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Endocrine Abstracts (2014) 34 OC5.6 | DOI: 10.1530/endoabs.34.OC5.6

SFEBES2014 Oral Communications Pituitary (6 abstracts)

A GH antagonist fusion with GH binding protein is biologically active, shows delayed clearance and inhibits growth in a rabbit model

Ian Wilkinson , Michael Phipps , Jon Sayers , Peter Artymiuk & Richard Ross

Sheffield University, South Yorkshire, UK.

Background: Acromegaly is associated with increased morbidity and mortality, however currect medical treatment controls the disease in <60% of patients. Pegvisomant, a pegylated GH antagonist, controls the disease in over 95% of cases, but is not cost effective as it requires high dose daily injections and has side-effects. We have developed a technology for generating a long acting potent GH antagonist.

Hypothesis: That a GH antagonist fused to GH binding protein will generate a potent long acting antagonist.

Methods: Fusion proteins were purified from CHO cells and tested in a bioassay. Pharmacokinetic studies were conducted in rats and pharmacodynamic studies in growing New Zealand white rabbits. Full ethics approval was obtained for all experiments.

Results: GH antagonist fusions were cloned, expressed and purified. Given at 1 nmol/kg to 6 rats the antagonist showed delayed clearance with plasma half-life of 21.0 h compared to GH at 1.2 h. A single sc dose of GH antagonist at 0.5, 1.0 and 2.0 mg/kg resulted in decreased weight gain over 12 days compared to vehicle control and the decrease in weight gain was greater than that seen after Pegvisomant given as 5 separate injections of 3 mg/kg on days 1, 2, 6, 7 and 8 days (see table).

Table 1
GH antagonist fusion single dose s.c. at day zero
Rabbits n=3 per group weight gain over 12 daysVehicle0.5 mg/kg1 mg/kg2 mg/kgPegvisomant (5× doses at 3 mg/kg)
Mean % weight gain24.317.015.515.017.2

Conclusions: A fusion of GH antagonist to GH binding protein shows antagonist bioactivity in vitro, delayed clearance in vivo and inhibits growth in rabbits. Based on these observations a GH antagonist fusion has the potential for a potent once weekly subcutaneous therapy for patients with acromegaly.

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