Biomedical Engineering Reference
In-Depth Information
RECEPTOR-Fc AND LIGAND TRAPS AS HIGH-AFFINITY
BIOLOGICAL BLOCKERS: DEVELOPMENT AND
CLINICAL APPLICATIONS
A
RIS
N. E
CONOMIDES AND
N
EIL
S
TAHL
Regeneron Pharmaceuticals, Tarrytown, NY, USA
9.1 Introduction
9.2 Etanercept as a prototypical receptor-Fc-based cytokine
blocker
9.3 Heteromeric traps for ligands utilizing multicomponent
receptor systems with shared subunits
9.4 Development and clinical application of an interleukin 1 trap:
rilonacept
9.5 Development and clinical application of a VEGF trap
9.6 “To trap or not to trap?” advantages and disadvantages of
receptor-Fc fusions and traps versus antibodies
9.7 Conclusion
Acknowledgment
References
Traps that target secreted factors and cytokines. Other types
of peptide-Fc fusions, such as ligand-Fc fusions, or artificial
proteins based on other scaffolds have been reviewed exten-
sively elsewhere [1-9].
The idea that receptor ectodomains can act as modulators
of growth factor and cytokine signaling has its origins in the
discovery of naturally produced soluble receptors. The
presence of these proteins was first demonstrated in cell
culture for the epidermal growth factor (EGF) [10] and
interleukin-2 receptors (IL-2R) [11], then in rapid succes-
sion found to be a property of many cytokine and growth
factor receptor systems. These soluble receptors arise either
through proteolytic cleavage mediated by “sheddases” or
through translation of alternatively spliced transcripts [12].
Furthermore, they are present in bodily fluids, and their
production is altered during disease [13-18]. These discov-
eries led to the realization that soluble receptors may
represent endogenous modulators of growth factor and
cytokine action, and gave rise to the idea of using soluble
receptors as therapeutics in diseases where aberrant expres-
sion of a factor or cytokine plays a key role in pathogenesis
[19-24].
The ability of soluble receptors to act as blockers or
decoys for their cognate ligand was initially demonstrated in
the IL-2-R system [25,26], and subsequently was shown to
hold true for other cytokines (for reviews, see References
[21,27], and [28]). In fact, modulation of cytokine and
growth factor signaling by decoy receptors [21], coreceptors
[29-31], as well as various other receptor-like modulators
[32-39], and secreted blockers [40-45] has been demon-
strated for many different types of extracellular signaling
9.1
INTRODUCTION
The ability to inhibit the action of growth factors and
cytokines via pharmacologic reagents has been of great
interest and utility. One important class of blockers is based
on extracellular domains (ectodomains) of receptors that
function as decoys when engineered as soluble proteins.
Proteins composed of receptor ectodomains fused to a
stabilizing moiety, usually the fragment crystallizable (Fc)
region of IgG, as well as more complex hybrids with Fc
such as Traps that incorporate more than one ectodomain,
have been used successfully both in research and in the
clinic. This review focuses on the various clinically relevant
receptor ectodomain-Fc (receptor-Fc) fusion proteins and
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