Biomedical Engineering Reference
In-Depth Information
12
TRANSFERRIN FUSION PROTEIN THERAPIES:
ACETYLCHOLINE RECEPTOR-TRANSFERRIN
FUSION PROTEIN AS A MODEL
D ENNIS K EEFE ,M ICHAEL H EARTLEIN , AND S ERENE J OSIAH
Shire Human Genetic Therapies, Lexington, MA, USA
12.1 Disease overview
12.2 Fusion protein SHG2210 design
12.3 Characterization of SHG2210
12.4 Applications and indications
12.5 Future perspectives
12.6 Conclusion
References
motor disturbances, difficulty in chewing and swallowing,
breathlessness, and difficulty in speaking. While MG can
present at any age, it typically appears in the late 20s
(females) to 40s (males), and results in mortality in 3-4%
of cases.
Approximately 80% of MG patients develop antibodies
to the AChR, while about half of the remaining individuals
develop antibodies to muscle-specific tyrosine kinase
(MuSK) [1,5] The clinical improvement seen in patients
following plasmapheresis supports the assessment that auto-
antibodies promote disease presentation [6]. Animal studies
also provide evidence that the MG phenotype is through
autoantibodies against AChR. MG disease presentation can
be induced in animal models either by immunization with
purified AChR receptor or passive transfer of patient sera or
monoclonal antibodies to the main immunogenic region
(MIR) of the AChR [7,8]. Thus, it is well established
that autoantibodies against AChR are the primary effectors
of MG.
The presence of anti-AChR antibodies in serum is diag-
nostic for MG. Current treatment strategies for MG include
thymectomy, steroids, immunosuppressive agents, plasma-
pheresis, or intravenous immunoglobulin (IVIG) treatment
[9]. Clinical improvement associated with a particular ther-
apy or combination of therapies is generally correlated with
a notable decrease in circulating autoantibody levels.
The AChR is a transmembrame pentameric protein con-
taining two a -subunits and one each of b , d , and
12.1 DISEASE OVERVIEW
Myasthenia gravis (MG) is a rare antibody-mediated auto-
immune disease with a prevalence of
40,000 patients in the
United States. The disease pathogenesis is well described
and a hallmark of the disease is the development of anti-
bodies targeted to the nicotinic acetylcholine receptor
(AChR) located at the surface of neuromuscular junctions
(NMJ) (reviewed in Reference [1]). The binding of auto-
antibodies to the receptor leads to multiple complications
leading ultimately to loss of functional NMJ. The antibodies
can (1) interfere with the acetylcholine signaling pathway,
(2) downregulate AChR expression on the cell surface, and
(3) activate the complement cascade promoting formation of
the membrane attack complex (MAC). Together, these
events lead to necrosis and inflammation [2-4], which
results in failure of appropriate neuromuscular synaptic
transmission and the subsequent muscle weakness seen in
MG patients. In addition to muscle weakness in the arms and
legs, other clinical signs include drooping eyelids, ocular
subunits
[10]. It is likely that the autoantibodies cross-react with
multiple subunits as there is
e
40% amino acid sequence
homology between the subunits [11]. The antibody response
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