Clearance of pegylated interferon by Kupffer cells limits NK cell activation and therapy response of patients with HBV infection

Abstract

Pegylated interferon-α (PEG–IFN-α), where IFN-α is attached to polyethylene glycol (PEG), is an approved treatment for chronic hepatitis B virus (HBV) infection, a disease that causes liver-related morbidity and mortality in 257 million people worldwide. It is unknown why only a minority of patients respond to PEG–IFN-α. Using sequential blood samples and liver biopsies of patients with chronic HBV infection before, during, and after PEG–IFN-α treatment, we find that patients with early natural killer (NK) cell activation after PEG–IFN-α injection experienced greater liver inflammation, lysis of HBV-infected hepatocytes, and hepatitis B surface antigen (HBsAg) decline than those without. NK cell activation was associated with induction of interferon-stimulated genes and determined by PEG–IFN-α pharmacokinetics. Patients with delayed increases in PEG–IFN-α concentrations had greater amounts of PEG-specific immunoglobulin M (IgM) immune complexes in the blood and more PEG and IgM detected in the liver than patients with rapid increase in PEG–IFN-α concentration. This was associated with reduced NK cell activation. These results indicate that the immunomodulatory functions of PEG–IFN-α, particularly activation of NK cells, play a pivotal role in the response to treatment and further demonstrate that these functions are affected by PEG–IFN-α pharmacokinetics. Accelerated clearance of antibody-complexed pegylated drugs by Kupffer cells may be important beyond the field of HBV therapeutics. Thus, these findings may contribute to improving the efficacy of pegylated drugs that are now being developed for other chronic diseases and cancer.