PEPTIDE-Fc FUSION THERAPEUTICS: APPLICATIONS AND CHALLENGES - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 123

FIGURE 8.1 Schematic representation of selected Fc-fusion proteins. (A) Typical receptor-Fc-
fusion protein in which ECD from the same receptor is fused to the Fc domain; (B) multiple ligand
binding domains from different receptors are fused to the Fc domain; (C) monomeric-Fc fusion in
which only one protein is fused to the Fc domain; (D) MIMETIBODY TM platform; (E) two different
Fc-fusion chains form a heterodimer Fc-fusion molecule; (F) single chain Fv (scFv) is fused to the Fc
domain; (G) single domain Ab-Fc; (H) single-domain Abs are fused to both N- and C-termini of the
Fc domain (Harbour Antibodies). Source: Reprinted from Curr. Opin. Biotechnol., 20 (6), Huang C.,
Receptor-Fc fusion therapeutics, traps, and MIMETIBODY technology. pp. 692-699, Copyright
(2009), with permission from Elsevier.

have become an important addition to an ever-growing
armamentarium of protein therapeutics. Seven Fc-fusion
proteins have been approved by Food and Drug Adminis-
tration (FDA) as therapeutic drugs and more are in different
stages of clinical trials (Tables 8.1 and 8.2).

arthritis. Along with other TNF- a antagonist drugs, such as
Remicade, an anti-TNF- a chimeric mAb, Etanercept has had
a tremendous impact in the treatment and management of RA
and enjoyed concomitant commercial success. The sales of
this drug reached nearly US$3.6 billion in 2008.

8.4.2.1 Enbrel 1 Enbrel (Etanercept), composed of the
75 kDa soluble ECD of the tumor necrosis factor (TNF)- a
receptor II (TNFR II) fused to the Fc domain of human IgG1,
is the first successful example of using a soluble receptor as a
therapeutic drug. The prototype molecule was designed and
was demonstrated to have in vivo activity in the early 1990s in
laboratory of Bruce Beutler [56,71]. It neutralizes both mem-
brane-bound and soluble forms of TNF- a and thereby
indirectly reduces the concentration of serum inflammatory
cytokines, serummatrix metalloproteases, and adhesion mol-
ecules. The mean circulating half-life of the drug in human is
about 68 h [57]. Etanercept was approved by the FDA in 1998
for treatment of rheumatoid arthritis (RA) and other forms of

8.4.2.2 Amevive 1 Amevive (Alefacept) is the first bio-
logical drug approved for the treatment of patients with
moderate-to-severe plaque psoriasis. It is composed of the
first ECD of lymphocyte function-associated antigen 3
(LFA-3, CD58) fused to the human IgG1 Fc domain
[58]. LFA-3, expressed on many cell types including
antigen-presenting cells (APCs), is the primary co-receptor
for CD2 on T cells and NK cells. The interaction of CD2 on
T or NK cells with LFA-3 on APCs provides a costimu-
latory signal for activating T cells, including the release of
inflammatory cytokines, such as IFN- g . The majority of
T cells in psoriatic lesions are of the memory effector
phenotype characterized by the presence of the CD45RO