Abstract
Bispecific T-cell engager antibodies (BiTE) have been explored as a means to recruit cytolytic T cells to kill tumor cells. The transferrin receptor (TfR) is highly expressed on the surface of rapidly proliferating tumor cells. Therefore, it holds great potential in T cell redirecting therapies. In this research, we developed a BiTE targeting TfR and CD3 (TfR-BiTE) and studied its therapeutic impact on TfR-positive cancer. TfR-BiTE had the ability to induce the selective lysis of various TfR-positive cancer cells through the activation of T cells, the release of cytokines, and then the coming proliferation of T cells, whereas TfR-negative cells were not affected. In a subcutaneous HepG2 xenograft model, low concentrations of TfR-BiTE inhibited tumor growth. Overall, these results reveal that TfR-BiTE can selectively deplete TfR-positive HepG2 cells; hence, it represents a novel immunotherapeutic approach for the treatment of hepatocellular carcinoma.
Highlights
Redirecting the activity of T cells by bispecific antibodies against tumor cells, independent of their intrinsic antigen-specific T cell receptor (TCR) recognition, is a potent approach to treat cancer [1,2,3,4]
The transferrin receptor (TfR)-Bispecific T-cell engager antibodies (BiTE) was constructed into the pOptiVEC vector encoding dihydrofolate reductase (DHFR)
We described the generation of a BiTE to redirect T cells to TfR-positive malignancies (TfR-BiTE)
Summary
Redirecting the activity of T cells by bispecific antibodies against tumor cells, independent of their intrinsic antigen-specific T cell receptor (TCR) recognition, is a potent approach to treat cancer [1,2,3,4]. It bridges malignant tumor cells directly to CD3-positive T cells, bypassing TCR specificity, and major histocompatibility complex (MHC) class I molecules [7,8,9]. This triggers T cell activation, including the release of cytotoxic molecules, cytokines, and induction of T-cell proliferation [10]. Blinatumomab (Blincyto), which is reactive with the pan B cell antigen CD19, has been approved by the FDA for treatment of B cell neoplasms in 2014 [11,12,13]
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