Biomedical Engineering Reference
In-Depth Information
different autoimmune diseases, and even different clinical
phases of the same disease, a diverse collection of SCP,
targeting a range of target cells, could ultimately provide the
means for tailoring autoimmune therapies.
Another consideration is the respective affinities of fusion
protein components for their respective counter-receptors.
Binding affinities between costimulator receptors and their
cognate ligands vary considerably, ranging over at least
three log orders. While high affinity interaction should
benefit in vivo homing, lower affinity interaction may offer
a better therapeutic window for those costimulators that are
promiscuously expressed, but are very highly expressed on
pathogenic T cells. In the case of monoclonal antibodies,
above a threshold affinity, other factors appear to dictate
optimal in vivo targeting [114]. Moreover, for CoSR
PD-L1, for example, with respect to T-cell subset orientation
[124], substituting PD-L2 for PD-L1 within these CoI
CoI
SCP would modify their functional profiles.
There are yet other ways to invoke SCP for the inhibition
of immune responses. SCP that can amplify regulatory T-cell
numbers and function would serve to indirectly inhibit
effector T cells. To this end, one can select SCP components
that are known to positively influence regulatory T-cell
pathways. This points to yet another mechanistic angle
for PDL1-containing SCP since PD-1 triggering not only
inhibits effector T cells, but also stimulates regulatory
T cells [125]. CTLA-4 (CD152) [126], ICOS (CD278)
[127-129], and CD30 [130,131] also offer
interesting
options in this regard.
One can also broaden the inhibitory SCP landscape by
reaching beyond lymphoid and cancer cell targets. Such SCP
would conceptually fit into a larger therapeutic framework—
the use of SCP for what might be termed SCP-mediated cell
deletion therapy, where the goal is to selectively eliminate
diverse pathogenic cells using death-inducing SCP. In the
immunological realm, mast cells [132,133], natural killer
T(NKT) cells [134-136], and natural killer (NK) cells of the
female reproductive tract [137,138] are particularly inter-
esting cellular targets, given the ever-growing spectrum of
diseases linked to them. Beyond the immune system, there is
also much room for creativity in the choice of pathogenic
cell targets and associated SCP designs. Out-of-the-box
thinking might even bring into the fold certain under-studied,
high-prevalence conditions such as postsurgical adhesions.
SCP cell deletion therapies could be devised to target the cells
driving inappropriate fibrogenesis in these conditions. Other
SCP-based cell deletion therapies might target virally infected
cells, parenchymal cells driving inflammatory disorders, and
many other types of pathogenic cells.
SCP could be invoked to indirectly sensitize target cells
to other death-inducing agents. Along these lines, one
intriguing approach would be to promote macrophage-
mediated clearance of damaged target cells by interfering
with macrophage-directed “don't eat me” signals, such as
the one sent by surface CD47, a member of the immuno-
globulin superfamily. Blocking anti-CD47 antibody enables
macrophage-mediated phagocytosis of cancer cells, includ-
ing acute myeloid leukemia cells [139] and bladder cancer
cells [140]. A SIRP
a
CoI
SCP, an “affinity ratio” (defined as the CosR:CoS affinity
divided by the CoI:CoIR affinity) might govern in vivo
localization and function.
Immune inhibitory SCP need not be confined to the
CoSR
CoI motif. In place of the CoSR component, one
might substitute elements that bind to other classes of
surface molecules, for example, ligands (or antibody deriv-
atives) that engage chemokine receptors (CR). There is
substantial data available pegging chemokine receptor
expression to homing and other functional properties of
distinct lymphoid cell subsets [115], making them interest-
ing subjects for CR
CoI SCP design.
Yet another inhibitory SCP class would bring together
two coinhibitor elements, generating CoI
CoI fusions with
the capacity to elicit dual-signaling autoinhibitory loops.
The coinhibitor programmed cell death 1 ligand (PD-L1;
B7-H1; CD274) [111,116] is of special interest for such
fusions in light of its being a type I transmembrane protein.
Elegant type I
II chimeric proteins can be developed by
fusing PD-L1 to inhibitory TNF superfamily members,
generating SCP such as PD-L1
FasL and PD-L1
TRAIL.
These CoI
CoI SCP would target, in a cis loop-back mode,
activated T cells co-expressing PD-L1's receptor, PD-1
[117], along with Fas or TRAIL-R receptors. Here again,
the SCP would have other mechanistic possibilities. Inter-
estingly, PD-L1 has significant affinity for B7-1 (CD80)
[118]. This affords PD-L1-containing SCP the potential for
trans signal conversion, immune modulation via reverse
signaling through B7-1, and elicitation of immuno-
suppressive cytokine production by PD-1-triggered mono-
cytes [119]. There might even be a fortuitous synergy
between the trans signal conversion and cis loop-back
mechanisms in this case, in light of the demonstration
that costimulator blockade requires an intact PD-L/PD-1
signaling axis [120]. Moreover, the therapeutic reach of
these SCP spans autoimmunity and cancer, in light of
reported associations of PD-L1:PD-1 interaction with these
disease entities [121-123]. Since the functional repertoire of
PD-1's other ligand, PD-L2 (CD273), diverges from that of
TRAIL SCP fusion, incorporating
CD47's counter-receptor, SIRP
a
(CD172A), could serve
to induce tumor cell apoptosis (via the TRAIL end), while
simultaneously sensitizing them to macrophage-mediated
apoptotic cell destruction and clearance (via the SIRP
a
end),
in an auto-signaling mode. There is considerable reach for
this SCP since CD47's role in modulating macrophage
tumor surveillance likely extends to a range of tumor types
[141]. Additional dividends for a SIRP
a
TRAIL SCP would
be promotion of tumor antigen representation by macro-
phage and pro-apoptotic signaling in trans to neighboring
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