Immunogenicity, toxicology, pharmacokinetics and pharmacodynamics of growth hormone ligand-receptor fusions.
Résumé
A fundamental concern for all new biological therapeutics is the possibility of inducing an immune response. We have recently demonstrated that a ligand-receptor fusion (LR-fusion) of growth hormone generates a potent long-acting agonist, however the immunogenicity and toxicity of these molecules have not been tested. To address these issues we have designed molecules with low potential as immunogens and undertaken immunogenicity and toxicology studies in Macaca fascicularis and pharmacokinetic and pharmacodynamic studies in rats. Two variants of the LR-fusion, one with a flexible linker (GH-LRv2) and the other without (GH-LRv3), were tested. Comparison was made with native human GH. GH-LRv2 and GH-LRv3 demonstrated similar pharmacokinetics in rats, showing reduced clearance compared to native GH and potent agonist activity with respect to body weight gain in a hypophysectomised rat model. In M. fascicularis a low level of antibodies to GH-LRv2 was found in one sample but there was no other evidence of any immunogenic response to the other fusion protein. There were no toxic effects and specifically no changes in histology at injection sites after two repeated administrations. The pharmacokinetic profiles in monkeys confirmed long half lives for both GH-LRv2 and GH-LRv3 representing exceptionally delayed clearance over rhGH. The results suggest that repeated administration of a GH LR-fusion is safe, non-toxic and the pharmacokinetic profile suggests that two to three weekly administration is a potential therapeutic regimen for humans.
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