Biomedical Engineering Reference
In-Depth Information
and the IL-1 receptor accessory protein (IL-1RAcP). In this
molecule, the C-terminus of the IL-1RAcP ligand binding
region is fused to the N-terminus of the IL-1RI extracellular
region followed by the Fc portion of human immunoglobulin
G1 (IgG1). It is a very potent IL-1R antagonist with a binding
affinity of
have more than one copy of the peptide fused to one Fc
domain. Table 8.1 lists selected peptide-Fc-fusion therapeu-
tics in different stages of development.
8.5.1 Peptibody
6.5 pM in in vitro
cell-based assays [75]. One big advantage of Rilonacept is its
long circulation half-life (8.6 days) allowing a dosing regimen
of once a week. In comparison, another IL-1 antagonist drug,
Anakinra (recombinant human IL-1 receptor antagonist), must
be administered daily owing to rapid clearance in vivo [43].
Other therapeutic traps that have been developed as poten-
tial therapeutics include the VEGF, IL-4, IL-6, and IL-4/IL-13
traps [5]. VEGF trap (Aflibercept) was recently approved for
wet macular degeneration and is in Phase III clinical trials for
multiple oncology indications; however, all other traps listed
were ultimately dropped from development.
1.5 pM to IL-1
b
andanIC50of
Peptibody, developed by Amgen Inc., is a technology in
which one functional peptide, or in some cases, two copies
of the peptide separated with a flexible linker are fused to
either the N-terminus or the C-terminus of the human IgG Fc
domain. Unlike other Fc-fusion therapeutics, which are
typically produced in mammalian cells, most of Amgen's
peptibodies were produced in an Escherichia coli expression
system. Several specific peptibodies, marketed and in clini-
cal trials, are discussed in detail in the following sections.
8.5.1.1 NPlate
1
(Romiplostim, AMG531)
NPlate
(also called AMG 531, Romiplostim), the most advanced
peptibody, consists of a human IgG1 Fc domain, genetically
fused at the C-terminus with two copies of a 14 amino acid
long thrombopoietin (TPO) receptor (also known as c-Mpl)-
binding peptide identified by phage display. A five amino
acid long flexible glycine linker was placed between the Fc
and the first peptide, and another longer flexible glycine
linker was inserted between the first and second copy of the
mimetic peptide [80]. Similar to TPO, binding of NPlate to
c-Mpl activates a number of signaling pathways, including
tyrosine phosphorylation of c-Mpl, Janus kinase 2, and
signal transducer and activator of transcription 5
(STAT5). Since the active peptide of NPlate shares no amino
acid sequence homology to endogenous TPO, it theoreti-
cally avoids the risk of eliciting cross-reacting neutralizing
antibodies to TPO, and indeed no such antibodies have been
observed so far [81]. The serum half-life of NPlate ranged
from 1 to 34 (median 3.5) days following subcutaneous
administration of 3-15 mg/kg/week [81]. The elimination of
the drug in serum is partly dependent on the c-Mpl receptor
on platelets. Therefore, for a given dose of the drug, patients
with high and low platelet counts are associated with low
and high serum drug concentrations, respectively [81].
In Phase III trials, NPlate was able to increase and sustain
platelet counts in both splenectomized and nonsplenectom-
ized patients. The drug appears to be generally well toler-
ated. Eighty-three percent of the NPlate treated patients
achieved an overall platelet response compared with 7%
of patients receiving placebo. The drug provides a valid
treatment option that may bring about a change in the way
that patients with immune thrombocytopenia purpura (ITP)
are treated in the future. NPlate was approved by the FDA in
2008 for the treatment of thrombocytopaenia in patients with
chronic ITP [81-84].
8.4.2.5 Other Fc-Fusion Protein Therapeutics
Several
other receptor-Fc-fusion proteins are listed in Table 8.2,
including Merck Serono and ZymoGenetics' Atacicept (also
called TACI-Ig), Biogen Idec and Genentech's Briobacept
(also called BR3-Fc), Y's Therapeutics' YSPSL,
Apogenix's APG 101, Acceleron Pharma's ACE-011 and
ACE-031, and Five Prime's FP1039. Enzymes, hormones,
and ligands fused to Fc domains are all represented in Table
8.2.
The Fc domain has also been used to extend the serum
half-life of antibody fragments, such as single chain Fv
(scFv) (Figure 8.1F), single-domain antibody (V
HH
)or
domain antibodies (dAbs) (Figure 8.1G and H), and different
alternative scaffolds. Several antibody fragment-Fc-fusion
therapeutics are currently in clinical trials, including Emer-
gent Biosolutions (formerly Trubion) TRU-015 and SBI-
087; these are representatives of Trubion's small modular
immunopharmaceutical (SMIP
TM
) technology. Two anti-
CD20 SMIP
TM
proteins are in clinical trials for the treatment
of RA and SLE [109,110]. Arana Therapeutics' anti-TNF-
a
dAb ART621 is an example of using the Fc domain to extend
circulating half-life of dAb [111]. Similarly, Harbour Anti-
bodies has genetically fused V
H
-binding domains to both the
N- and C-termini of an Fc domain to generate a tetravalent
antibody as shown in Figure 8.1H [5].
8.5 PEPTIDE-Fc-FUSION THERAPEUTICS
The peptide-Fc-fusion approach has been used by several
pharmaceutical companies, including Amgen, Eli Lilly, and
Centocor, to extend the serum half-life of bioactive peptides.
A peptide can be genetically fused to either the N- or C-
terminus of an IgG Fc domain. Modifications to the link-
er/hinge and Fc region are customized to fit the different
needs for drug development. Some of the peptide-Fc fusions
8.5.1.2 AMG 386 (2xCon4(C))
Currently in clinical tri-
als, AMG 386 (previously also called 2xCon4(C)) is an
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