CELL-SPECIFIC TARGETING OF FUSION PROTEINS THROUGH HEPARIN BINDING - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 398

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CELL-SPECIFIC TARGETING OF FUSION PROTEINS
THROUGH HEPARIN BINDING

J IAJING W ANG ,Z HENZHONG M A , AND J EFFREY A. L OEB

Department of Neurology, Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA

27.1 Why target heparan-sulfate proteoglycans with fusion
proteins?
27.2 Heparan sulfate structure and biosynthesis create diversity
and a template for targeting specificity
27.3 Tissue-specific expression of HSPGs and the enzymes that
modify them
27.4 Heparin-binding proteins and growth factors
27.5 Viruses target cells through heparin binding
27.6 Dissecting heparin-binding protein domains for tissue-
specific targeting
27.7 Fusion proteins incorporating HBDs
27.8 The neuregulin 1 growth factor has a unique and highly
specific HBD
27.9 Using neuregulin's HBD to generate a targeted neuregulin
antagonist
27.10 Tissue targeting and therapeutic efficacy of a heparin-
targeted NRG1 antagonist fusion protein
27.11 Conclusions and future perspectives
References

block-specific biological processes to treat human diseases.
One of the foremost obstacles is getting these powerful
biopharmaceuticals to diseased tissues specifically. This is
critical not only to achieve sufficient levels of drug for efficacy
but also to minimize unwanted side effects in other tissues
[1,2]. However, many new biopharmaceutical drugs have
failed in clinical trials despite extensive preclinical testing
both in culture and in animal models. Inmany cases, this is due
to the lack of specific targeting resulting in unwanted toxicity
and/or failed efficacy. An important example comes from
neurotrophic factors that have been used to treat neuro-
degenerative disorders, such as brain-derived neurotrophic
factor (BDNF; Regeneron) and glial cell line-derived neuro-
trophic factor (GDNF; Amgen), that failed in clinical trials in
part because of poor targeting [3].
One of the ways that nature has learned to target growth
factors and viruses to specific cells is through specific
interactions with cell-surface molecules many of which
reside in the extracellular matrix (ECM). The ECM provides
cells with not only scaffold and support but also appears to
be critical for important cellular and tissue functions includ-
ing differentiation, proliferation, migration, and chemotaxis
[4]. The ECM is composed of heterogeneous mixtures of
various key proteins, such as collagens and proteoglycans.
Proteoglycans produce some of the most diverse set of
structures that give each cell, or portions of that cell, a
unique cell-surface signature. Proteoglycans are large trans-
membrane or extracellular secreted proteins with a majority
of their molecular composition consisting of covalently
attached glycosaminoglycan (GAG) side chains. GAGs
can be classified as keratan sulfate (KS), chondroitin sulfate

27.1 WHY TARGET HEPARAN-SULFATE
PROTEOGLYCANS WITH FUSION PROTEINS?

The current revolution in functional genomic technologies has
led to the identification of novel genes that have the potential
to become powerful new drugs to treat human diseases from
cancer to neurodegenerative disorders. Those drugs are often
called biopharmaceuticals because they consist of recombi-
nant proteins and/or nucleic acids and can be used to initiate or