Biomedical Engineering Reference
In-Depth Information
exquisitely specific for its target, RANKL, OPG has two
known ligands: RANKL and TRAIL [167,168]. Concerns
that inhibition of TRAIL by Fc-OPG might enhance tumor-
igenesis, as well as concerns of immunogenicity and forma-
tion of neutralizing antibodies to OPG (see below),
combined with the fact that denosumab exhibited a better
pharmacokinetic profile, led to the decision to abandon
further development of Fc-OPG in favor of denosumab
[114,169].
A more complex situation is presented by the compari-
son of atacicept to belimumab. This is an evolving story; so
far, the clinical results obtained with atacicept differ from
those obtained with belimumab [170], a monoclonal anti-
body targeting BLyS [171], but there have been no direct
comparisons of the two agents in the same trial. What are
the main differences and how might they arise? One key
difference in the mechanism of action of these two drugs is
that atacicept recognizes two ligands, BLyS or BAFF (also
known as TNFSF13B), and APRIL (also known as
TNFSF13) [172,173], whereas belimumab inhibits only
BLyS. The biological significance of this is illuminated by
studies in transgenic and knockout animals as well as
studies performed with human cells, all of which have
demonstrated that APRIL and BLyS have different roles
in vivo (reviewed in References [174] and [175]. For
example, BLyS signaling through the BAFF receptor
(BAFFR; also known as TNFRSF13C) appears to be
required for na
Therefore, overall, for the majority of receptor-Fc fusions
and Traps that bind multiple ligands it is unclear whether this
property is clinically desirable. However, this is still an
unfolding story and further laboratory experimentation
along with analysis of clinical data will be needed to
illuminate this question.
9.6.2 Signaling of Receptor-Fc Fusions
The second potential difference between receptor-Fc fusions
or Traps and an antibody is that these Fc fusion proteins
might differentially mimic a natural process. One of these
processes is reverse signaling—that is, the ability of a
transmembrane ligand to act as a receptor and signal trans-
ducer. The clinical significance of this process has not been
investigated systematically in clinical settings, but has been
noted for both anti-BLyS and anti-TNF therapeutics. For
example, atacicept and belimumab differ in their ability to
induce reverse signaling [22,24,188] in cells expressing the
transmembrane form of BLyS. Jeon et al. [189] demon-
strated that TACI-Ig induces reverse signaling in cells
expressing BLyS, and showed that this can also be accom-
plished by monoclonal antibodies, albeit with lesser effec-
tiveness. Belimumab was not one of the antibodies tested but
given that belimumab binds the soluble but not the trans-
membrane form of BLyS [171], it is probable that unlike
TACI-Ig, belimumab will not induce reverse signaling. The
inverse property has been noted for TNF blockers, where
etanercept is not as efficient as anti-TNF-
a
antibodies to
induce reverse signaling [22,59,190,191].
Another process that can be selectively blocked by
receptor-Fc fusions or Traps is trans-signaling—that
ıve B-cell survival and selection, as well
as Ig class switching and plasma cell differentiation in
response to infection [176,177]. In contrast, APRIL cannot
signal through BAFFR; APRIL signals through TACI and
BCMA (also known as TNFRSF17) to maintain mucosal
immunity, as well as drive Ig class switching to IgG1 and
IgA, but it is not involved in na
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is,
signaling initiated by a soluble receptor
ligand complex
on cells that are otherwise unresponsive to the ligand.
The most extensively studied example of trans-signaling
is that mediated by IL-6 bound to soluble IL-6R (sIL-6R)
and acting on cells that do not express IL-6R, but which do
express the shared signal-transducing receptor, gp130
[117,124,192] (Figure 9.3). Trans-signaling by the IL-
6/sIL-6R is modulated in vivo by endogenous soluble
gp130 [131]. In addition, in some animal models of disease,
IL-6/sIL-6R trans-signaling appears to be the main driver of
pathologic IL-6 signaling, whereas signaling mediated by
the membrane-bound form of IL-6R results in desirable anti-
inflammatory outcomes [193,194]. These observations have
led to the hypothesis that selective inhibition of IL-6/sIL-6R
trans-signaling (via gp130-Fc) may be therapeutically desir-
able over inhibition of total IL-6 signaling [96,132,195,196],
and to this effect several versions of gp130-Fc have
been engineered [197]. One of them, CR5/18, is currently
in preclinical development [23,97,98] (Table 9.1). However,
there are no published preclinical studies directly
comparing the efficacy of CR5/18 with approved therapeu-
tics targeting IL-6 signaling, such as the anti-IL-6R
ıve B-cell selection or
survival [178]. The differences in biological effects
observed between BLyS and APRIL are reflected in the
corresponding nonclinical toxicology studies of belimu-
mab [179] and atacicept [180], whereas treatment with
either one of these therapeutics results in reversible
decreases of circulating mature B cells, only atacicept
brings about near complete inhibition—see also a recent
review by Reference [170].
The clinical picture is further complicated by the fact that
the expression profiles of BLyS and APRIL are differentially
regulated in different diseases [181-185]. In addition, BLyS
and APRIL form heterotrimers whose levels are elevated in
systemic rheumatic diseases (SLE, RA, Reiter's syndrome,
psoriatic arthritis, and ankylosing spondylitis) [186,187].
Therefore, it is possible that depending on the target disease
it may be desirable to “inhibit” only BLyS or both BLyS and
APRIL. It remains to be seen how these differences will
affect the clinical application of atacicept (which is still
undergoing clinical development) compared to belimumab
(which is an approved therapeutic).
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