PEPTIDE-Fc FUSION THERAPEUTICS: APPLICATIONS AND CHALLENGES - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 124

TABLE 8.1 Selected Peptide-Fc and Other Fc Fusion Therapeutics

Fusion
Protein

Mechanism of
Action Drug Target Indication Stage Company References

Romiplostim
(Nplate)

Peptide Thrombopoietin

receptor

Thrombopoietin
receptor
agonists

Immune thrombocytopenic
purpura

Launched Amgen [43]

AMG 386 Peptide Angiopoietin

receptor, Tie2

Angiopoietin-1
and -2
inhibitors

Cancers Phase II Amgen [44]

AMG 623 Peptide Blys B-cell inhibitors Systemic lupus

erythematosus

Phase I Amgen Anthera

Pharmaceuticals

[45,46]

CNTO 528 EPO

mimetic
peptide 1

EPO receptor EPO receptor

agonists

Anemia Phase I Centocor [91]

Factor IX-Fc Factor IX Factor IX Factor IX

stimulants

Hemophilia B Phase II Syntonix

Pharmaceuticals
and Biovitrum

[53]

SBI 087 Anti-CD20

scFv

CD20 CD20 antigen

inhibitors

Rheumatoid arthritis and
systemic lupus
erythematosus

Phase I Trubion

Pharmaceuticals
and Wyeth

[108]

TRU 015 Anti-CD20

scFv

CD20 CD20 antigen

inhibitors

Rheumatoid arthritis Phase II Trubion

Pharmaceuticals
and Wyeth

[109,110]

ART 621 Anti-TNF

dAb

TNF- a TNF- a

inhibitors

Psoriasis and rheumatoid
arthritis

Phase II Arana Therapeutics

and Domantis

[111]

marker. They express high level of cell surface CD2 and
therefore are the specific target of Alefacept. By binding to
CD2 on T cells, Alefacept can effectively prevent the cross
talk of APCs with T cells and therefore inhibits T-cell
activation. Alefacept has a significantly better pharmaco-
kinetic profile than Etanercept with a mean circulating
half-lifeof12daysinhumans[72].

ongoing for additional indications, including Crohn's dis-
ease, systemic sclerodema, ulcerative colitis, psoriatic
arthritis, and systemic lupus erythematosus (SLE).

8.4.2.4 Arcalyst 1 (Also Known as IL-1 Trap or Rilona-
cept) Some receptors, including many cytokine receptors,
require two or more distinct receptor chains to bind their
ligands with high affinity. For example, high affinity binding
of IL-1 requires both type I receptors (IL-1RI) and IL-1R
accessory proteins (IL-1RacP). For this type of receptor,
ligand-binding domains from both receptors have to be
incorporated into the Fc-fusion protein to enable high affinity
binding. To this end, Regeneron Pharmaceuticals developed
the “trap” approach, in which two different ligand-binding
domains from different receptor chains were sequentially
fused to each other followed by the Fc (Figure 8.1B) [75].
Traps have been shown to be very potent, with IC50s in the
single digit picomolar range based on in vitro cell-based
assays [75]. The high binding affinity is attributed to simulta-
neous interaction, or “trapping” of a ligand to both chains.
Arcalyst, an example of a cytokine trap, was recently
approved by the FDA as an orphan drug for the treatment of
patients with a rare autoinflammatory disease known as cry-
opyrin-associated periodic syndromes (CAPS), which includes
familial cold autoinflammatory syndrome, Muckle-Wells syn-
drome, and neonatal onset multisystem inflammatory disease
(Table 8.2). The IL-1 trap consists of the ligand-binding
domains of the human IL-1 receptor component (IL-1RI)

8.4.2.3 Orencia 1 Orencia (Abatacept) was developed
by Bristol-Myers-Squibb (New York, New York) and
approved for the treatment of RA. This drug consists of
the ECD of human cytotoxic T lymphocyte associated
molecule-4 (CTLA-4) fused to a human IgG1 Fc domain.
It was designed to block the interactions between CD80 and
CD86 on APCs with CD28 on T cells, which provides the
secondary costimulatory signal needed for T-cell activation.
By binding both CD80 and CD86 with higher affinity
than CD28, abatacept effectively prevents the engagement
of CD28 on T cells with APCs and therefore blocks T-cell
activation and inflammatory cytokine release [73]. To
prevent the killing of APCs, both the complement-
dependent cytotoxicity (CDC) and the antibody-dependent
cellular cytotoxicity (ADCC) activities of abatacept were
minimized by the introduction of four single amino acid
replacement mutations into the Fc region [74]. The mean
terminal half-life of abatacept is 16.7 days in healthy people
and 13.1 days in RA patients [69]. Although this drug is
currently approved for the treatment of RA, several trials are