Biomedical Engineering Reference
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While not definitive proof that antibodies will not be
generated against the LR-fusions in humans, the fact that the
fusion proteins, given at 10 times the human physiological
dose, do not initiate an immune response in these animals
gives strong reassurance of their nonimmunogenicity when
used as a biopharmaceutical in humans.
15.4.6 Toxicology
The animals used in the immunology study were also used to
investigate the toxicological effects of the LR-fusions.
Blood and urine samples were taken for analysis prior to
the start of the treatment and then during week six. After
necropsy, external and internal examinations of the monkeys
were performed; this included an examination of the major
organs and the injection site.
No treatment-related effects on clinical signs, body
weights, hematology, blood chemistry, urine analysis, organ
weight, or necropsy were observed during the study. There
was no evidence of lipoatrophy or reaction at the injection site.
FIGURE 15.8
The rate of clearance of GH is reduced by the
formation a GH-GHBP complex. The GH LR-fusions have a
reduced rate of clearance and this is thought to be due to the
formation of an inactive LR-fusion dimer.
15.5 LR-FUSIONS: THE NEXT GENERATION IN
HORMONE TREATMENT
15.6 CONCLUSION
Fusions of growth hormone (GH) and its receptor (GHR)
have been generated to produce molecules that mimic the
effects of GH with the added advantage of a much reduced
rate of clearance from the vascular system. These ligand-
receptor (LR) fusions were observed to form head to tail
reciprocal dimers; this characteristic of the GH LR-fusions
is thought to further extend the circulating half-life of these
molecules. LR fusions have the potential to generate potent
long-acting biologicals.
The GH LR-fusions demonstrate a potential long-acting GH
therapy. The use of GH LR-fusion proteins as a therapeutic
in lieu of hGH is attractive for a number of reasons. The
main advantage of the GH LR-fusions over hGH is their
exceptional pharmacokinetic and pharmacodynamic effects.
Which could enable 3-4 weekly injections of the GH LR-
fusion rather than daily injections of hGH. This would
increase convenience to the patient and so increase his/her
“quality of life.”
They are also produced as a single amino acid chain and do
not require further modification after purification, and so both
the heterogeneity and cost of production of the final product
are greatly reduced in comparison to PEGylatedGHand depot
preparations. The GH LR-fusions show low immunogenicity
and no toxicological effects of the GH LR-fusions were
observed in the studies in monkeys and there were no
reactions at the injection sites or evidence of lipoatrophy.
These studies demonstrate that the reduced rate of clear-
ance shown by the GH LR-fusion is due to the dimerization
of the GH-GHRec molecules. We propose a hypothesis in
which the LR-fusion circulates as an inactive dimer
“reservoir” which is in equilibrium with the active monomer
form. The fusion monomers are active and have a reduced
rate of clearance compared to GH while the dimers are
inactive and are even less readily cleared from the vascular
system (Figure 15.8).
The LR-fusion technology can be used in other ligand-
receptor systems and may provide the basis of a range of
next-generation hormone replacement therapeutics.
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with polyethylene glycol. J. Biol. Chem. 271, 21969-21977.
3. Touraine P, D'Souza GA, Kourides I, Abs R, Barclay P, et al.
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4. Hodish I, Barkan A. (2008) Long-term effects of pegvisomant
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