A fundamental concern for all new biological therapeutics is the possibility of inducing an immune response. We have recently demonstrated that an LR-fusion (ligand–receptor 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 (growth hormone). GH–LRv2 and GH–LRv3 demonstrated similar pharmacokinetics in rats, showing reduced clearance compared with native GH and potent agonist activity with respect to body weight gain in a hypophysectomized 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 (recombinant human GH). 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 administrations is a potential therapeutic regimen for humans.
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Research Article|
August 17 2010
Immunogenicity, toxicology, pharmacokinetics and pharmacodynamics of growth hormone ligand–receptor fusions
Eric Ferrandis;
Eric Ferrandis
1
*Institut Henri Beaufour, Ipsen, Les Ulis, Cédex 91966, France
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Sarbendra L. Pradhananga;
†Department of Infection and Immunity, University of Sheffield, Sheffield S10 2RX, U.K.
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Caroline Touvay;
Caroline Touvay
*Institut Henri Beaufour, Ipsen, Les Ulis, Cédex 91966, France
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Carol Kinoshita;
Carol Kinoshita
‡Ipsen Biomeasure, Milford, MA 01757, U.S.A.
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Ian R. Wilkinson;
Ian R. Wilkinson
2
§Department of Human Metabolism, University of Sheffield, Sheffield S10 2RX, U.K.
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Kevin Stafford;
Kevin Stafford
‡Ipsen Biomeasure, Milford, MA 01757, U.S.A.
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Zida Wu;
Zida Wu
∥Department of Medicine, Campus Mitte Charite-Universitatsmedizim, 10117 Berlin, Germany
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Christian J. Strasburger;
Christian J. Strasburger
∥Department of Medicine, Campus Mitte Charite-Universitatsmedizim, 10117 Berlin, Germany
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Jon R. Sayers;
Jon R. Sayers
2
†Department of Infection and Immunity, University of Sheffield, Sheffield S10 2RX, U.K.
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Peter J. Artymiuk;
Peter J. Artymiuk
2
¶Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, U.K.
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Richard J. Ross
Richard J. Ross
2
§Department of Human Metabolism, University of Sheffield, Sheffield S10 2RX, U.K.
Correspondence: Professor Richard J. Ross (email [email protected]).
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Publisher: Portland Press Ltd
Received:
April 30 2010
Revision Received:
June 14 2010
Accepted:
July 02 2010
Accepted Manuscript online:
July 02 2010
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2010 Biochemical Society
2010
Clin Sci (Lond) (2010) 119 (11): 483–491.
Article history
Received:
April 30 2010
Revision Received:
June 14 2010
Accepted:
July 02 2010
Accepted Manuscript online:
July 02 2010
Citation
Eric Ferrandis, Sarbendra L. Pradhananga, Caroline Touvay, Carol Kinoshita, Ian R. Wilkinson, Kevin Stafford, Zida Wu, Christian J. Strasburger, Jon R. Sayers, Peter J. Artymiuk, Richard J. Ross; Immunogenicity, toxicology, pharmacokinetics and pharmacodynamics of growth hormone ligand–receptor fusions. Clin Sci (Lond) 1 December 2010; 119 (11): 483–491. doi: https://doi.org/10.1042/CS20100241
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