Nanobody-based bispecific T-cell engager (Nb-BiTE): a new platform for enhanced T-cell immunotherapy
Xiaomei Yang, Xuandong Lin, Wei Shi, Shenxia Xie, Xianing Huang, Shihua Yin, Xiaobing Jiang, Bruce D. Hammock, Zhi Ping Xu, Xiaoling Lü
Abstract
A novel bispecific T-cell engager (BiTE) has been developed as an efficient immunotherapeutic molecule specifically bringing the T-cell and the tumor target together for enhanced immunotherapy. The general BiTE construct consists of two single-chain variable antibody fragments (scFvs) targeting a tumor-associated antigen (TAA) and a T-cell marker in tandem. The binding of BiTEs to tumor antigens induces immediate T-cells’ cytotoxicity against tumor cells without involving any typical costimulatory signals, specific TCR and MHC recognition. BiTE-based T-cell immunotherapies have succeeded in several preclinical and clinical trials, and one BiTE, i.e., Blinatumomab® (CD3×CD19), has been approved by FDA to treat leukemia. Even though there have been several new BiTEs developed to target various types of solid tumors, only Pasotuxizumab® (CD3×PSMA) has entered clinical trial for the treatment of prostate cancer. 1 Treatment of solid tumors with these BITEs is far less satisfied with severe off-target adverse events, possibly due to (1) inherent mismatch of scFv molecules between their single light (VL)/heavy chain (VH) domain and hinge region causing low dual targeting, (2) off-target toxicity to non-tumoral cells, and (3) the complex tumor microenvironment as well as limited tumor penetration. 2 , 3 To overcome these limitations of traditional BiTEs, developing new BiTEs is imperative, and this research has demonstrated that nanobody-based BiTE (Nb-BiTE) is one such candidate, with significantly increased therapeutic efficacy and reduced side effects in the animal model.