TARGETING INTERFERON-a TO THE LIVER: APOLIPOPROTEIN A-I AS A SCAFFOLD FOR PROTEIN DELIVERY - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 424

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TARGETING INTERFERON- a TO THE LIVER:
APOLIPOPROTEIN A-I AS A SCAFFOLD FOR PROTEIN
DELIVERY

J ESSICA F IORAVANTI ,J ES ´ S P RIETO , AND P EDRO B ERRAONDO

Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra,
Pamplona; Liver Unit, University Clinic, CIBER-EHD, Pamplona, Navarra, Spain

29.1 Detailed description of the concept
29.2 Technological aspects
29.3 Typical applications and indications
29.4 Alternatives and variants of this approach
29.5 Conclusions and future perspectives
References

13 IFN-as, whereas there is only one type of IFN-b,
IFN-v, IFN- , or IFN-k. Among mammals, the number

of type I IFN genes is variable; some have unique types
(for example, IFN-d occurs only in pigs and IFN-t only in
ruminants) and others are devoid of a particular type (for
example, IFN-v in mice). Consistent with the universal
biological definition of IFNs (proteins able to induce rela-
tively species-specific antiviral effects), all type I IFNs,
which are mostly nonglycosylated proteins of 165-200
amino acids, share homologies that range from 30% to
85% within a species. Essentially, all have relatively high
specific potencies (10 7 -10 9 antiviral units per milligram
protein). The type III IFN family with three subtypes of
IFN-l, which are coproduced with IFN-b, activate the same
main signaling pathway as type I IFNs but have evolved a
completely different receptor structure [3].
Production of IFNs, both in vitro and in vivo, is transient
and requires stimulation. In the course of the discovery of
IFNs, after identification of live or heat-inactivated influenza
viruses as inducers, other microbial products, including
those of bacteria, protozoa, and RNA and DNA viruses,
were recognized also to induce IFN [4]. It was also shown
that microbial nucleic acids, lipids, polysaccharides, or
proteins trigger synthesis of IFNs through activation of
toll-like receptors (TLRs). The discovery of double-stranded
(ds) ribonucleic acids (RNAs), both natural and synthetic, as a
potent IFN inducer [5], led to the simplistic perspective that
viruses induce IFNs by the production of dsRNA; in reality, it
is only one of the viral gene products responsible for induc-
tion. Nonetheless, the study of cellular responses that lead to

e

29.1 DETAILED DESCRIPTION OF THE
CONCEPT

29.1.1 Interferons

Interferons (IFN) were discovered by Lindemann and Isaacs
in 1957, who detected their ability to induce interference by
heat-inactivated influenza virus with the growth of live virus
in fresh pieces of chorioallantoic membrane [1]. IFNs are
potent biologically active cytokines synthesized and
secreted by virtually all eukaryotic cells. Three classes of
IFNs have been identified, which are classified according to
the receptor complex they signal through (Figure 29.1). The
type II class of IFN comprises the single interferon-g
(IFN-g) gene product that binds the interferon-g receptor
(IFNGR) complex, and mediates broad immune responses to
pathogens other than viruses. The number of functional
genes identified that encode type I IFNs has subsequently
grown: 17 genes have now been described in humans. All are
intronless and cluster on chromosome 9 [2]. There are