Characterization of a novel bispecific antibody targeting tissue factor-positive tumors with T cell engagement

Abstract

T cell engaging bispecific antibody (TCB) is an effective immunotherapy for cancer treatment. Through co-targeting CD3 and tumor-associated antigen (TAA), TCB can redirect CD3⁺ T cells to eliminate tumor cells regardless of the specificity of T cell receptor. Tissue factor (TF) is a TAA that involved in tumor progression. Here, we designed and characterized a novel TCB targeting TF (TF-TCB) for the treatment of TF-positive tumors. In vitro, robust T cell activation, tumor cell lysis and T cell proliferation were induced by TF-TCB. The tumor cell lysis activity was dependent upon both CD3 and TF binding moieties of the TF-TCB, and was related to TF expression level of tumor cells. In vivo, in both tumor cell/human peripheral blood mononuclear cells (PBMC) co-grafting model and established tumor models with poor T cell infiltration, tumor growth was strongly inhibited by TF-TCB. T cell infiltration into tumors was induced during the treatment. Furthermore, efficacy of TF-TCB was further improved by combination with immune checkpoint inhibitors. For the first time, our results validated the feasibility of using TF as a target for TCB and highlighted the potential for TF-TCB to demonstrate efficacy in solid tumor treatment.

Keywords: AUC0–t, area under the curve from time zero to the last quantifiable concentration; CL, clearance; Cmax, the maximum plasma concentration; DSC, differential scanning calorimetry; FVII, factor VII; H-scores, Histo scores; IHC, immunohistochemistry; Immunotherapy; Lung cancer; MFI, mean fluorescence intensity; PBMC, human peripheral blood mononuclear cells; PD-1 antibody; PEI, polyethyleneimine; PK, pharmacokinetics; Pancreatic cancer; SE-HPLC, size exclusion-high performance liquid chromatography; Solid tumor; T cell engaging bispecific antibody; TAA, tumor-associated antigen; TCB, T cell engaging bispecific antibody; TF, Tissue factor; Tissue factor; UPLC–QTOF-MS, ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry; Vd,ss, steady-state volume of distribution; i.p., intraperitoneally; i.v., intravenously; s.c., subcutaneously; t1/2, half-life.