SIGNAL CONVERTER PROTEINS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 444

particular CTLA-4 derivative may well hold for others,
including CTLA-4-containing SCP. If so, an SCP designed
for deleting pathogenic T cells may prove to convey addi-
tional benefits in artificially promoting regulatory T-cell
expansion, in this way further amplifying this chimeric
protein's anti-inflammatory therapeutic potential.
The mechanistic picture for any given SCP is likely to
evolve over time, not only as a consequence of new func-
tionalities ascribed to its constituents, but also as a byprod-
uct of a better understanding of structural and contextual
determinants that dictate surface protein action and interac-
tion. Seemingly well-delineated ligand-receptor pairs com-
monly give way to more complex protein interaction
matrices, with ligands proving to have more than one
receptor and vice versa. Many surface proteins exhibit
functionally significant structural dynamism, with cell
state-dependent binding and functional properties [95]. Dif-
ferent isoforms of a receptor can mediate opposing effects
on a cell, even when engaging the same counter-receptor
[96]. The interplay and interdependency between signaling
systems creates an increasingly intricate web of interaction
that extends the reach of any given SCP component signal
and its outward functional ripple. Through these and other
ways, the functional picture for each SCP invariably
becomes more intricate.

developed at the outset as an inhibitor of activated auto-
immune and alloimune T cells. In this case, it had been
originally designed to function primarily via a cis loop-back
mechanism that additionally invokes bidirectional signaling
reinforcement. Its further therapeutic ability to eradicate
transformed T cells expressing the cognate counter-receptors,
CD40L (CD154) and Fas (CD95), draws mechanistically
upon the same CLBP mode of activity [97]. Of note, in
addition to eliciting transformed T-cell suicide, CD40 FasL

can in parallel promote Fas-dependent T-T fratricide, in
bridging Fas þ target cells with neighboring CD40L þ tumor
cells, or even infiltrating, activated CD40L þ T cells.
Fn14

TRAIL provides yet another example, in this case
leading to a cancer therapy for solid tumors. Originally, this
SCP was showcased as a TSRP, capable of interfering with a
proinflammatory intercellular signal (TWEAK) and redi-
recting a converted inhibitory signal (TRAIL; CD253) that
targets activated autoimmune T cells. However, neoexpres-
sion of TWEAK and its TRAIL counter-receptors on the
surfaces of various solid tumor types, including those of
breast, liver, pancreas, brain, and colon [98-102], has
opened up another avenue for leveraging Fn14

TRAIL

therapeutically. By deploying Fn14 TRAIL in a cancer

context, one can draw upon its additional capacity to func-
tion as a CLBP to autotrigger apoptosis in molecularly
defined tumor cells. In this way, cancer cells have come
to share the limelight with activated T cells as prime targets
for single multifaceted SCP, and in the process, a therapeutic
agent for autoimmunity has morphed into an anticancer
therapeutic for solid tumors.
Fn14

30.7 TARGETING MULTIPLE DISEASES WITH
INDIVIDUAL SIGNAL CONVERTERS

SCP mechanisms of action are diverse, and so are the disease
applications. As each individual SCP is probed more fully, it
seems to invariably reveal therapeutic potential beyond that
which was originally planned in the original SCP design.
Thus, SCP multifunctionality, as it unfolds, often serves to
extend the therapeutic range of each to a variety of cellular
targets and pathogenic processes.
Lymphoid-directed, FasL (CD95L)-containing SCP are a
case example of this sort of therapeutic range extension.
CTLA-4

TRAIL's applicability to cancer therapy draws in
yet other ways upon this SCP's mechanistic diversity. Vari-
ous known TWEAK functions happen to be ones that are
expected to promote tumor progression under certain cir-
cumstances. These functions relate to the promotion of
proliferation, invasion, angiogenesis, and inflammation.
As a TWEAK blocker, Fn14 TRAIL can thus exert anti-

cancer effects in these pathogenic realms. From another
perspective, Fn14

TRAIL can be viewed as a more potent
soluble TRAIL derivative. Soluble TRAIL has been under
active development as a cancer therapeutic capable of
inducing tumor cell apoptosis [103], taking advantage of
the fact that TRAIL receptors are expressed by, or are
upregulated in, many cancer types. Fn14

FasL was first designed with autoimmunity and
transplantation diseases in mind, and to this end, it was
configured as a trans signal converter capable of substituting
an APC-to-T-cell inhibitory signal (FasL/CD95L) in place
of a costimulation signal (B7-1/CD80; B7-2/CD86). How-
ever, co-expression of the fusion protein's cognate counter-
receptors, CD80/86 and CD95L, on hematopoietic malig-
nancies of the B-cell lineage prompted an evaluation of its
apoptosis-inducing potential against these transformed cell
types. In this context, CTLA-4

TRAIL, by virtue
of its cell-associating and multimerization characteristics,
turns out to be far more effective than soluble TRAIL in
promoting tumor cell apoptosis. In this context, it is mirror-
ing monocyte/macrophages, which rapidly express TRAIL
after activation and thereby acquire the ability to efficiently
kill tumor cells [60,104].
Extrapolating from these examples, a new class of cancer
therapeutics can be defined—fusion protein inducers of
tumor cell auto-apoptosis. By drawing upon known inducers
of tumor cell apoptosis as building blocks, including ones

FasL would be additionally
functioning in a cis loop-back, pro-apoptotic autotriggering
mode, that is, as a CLBP as opposed to a TSCP. CTLA-
4

FasL's efficacy in this cancer setting was indeed substan-
tiated by us [97]. Furthermore, the same held true for another
FasL-containing SCP, CD40 FasL, which had also been