TARGETING INTERFERON-a TO THE LIVER: APOLIPOPROTEIN A-I AS A SCAFFOLD FOR PROTEIN DELIVERY - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 425

FIGURE 29.1 The IFN signaling pathways. The type I interferons (IFNs) interact with the IFN
receptor 1 (IFNAR1) and IFNAR2. The type II IFN-g with IFN-g receptor 1 and 2 (IFNGR1 and
IFNGR2), and type III IFN-ls with IFN-l receptor 1 (IFNLR1) and interleukin 10 receptor 2
(IL10R2). All these receptors are associated with two JAK family kinases: either JAK1 and TYK2 for
type I and III IFNs or JAK1 and JAK2 for type II IFN. These kinases phosphorylate STAT1 and
STAT2, which after dimerization end promoting gene transcription, complexed or not to IRF9. GAS,
IFN-g-activated site; IRF9, IFN regulatory factor 9; ISRE, IFN-stimulated response element;
STAT1/2, signal transducers and activators of transcription 1/2; and P, phosphate.

induction was headed by the analysis of dsRNA-mediated
signaling pathways (reviewed by Borden et al. [6]).
Because of their pleiotropic effects, these proteins have
therapeutic potential for a wide range of disorders. IFN-a,
discovered initially for its antiviral action, is also a key
mediator of the innate and adaptive immune response. It
combatcs viruses directly by inhibiting viral replication
(displaying its antiviral properties), or by playing immuno-
regulatory roles, that help to shape the innate and adaptive
immune responses acting directly or indirectly on NK cells,
T cells, B cells, and dendritic cells (DCs) [7]. IFN-a also
plays a key role in the regulation of cell growth and
differentiation, exerting antiproliferative [8] and/or proa-
poptotic effects [9].

dosing necessary. To improve the pharmacokinetics of IFN-
a and decrease dosing frequency, several stabilizing strate-
gies have been developed, such as association with chemical
species such as 2-sulfo-9-fluorenylmethoxycarbonyl [10],
recombinant long-acting fusion protein of human albumin-
IFN-a2b [11], or other approaches such as linking the
protein to larger structures such as polyethylene glycol
(PEG). Two peginterferons are currently available for treat-
ment of viral hepatitis: peginterferon-a-2a (Pegasys 1 ) [12]
and peginterferon-a-2b (PegIntron 1 ) [13]. They differ in the
IFN-a that is modified, and in the size and nature of the
pegylation. IFN-a-2a and IFN-a-2b are recombinant mol-
ecules differing by a single amino acid. In contrast, the
covalent PEG is significantly different, resulting in differ-
ences in pharmacokinetic and pharmacodynamic properties,
with an impact on their clinical use and performance [14].
Pegylation results in a longer serum half-life than standard
IFN-a and maintenance of therapeutic concentrations
throughout the dosing interval, allowing for once-weekly
administration. This

29.1.2 Stabilization of IFN- a

IFN-a is indicated for the treatment of certain viral infec-
tions, including hepatitis B and C, and cancers. But the short
circulating half-life of unmodified IFN-a makes frequent conjugation decreases the renal