
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 16 Issue 1 Pg. 115 (11 29 2023) ISSN: 1756-8722 [Electronic] England
• PMID: 38031188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• Niobium
• Antibodies, Bispecific

Topics

• Humans
• Mice
• Animals
• Niobium (metabolism)
• Neoplasms (therapy)
• Immunosuppression Therapy
• T-Lymphocytes
• Immune Tolerance
• Antibodies, Bispecific (pharmacology, therapeutic use, metabolism)