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. Overall design: 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).