First-in-class humanized antibody against alternatively spliced tissue factor augments anti-metastatic efficacy of chemotherapy in a preclinical model of pancreatic ductal adenocarcinoma

Alternatively spliced tissue factor (asTF) promotes progression of pancreatic ductal adenocarcinoma (PDAC) by activating beta1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class, humanized, inhibitory, anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown. Study results. When administered alone, hRabMab1 achieved only marginal penetration of experimental tumor tissue; however, hRabMab1 was abundant in tumor tissue when co-administered with gem/PTX which resulted in a significant decrease in tumor cell proliferation; leukocyte infiltration; and neovascularization. Gem/PTX alone reduced primary tumor volume, but not metastatic spread; only the combination of hRabMab1 and gem/PTX significantly reduced metastatic spread. RNAseq analysis of primary tumors showed that the addition of hRabMab1 to gem/paclitaxel enhanced the downregulation of tubulin binding and microtubule motor activity. In the liver, hRabMab1 reduced liver metastasis as a single agent. Only the combination of hRabMab1 and gem/PTX eliminated tumor cell-induced leukocytosis. Conclusions. This study demonstrates that hRabMab1 may help suppress metastasis in PDAC. We used KRAS mutant human PDAC cell line PaCa44 to generate aggressive primary orthotopic tumors. Experimental design featured orthotopic tumors formed by implantation of luciferase-labeled PaCa44 cells into the pancreata of mice. Four groups of mice were treated with vehicle; hRabMab1 alone; gemcitabine/paclitaxel (gem/PTX) alone; and the combination of hRabMab1 and gem/PTX).