Novel pegylated interferon‐β as strong suppressor of the malignant ascites in a peritoneal metastasis model of human cancer

Malignant ascites manifests as an end‐stage event during the progression of a number of cancers and lacks a generally accepted standard therapy. Interferon‐β (IFN‐β) has been used to treat several cancer indications; however, little is known about the efficacy of IFN‐β on malignant ascites. In the present study, we report on the development of a novel, engineered form of human and murine IFN‐β, each conjugated with a polyethylene glycol molecule (PEG‐hIFN‐β and PEG‐mIFN‐β, respectively). We provide evidence that these IFN‐β molecules retain anti‐viral potency comparable to unmodified IFN‐β in vitro and manifested improved pharmacokinetics in vivo. Interestingly, PEG‐mIFN‐β significantly inhibited the accumulation of ascites fluid and vascular permeability of the peritoneal membrane in models of ovarian cancer and gastric cancer cell xenograft mice. We further show that PEG‐hIFN‐β directly suppresses VEGF165‐induced hyperpermeability in a monolayer of human vascular endothelial cells and that PEG‐mIFN‐β enhanced gene expression for a number of cell adhesion related molecules in mouse vascular endothelial cells. Taken together, these findings unveil a hitherto unrecognized potential of IFN‐β in maintaining vascular integrity, and provide proof‐of‐mechanism for a novel and long‐acting pegylated hIFN‐β for the therapeutic treatment of malignant ascites. Malignant ascites manifests as an end‐stage event during the progression of a number of cancers and is associated with significant morbidity. In this study, we report on the development of a novel, long‐acting formulation of human and mouse interferon‐β (IFN‐β). Pegylated IFN‐β contains the site‐specific conjugation of polyethylene glycol residue to IFN‐β. We demonstrated that PEG‐mIFN‐β, but not PEG‐hIFN‐β, significantly suppressed the accumulation of ascites fluid in this model. These findings reveal a new facet of the long‐acting PEG‐hIFN‐β and provide a therapeutic rationale for evaluating long‐acting PEG‐IFN‐β in the treatment of malignant ascites.