Biomedical Engineering Reference
In-Depth Information
15
LIGAND-RECEPTOR FUSION DIMERS
S ARBENDRA L. P RADHANANGA , 1 I AN R. W ILKINSON , 1 E RIC F ERRANDIS , 2 P ETER J. A RTYMIUK , 3 J ON R. S AYERS , 4
AND R ICHARD J. R OSS 1
1 Department of Human Metabolism, University of Sheffield, Medical School, Sheffield, UK
2 IPSEN, Institut Henri Beaufour, Les Ulis, France
3 Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, UK
4 Department of Infection & Immunity, University of Sheffield, Medical School, Sheffield, UK
15.1 Introduction
15.2 The GHLR-fusions
15.3 Expression and purification
15.4 Analysis of the LR-fusions
15.5 LR-fusions: the next generation in hormone treatment
15.6 Conclusion
References
been taken to extend the clearance half-life of GH, thereby
decreasing the frequency of the GH injections and so
providing greater convenience to the patient.
PEGylation of the GH molecule (where poly(ethylene
glycol) molecules are covalently bound to the GH molecule)
increases the size of the therapeutic molecule hence reduc-
ing its clearance rate via the kidneys, decreasing the
hormone's immunogenic profile and also protecting the
GH molecule from proteases [2]. However, PEGylation
greatly reduces the affinity of the hormone for its receptor
[2] and has been associated with lipoatrophy [3] and hepa-
totoxic effects [4,5]. It is thought that the lack of renal
clearance may allow the levels of the PEGylated proteins to
accumulate to toxic levels [6].
A sustained-release or depot preparation, where GH is
encapsulated in microspheres, is another means of
increasing the intervals of injections during GH treat-
ment [7-9]. However, this method also has some dis-
advantages; namely, bruising and pain at the injection
site [10], the formation of small erythematous nodules at
the injection site [8,10] and initial supra-physiological
GH levels followed by a slow decline over the dosing
period [11].
PEGylation and depot preparations of GH are both
relatively expensive to manufacture due to the complex
processing required to produce these therapies. A therapeu-
tic that does not require the complex processing required by
the aforementioned products, while maintaining their pro-
longed activity would be highly desirable to the manufac-
turer, the clinician, and patient.
15.1
INTRODUCTION
Growth hormone (GH) is a cytokine hormone that regulates
linear growth in childhood and normal body composition in
adults [1]. GH therapy is used to treat GH deficiency; in
children, treatment has obvious benefits with the deficient
child showing an increase in growth rate within a few
months of starting treatment, other benefits may also be
noticed such as increased strength and reduction of body fat.
In adults, the effects of GH treatment are less obvious but
still measurable and include improved bone density,
increased muscle mass, decreased adipose tissue, a strength-
ened immune system, improved circulatory system, and
blood lipid levels. GH has also been used to treat wasting
due to HIV, and short stature in Turner's and Prader-Willi
syndrome and chronic renal failure.
The current therapeutic regimen for GH therapy is once-
daily subcutaneous injections, which are expensive and
inconvenient to the patient. A number of approaches have
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