RECEPTOR-Fc AND LIGAND TRAPS AS HIGH-AFFINITY BIOLOGICAL BLOCKERS: DEVELOPMENT AND CLINICAL APPLICATIONS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 147

Afliber cept met its prima ry endpoi nt of increasing overall
survival in a Phase III trial in colo rectal cancer in combina -
tion with the chemot herapeut ic regimen known as FOLFIRI.
Recent ly announced top line resu lts have indicated a positive
benefit of the addition of aflibe rcept to FOLFI RI in terms of
overall survival and progr ession free survival in the second
line setting. Adverse events that occurred with mor e than 2%
greater inciden ce in the afliberce pt arm than in the plac ebo
include d diarrho ea, fatigue, stomati tis, infection s, hyper-
tension , gast rointestinal and abdom inal pain s, neutrope nia,
neutrope nic complicati ons, and protei nuria. Other studies
with afliberce pt in differ ent cance r indicati ons are ongoing.

9.6 “TO TRAP OR NOT TO TRAP?”
ADVANTAGES AND DISADVANTAGES OF
RECEPTOR-Fc FUSIONS AND TRAPS VERSUS
ANTIBODIES

FIGURE 9.4 The VEGF Trap. The VEGF Trap is an in-line
fusion protein composed of the second Ig domain of VEGFR1
followed by the third Ig domain of VEGFR2, and fused to the Fc
domain of human IgG1, which also drives dimerization of each
Trap monomer resulting in 1:1 binding with the VEGF dimer.

In as much as the successful engineering of the Traps opened
up new vistas in therapeutic possibilities, their development
in the clinic has been limited, reflecting the fact that Traps
require careful engineering to achieve good pharmaceutical
properties, and robust expression and manufacturing.
In addition, the recent technological advancement of
VelocIm mune 1 (ht tp://www.regeneron.com/ velocimm une),
which enables the generation and selection of completely
human therapeutic antibodies, has in most cases replaced
the preclinical and clinical exploration of new Traps or
Trap-like proteins. Therefore, the question arises whether
there are any advantages of trap-based therapies over use
of therapeutic monoclonal antibodies raised against

30 days for ranibi zumab, largely based on their differ ing
affinities for VEG F [152] .
Positive resu lts with VEG F Trap- Eye in AM D Phase I
and Phase II studies [153,1 54] led to the desi gn of two
parallel Phase III clini cal trials called VI EW 1 and VIEW 2.
The resu lts of these studies have not yet been present ed in
peer-reviewed publica tions, but initial analysis pres ented in
press releases and rev iewed in Reference [144] showed that
VEGF Trap-E ye met its prima ry endpoint of nonin feriority
to the anti-V EGFA antibody fragme nt ranibi zumab in mea -
sureme nts of vision maintenan ce. Im portantly, VEG F Trap-
Eye achieved noninfer iority with every 8-week adm inistra-
tion compare d to monthl y d osing with ranibi zumab, which
may result in a decr ease in the treatment burden experienced
by AM D patients. Th e safety profil e showed no significa nt
differ ences betwee n VEG F Trap-Eye and ranibizum ab.
Common adverse events were those typicall y associa ted
with intravitreal injecti ons or the underlying dise ase, and
include d conj unctival hemorr hage, mac ular degeneration,
eye pain , retina l haemorrhage , and vitreo us floate rs. VEGF
Trap- Eye has also dem onstrated p ositive results in a Phase II
study for diab etic macula r edema (D ME), and is current ly in
additional clinical trials, for exampl e, for macular edema
due to central retina l vein occl usion (GALI LEO stud y). In
line with adverse events reporte d in AMD trials, VEGF
Trap- Eye was well tolera ted in DME; the mos t fre quent
adverse events wer e thos e assoc iated wi th the injecti on
procedure , such as conjunct ival hem orrhage, eye pain, ocu-
lar hyper emia, and increas ed intrao cular pres sure [155].

the

same targets.
There are several ways in which both receptor-Fc fusions
and Traps differ from monoclonal antibodies, and it is on the
basis of these differences that any advantages or disadvan-
tages of these fusion proteins over antibodies should be
evaluated.

9.6.1 Multiple Ligand Binding

A key difference between these Fc fusions and monoclonal
antibodies is that receptor-Fc fusions and Traps should
recapitulate the binding specificities of the receptor compo-
nent(s) they encompass and therefore should be able to bind
multiple ligands. This is clear for the IL-1 Trap (rilonacept),
the VEGF Trap (aflibercept), as well as the receptor-Fc
fusions TACI-Ig (atacicept), CTLA4-Ig (alefacept and bela-
tacept), gp130-Fc (CR5/18), Fc-OPG, ACVR2A-Fc (ACE-
011), ACVR2B-Fc (ACE-031), and ACVRL1-Fc (ACE-
041) (Table 9.2). Consequently, the question that arises is
whether the ability of a Trap or receptor-Fc fusion to block
the activity of multiple ligands is desirable, or whether it can
be a complicating factor resulting in undesirable outcomes.