Interferons

CHAPTER 9

Interferons

Robert C. Lowe

Boston University School of Medicine, Boston, MA, USA

Introduction

Interferons were first described by Isaacs and Lindenmann in 1957 as a group of unknown factors that “interfered” with the replication of influenza virus in an experimental chicken egg model. The molecules themselves were isolated in the 1970s, and they are currently identified as a superfamily of more than 20 proteins with diverse roles in the immune response to exogenous pathogens. They are utilized clinically in the treatment of viral infections, neurological disorders, congenital immune deficiency diseases, and as a component of chemotherapy regimens for a select group of malignancies.

Mechanism of action

Interferons are produced as part of the innate immune response when pathogen-associated molecular patterns (PAMPs) are recognized by Toll-like receptors and other recognition molecules on the surface and within the cytoplasm of dendritic cells. Interferons alpha, beta, and gamma have roles in innate immunity, but only IFN alpha has been used in the therapy of gastrointestinal disorders, specifically viral hepatitis B and C. Interferon beta has been proven effective in the treatment of multiple sclerosis, while IFN gamma has a role in the therapy of two rare conditions – chronic granulomatous disease and osteopetrosis. Interferon lambda is currently being studied in the treatment of chronic hepatitis C infection, but these studies are preliminary and there are currently no approved formulations for this indication. Interferon alpha is also a component of therapy for selected malignancies, including renal cell cancer, melanoma, hairy cell leukemia, lymphoma, multiple myeloma, and AIDS-related Kaposi’s sarcoma.

Interferon alpha acts by binding to a cell surface receptor (IFNAR), inducing a signaling cascade involving the JAK-STAT pathway, leading to the translocation of transcription factors to the cell nucleus and subsequent transcription of a number of cytokines and other proteins that both directly inhibit viral replication and stimulate helper T-cells to promote immune-mediated destruction of virus-infected hepatocytes. Interferons alpha and beta bind the same set of cell surface receptors, which are present on a wide variety of cell types. In contrast, interferon lambda binds a different set of receptors with a more restricted distribution, being expressed on primarily on hepatocytes but not on vascular endothelium or cells of the CNS; this limited distribution gives interferon lambda a much better side effect profile than interferon alpha, stimulating research into its use as therapy in chronic hepatitis

Pharmacology

IFN alpha is a polypeptide comprised of more than 160 amino acids, and thus is not orally bioavailable. Standard IFN alpha is administered by subcutaneous injection, with rapid absorption (peak levels occur within 12 hours) and rapid elimination via renal clearance. As such, therapy with IFN requires thrice-weekly injections, and serum drug levels fluctuate greatly throughout the week. Viral kinetic studies demonstrate that during the IFN trough, hepatitis C virus (HCV) levels rise, leading to a cycling of viral loads that contributes to the low rate of efficacy of this early HCV treatment; studies demonstrated only a 10–20% rate of sustained viral response after 48 weeks of therapy.

A major advance in IFN-based therapy came in 2001 with the development and testing of pegylated interferon molecules. These drugs consist of an interferon alpha polypeptide complexed to a large polyethylene glycol (PEG) molecule. The addition of PEG slows the renal clearance of interferon, decreases the volume of distribution of the drug, and promotes a slow and sustained absorption of IFN, leading to maintenance of high serum drug levels for several days after a single subcutaneous injection. The presence of the large carbohydrate molecule, however, creates steric interference at the interferon receptor, making each molecule less effective at binding to and activating the receptor; thus there is a tradeoff between serum drug level and per-molecule efficacy.

There are two commonly used formulations of pegylated interferon, which differ in their structure and pharmacologic properties. PEG-IFN alpha 2a (PegasysTM) has a large PEG molecule (40 kDa) complexed to IFN by an amide bond at a lysine residue. This strong covalent bond is responsible for the long serum half-life of this formulation (approximately 65 hrs), and its slow clearance not by the kidney, but by nonspecific serum protease activity. On the other hand, the large PEG molecule significantly limits the activity of the interferon component, resulting in < 10% of the antiviral activity of the noncomplexed molecule. The other commonly used pegylated interferon molecule is PEG-IFN alpha 2b (PEG-IntronTM), in which the IFN moiety is bound to a smaller (12 kDa) PEG molecule via a weaker bond at a histidine residue. This allows dissociation of the PEG from the IFN in about 50% of each dose, resulting in a longer serum half-life than standard interferon (approximately 30 hours), but not as prolonged as that of PEG-IFN alpha 2a. The efficacy of PEG-IFN alpha 2b, however, is nearly 30% that of the uncomplexed molecule due to the lesser degree of steric hindrance at the IFN receptor. The smaller PEG molecule also leads to an increased volume of distribution of drug, and as a result this formulation is dosed according to body weight, unlike the fixed dosing of PEG-IFN alpha 2a. It is clear that the two PEG-IFN molecules make different tradeoffs between per-molecule effectiveness and improved pharmacokinetics.

A recombinant form of alpha interferon was developed in 1996; this molecule, known as Interferon Alphacon-1 (InfergenTM), is designed to mimic the most common amino acid sequences from the known forms of alpha interferon, and is thus deemed a “consensus interferon.” It requires daily subcutaneous injection when used in combination with ribavirin for HCV treatment, and has thus not been widely used in the era of pegylated interferon therapies.

Clinical effectiveness

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