Biomedical Engineering Reference
In-Depth Information
andmay only become clearer in clinical development, if at all.
It should also be noted that in terms of facilitated dosing,
numerous other competing technologies exist outside of half-
life extension (discussed later in this chapter).
mAbs Humira and Remicade warn of the risk to TNF-
producing cells [13]. Cimzia
1
(certolizumab) is a further
non-FP TNF blocker, but consists of an Ab-binding domain
conjugated to PEG and does not therefore include an Fc
component. The anti-TNF biologics have enjoyed signifi-
cant levels of sales by offering improved efficacy to large
populations of autoimmune disorder patients via a mecha-
nism that was not previously possible using small molecule
drugs. Although pentoxifylline and bupropion have been
shown to have anti-TNF activity, levels of efficacy were only
low [17,18]. Other approaches have, however, been pro-
posed, such as by inhibiting TNF transcription, enhancing
TNF mRNA degradation, or blocking the formation of TNF
receptors via the preligand-binding assembly domain
(PLAD) [19,20]. As for all FP classes, developers must
stay aware of potential competing technologies that could
erode commercial advantages of the FP approach.
3.1.4 Decoy Receptors are the Largest FP Group
and Well Validated (1c)
The role of biochemical ligands in nature is to bind to
specific target proteins, causing a change in their status,
which can for example be linked to initiation of a signaling
cascade. Where this is implicated in a disease, pharmaco-
logical intervention can take place via either the target
receptor or its to inhibit the disease pathway. Decoy receptor
therapeutics use a ligand-binding component, such as a
receptor fragment,
to prevent
the ligand from binding
with its natural target.
The effectiveness of decoy receptor approaches for a
disorder can depend on a multitude of factors, including
reaction stoichiometry. Where the ligand is present in high
concentrations, receptor blockade may instead represent a
more efficient strategy. The specificity and side effect profile
may also vary. Decoy receptors can prevent the blocked ligand
frominteractingwith any other receptors thatmay be unrelated
to the disease, while receptor blockade can impact the path-
ways of other ligands that have affinity with the receptor.
Of the decoy receptor FPs we identified, nine are
cytokine traps, whereas the remaining two are T-cell
activator traps. These agents target 9 different ligands,
with development spanning 10 different lead indications.
This highlights the various roles for decoy receptors. In
comparison to other Fc fusion subclasses, decoy receptors
are the most mature, with four products launched on the
market—most notably, Enbrel. Despite its commercial
success, Enbrel is the only anti-TNF FP and it has lost
a considerable share of autoimmune disorder markets to
mAb anti-TNF competitors such as Remicade
1
and
Humira
1
(see Chapter 2). Primary differences between
the FP and mAb products relate to administration method
and frequency. Both classes of TNF blocker bind to the
target ligand with high affinity, although the mAbs disso-
ciate more slowly and have a longer serum half-life
[13,14]. Clinically significant differences have also been
revealed in certain indications, allowing the mAbs to
command broader labeling [15]. This is thought to relate
to subtle differences in the binding of TNF monomers and
trimer forms, which most likely resulted from binding
epitope differences rather being a function of broader
structural differences between the FPs and mAbs [16].
All of the decoy receptor FPs involve partnering with an
Fc portion of human IgG1 for half-life. Aside from Bristol-
Myers Squibb's Nulojix (belatacept), it is unclear whether
the Fc exerts any effector functions. These can cause
unintended cytotoxic effects and the labels for anti-TNF
3.1.5 Extended Half-Life Ligands (4c)
While decoy receptors involve receptor fragments to bind
and block ligands, extended half-life ligand FPs are instead
designed to utilize the function of a ligand. In both cases, the
ligand or receptor provides activity as well as binding
specificity. As such, no targeting partner is required to
deliver the active components.
Where the half-life of a receptor fragment or ligand alone
is sufficient, the unattached therapeutic proteins can be com-
mercially successful—such as recombinant blood factor
proteins or insulins. However, as described in earlier sections,
a longer half-life may be required for a product to be effica-
cious, or to offer benefits over competitors. In this group of
FPs, six are partnered with IgG Fc for half-life extension, with
the remaining two being albumin fusions. Endogenous ligands
are often short peptides as opposed to large proteins. Since the
short peptides can be made by synthetic approaches rather
than recombinant, decisions of whether to develop an FP or
use covalent attachment to a half-life moiety, can be highly
dependent on the nature of the ligand involved (discussed
further in manufacturing aspects later in this chapter).
The majority of identified extended half-life ligand FPs
are designed to bind to specific receptors and activate
signaling pathways. In keeping with this, all but one of
the lead development indications aim to restore normal
function in metabolic or hematological disorders, with the
ligand being either a recombinant human protein (such as
G-CSF or FVIII-Fc) or a mimetic (GLP-1 analog). Amgen's
Nplate is the only marketed product in this group, consisting
of a thrombopoietin (TPO) mimetic fused to IgG Fc and
approved for the treatment of thrombocytopenia. In a further
activation approach, Immutep's ImmuFact acts as an adju-
vant by binding to MHC class II receptors, resulting in the
production of cytokines required for an immune response.
Unlike these activating FPs, two ligand half-life FPs are
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