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Background Pancreatic cancer (PC) is highly aggressive, with a median survival time of less than 6 months and a 5-year overall survival rate of around 13%. 1 2 Current treatments are largely ineffective, representing a significant unmet medical need.Methods To address this, we used our novel TRBC platform technology to develop a novel multi-functional bispecific T-cell engager (TCE) targeting human tissue factor (TF), which is overexpressed in pancreatic cancer. This TCE immunotherapeutic, designated as HCW11-018b, comprises anti-TF/anti-CD3 single chain antibody domains as well as soluble TGFβRII (i.e., TGFβ trap) and soluble IL-15/IL-15RαSu complex. We conducted in vitro and in vivo experiments to assess the cytotoxicity, T-cell activation and anti-tumor efficacy of HCW11-018b. In vitro killing assay was performed using the AsPC-1 pancreatic tumor cell line and healthy donor peripheral blood mononuclear cells (PBMCs) at E:T ratio of 10:1 for 48 hrs and analyzed by flow cytometry utilizing Propidium Iodide dye to identify dead cells.Results Treatment with HCW11-018b induced robust, antigen-specific tumor cell killing and significantly increased expression of activation markers (CD69, CD25) on T cells compared to controls. In vivo, we evaluated human PBMC: tumor cell co-grafting in SCID mice and adoptive cell transfer (ACT) experiments in NSG mice to assess the anti-tumor efficacy of HCW11-018b. In the co-grafting model, human PBMC were administered with AsPC-1 cells (E:T, 1:1, s.c.) into SCID mice followed by treatment with HCW11-018b (1mg/kg, s.c.). 3 In ACT experiments, after s.c. AsPC-1 tumors reached 50-100mm3, mice received intravenous injection of either human PBMC or purified T cells followed by HCW11-018b (1mg/kg, s.c.) the following day. Treatments were administered every 5 days. TCE effectively engaged adoptively transferred human PBMCs or human T cells, induced T-cell activation (CD25), and subsequent tumor immune infiltration of cytotoxic (Granzyme B, NKG2D) CD8+ T cells to promote significant tumor regression and complete responses compared to controls. Currently we are further evaluating the anti-tumor efficacy of HCW11-018b in a patient-derived xenograft (PDX) mouse pancreatic cancer model. Additionally, HCW11-018b was well tolerated in tested mouse models (absence of lethargy, hunching) and its tolerability is being further evaluated in non-human primates. HCW11-018b is currently in an IND-enabling process for future clinical development against PC.Conclusions Altogether, these data demonstrate that (1) our TCE can induce potent anti-tumor activity against ‘difficult-to-treat’ pancreatic tumors and (2) the versatility of the TRBC platform can be used to create next-generation multi-specific T-cell engagers against solid tumors.References Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer . Lancet. 2004;363:1049–57.Siegel RL, Kratzer TB, Giaquinto AN. Cancer statistics, 2025. CA Cancer J Clin. 2025;75:10–45.Giffin MJ, Cooke K, Lobenhofer EK, Estrada J, et al. AMG 757, a half-life extended, DLL3-targeted bispecific T-cell engager, shows high potency and sensitivity in preclinical models of small-cell lung cancer. Clin Cancer Res. 2021;27:1526–1537.Ethics Approval HCW Biologics IACUC committee ID#VG2025-009SPNew