Biomedical Engineering Reference
In-Depth Information
TABLE 9.2 Reported Cognate Ligand Repertoire for Receptor-Fc Fusions and Traps
Trap
Ligands
IL-1 Trap
IL-1A, IL-1
b
, and to a lesser extent IL-1RN
gp130-Fc
Multiple cytokines of the IL-6 family [117]; in vivo repertoire may also be dependent on the presence of
soluble receptors of the IL-6 family [123,124]
ACVR2A-Fc (ActRIIA-Fc;
ACE-011)
Activin A [79]; multiple other BMPs [81,156]
ACVR2B-Fc (ActRIIB.hFc;
ACE-031)
MSTN (GDF8), GDF11, Activin A; BMP2, BMP7 to a lesser extent [85]; multiple other BMPs [81,156]
ACVRL1-Fc (Alk1-IgG1;
ACE-041)
BMP9, BMP10 [86,87]
Fc-OPG
RANKL, TRAIL [157]
VEFG Trap
VEGFA isoforms; VEGFB; PGF [65,142,158]
This list of ligands is only those for which there is supporting experimental evidence using the actual receptor-Fc or Trap. It should be noted that for some of
these fusion proteins not all the ligands predicted to interact with them have been tested, and also some of these interactions have been tested only in vitro.
Therefore, it might be necessary to understand at the orga-
nismal level in different disease models, and on a case-by-
case basis whether the ability to block multiple ligands is
desirable.
There are several examples of ligands for which receptor-
Fc blockers or Traps, as well as antibodies have been
developed clinically. For TNF-
a
: etanercept and several
anti-TNF-
a
antibodies (infliximab, adalimumab, goligu-
mab, and certolizumab); for RANKL: Fc-OPG and the
anti-RANKL antibody denosumab; for BLyS: atacicept
and the anti-BLyS antibody belimumab; for IL-1: rilonacept
and the anti-IL-1
b
antibody canakinumab; for VEGF: afli-
bercept and the anti-VEGF antibody bevacizumab [149];
and its affinity matured Fab counterpart ranibizumab [150].
It should be noted however that with the exception of the
above-referenced Phase III clinical comparison of VEGF
Trap-Eye to ranibizumab, there have not been any other
side-by-side comparisons in the same clinical setting, and
therefore any comparisons regarding clinical efficacy have
to rely on the cross-comparison of data from trials performed
with individual therapeutics.
Overall, there is currently no clear data from a clinical
setting to indicate that the ability of any individual receptor-
Fc fusion or Trap to inhibit the action of multiple ligands
confers an advantage over monoclonal antibodies that
inhibit the action of only single ligands. For example,
both rilonacept and canakinumab have been tested in trials
of CAPS and gout and both have shown efficacy that is
attributed to inhibition of IL-1
b
[134,139]. Unlike bevaci-
zumab and ranibizumab, which are pure VEGFA blockers,
VEGF Trap blocks VEGFA, VEGFB, and PGF [65], and the
latter has been hypothesized to also drive pathological
neovascularization in ocular and oncology disease settings.
However, there has not yet been a clinical finding that
conclusively demonstrates a clinical advantage over block-
ade of VEGFA alone, although further clinical studies are in
progress.
For ACVR2A-Fc and ACVR2B-Fc, it is clear that they
both interact with multiple BMPs found in mouse and
human sera [81], which likely cause numerous physiological
effects that may present challenges in clinical development.
In vitro, they display varying affinities for these BMPs and
they can block the majority of them. This contrasts with
clinical settings, where an ACVR2A-Fc protein, ACE-011,
has been promoted as a fairly specific activin A blocker, yet
the possibility that ACE-011 might be blocking other BMPs
appears not to have been investigated [79,82]. However, the
significance of this in clinical settings is unclear. For exam-
ple, the reasons for a change in the clinical indication under
development for ACE-011—from bone loss [82] to anemia
[83]—have not been explicitly attributed to any particular
BMP inhibited by ACE-011. In contrast, the preclinical
experience with ACE-031 has provided actionable data
with respect to which BMPs are important for the regulation
of muscle mass, demonstrating that in addition to myostatin,
at least one other BMP, activin A, is implicated. However, a
Phase II clinical trial of ACE-031 for Duchenne muscular
dystrophy (NCT01239758) has been suspended citing pre-
liminary safety concerns, and another, NCT01099761, has
been terminated. Still, mirroring ACE-011, it is currently not
known whether the ability of ACE-031 to inhibit the action
of multiple BMPs [81,156,85] is involved. Finally, it should
be noted that given the fact that BMPs interact with multiple
extracellular effector proteins, such as their own prodomains
[159], multiple receptors [160-162] and coreceptors [29],
antagonists [44,163], extracellular matrix, and other binding
proteins [116,120,164-166], the question of what are the
pharmacologically relevant ligands accessed by ACVR2A-
Fc and ACVR2B-Fc in a specific disease setting remains
open. Similar comments can be made for ACVRL1-Fc and
gp130-Fc.
Fc-OPG is an example where the ability of this decoy
receptor-Fc fusion to interact with more than one ligand was
deemed to be a drawback. Unlike denosumab, which is
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