After subcutaneous administration of 5 million units (MU)/kg of rFeIFN, serum concentrations increase gradually and a maximum concentration (C_max) of 577 U/mL occurs at 1.47 hours postadministration. Thereafter concentrations decrease slowly and are nondetectable after 24 hours. The elimination half-life is 1.72 hours.⁵ Even though serum levels are very short-lived, rFeIFN induces the activity of 2′-5′ oligoadenylate synthetase (OAS) in leukocytes in the peripheral blood and keeps the level elevated for 3 days.⁶ At least four isoenzymes of OAS are described in human beings. They are activated by double-stranded ribonucleic acid (RNA) and catalyze the formation of adenosine monophosphate (AMP) oligomers linked by a 2′-5′ diester bond. These oligomers then activate an RNAse, which is responsible for degradation of RNA at specific sequences, thus providing a system for the control of virus replication and gene expression.⁷

ADVERSE effects AND TOXICITY

Potential transient adverse effects postadministration include mild apathy, decreased appetite, sinus tachycardia, mild transient leukopenia, thrombocytopenia, and anemia. To date there are no studies on the long-term effects of rFeIFN. Its safety has not been determined in kittens less than 9 weeks of age, puppies younger than 1 month of age, and pregnant animals.⁵

Intravenous administration of 20 MU/kg rFeIFN to cats provoked a sinus tachycardia, mild apathy, mild increase of respiratory rate and body temperature; the latter two parameters were still within normal range.⁸

COMMERCIAL PREPARATION

rFeIFN is available commercially as Virbagen Omega (Virbac Santé Animale S.A., Carros, France) as a lyophilized powder plus solvent in 5 × 1 MU, 2 × 5 MU, or 10 × 1 MU per vial with a shelf life of 2 years when stored at 4° C. The product does not contain any preservatives and should be used immediately after reconstitution. The compound is stable for approximately 3 weeks at 4° C. Reconstituted Virbagen Omega can be frozen at −20° C and is stable for at least 6 months. Freeze-thaw cycles, however, should be avoided.

Virbagen Omega is licensed for use in the treatment of cats with feline leukemia virus (FeLV) and/or feline immunodeficiency virus (FIV) infection and for the treatment of parvovirus infections in dogs in the European Union, Switzerland, Argentina, Brazil, New Zealand, Australia, and Mexico. The drug currently is not licensed in the United States; however, there are ongoing discussions for licensing in the United States, Canada, and South Africa.

MECHANISM OF ACTION

Type I IFNs have multiple antiviral, antiproliferative, and immunomodulatory activities and exhibit autocrine as well as paracrine activities (Box 36-1).¹ The IFN response is very fast and limits virus spreading, thereby buying time for the generation of an acquired immune response to the invading virus. IFNs exert their actions through cell surface receptors.

Box 36-1 The Activities of IFN Type I

ANTIVIRAL RESPONSE

2′-5′ Oligoadenylate Synthetase System

• Leads to inhibition of protein synthesis by catalyzing cleavage of preferentially viral mRNA by activating L-RNAse and also by ribosomal inactivation leading to a translational inhibition.

Mx Proteins

• These are highly conserved GTPases that interfere with virus replication, probably by inhibiting the trafficking or activity of virus polymerases.

IFNs use the Janus kinase Jak/STAT (signal transducers and activators of transcription) pathway. The main induction event is the redistribution from the cytoplasm to the nucleus of the transcription factor NF-κB that plays a role in the transcriptional induction of many immunomodulatory genes, including other cytokines, MHC-I, and cell adhesion molecules that normally are expressed at low levels or are quiescent.

The IFN I receptor is composed of two major subunits, IFNAR1 (IFN-a receptor 1), associated with tyrosine kinase Tyk2, and IFNAR2 associated with Jak1. IFNAR 1 and 2 associate when IFN I binding occurs, thereby facilitating the transphosphorylation and activation of the two kinases, and creating a new docking site for STAT2 that is then phosphorylated and recruits itself STAT1, which also becomes phosphorylated. The phosphorylated STAT1/STAT2 heterodimers dissociate from the receptor and translocate to the nucleus where they associate with deoxyribonucleic (DNA)-binding protein p48 to form a heterotrimeric complex, ISGF3 (IFN-stimulated gene factor 3), which binds the ISRE (IFN-stimulated response element) of IFN I–responsive genes (Figure 36-1).

Figure 36-1 Schematic of IFN signaling by the Jak-STAT pathway: The signaling process is initiated by binding of the IFN ligand to its specific receptor, thereby activating Jak and Stat transcription factors by phosphorylation. In IFN I Tyk-2 and Jak-kinases are activated, which leads to phosphorylation and activation of Stat-1 and -2 proteins with subsequent translocation along with the IRF to the nucleus. The complex of these three proteins, called IFN-stimulated gene factor 3 (ISGF-3), activates the transcription of IFN-I-inducible genes through the ISRE. With IFN-γ, Jak-1 and -2 are activated, which leads to phosphorylation and homodimerization of STAT-1 and subsequent translocation to the nucleus where it activates the transcription of IFN-γ inducible genes through the gamma-interferon activated sequence (GAS) enhancer element.

(Adapted from Interferons in small animal medicine, Suffolk, 2007, Virbac Ltd., p 7 figure 1, by Severin Gutzwiller.)

IFN-γ induces a phosphorylation of only STAT1 and therefore another DNA-binding element GAF (gamma-IFN activating factor, which is a STAT1 dimer) is created. GAF binds to DNA sequence GAS (gamma-IFN activated sequence).

The primary step usually is inhibition of viral replication, induction of the protein kinase PKR, 2′,3′-oligoadenylate synthetase, and RNase L. All three of these induce apoptosis; RNA-specific adenosine deaminase ADAR1 and protein MxGTPase induce iNOS (inducible nitric oxide synthetase), repression of the cell cycle by the p202 IFN-I inducible gene product, down-regulation of c-myc transcription, and increase of MHC-I and -II molecules, all of which play an important role in immune responses to infections.⁷

Mainly by influencing Th1 type cytokine and chemokine induction and by regulating cytokine and chemokine receptor gene expression, IFN type I induces a Th1 type response and an adaptive CD8+ T-cell response that is likely to be efficacious against both chronic viral infections and neoplastic diseases that affect cats.⁹