Abstract
The long-acting growth hormone (LAGH) is a promising alternative biopharmaceutical to treat growth hormone (GH) deficiency in children, and it was developed using a variety of technologies by several pharmaceutical companies. Most LAGH preparations, such as Fc fusion protein, are currently undergoing preclinical study and clinical trials. Accurate determination of bioactivity is critical for the efficacy of quality control systems of LAGH. The current in vivo rat weight gain assays used to determine the bioactivity of recombinant human GH (rhGH) in pharmacopoeias are time-consuming, expensive, and imprecise, and there are no recommended bioassays for LAGH bioactivity in pharmacopoeias. Therefore, we developed a cell-based bioassay for bioactivity determination of therapeutic long-acting Fc-fusion recombinant human growth hormone (rhGH-Fc) based on the luciferase reporter gene system, which is involved in the full-length human GH receptor (hGHR) and the SG (SIE and GAS) response element. The established bioassay was comprehensively validated according to the International Council for Harmonization (ICH) Q2 (R1) guidelines and the Chinese Pharmacopoeia, and is highly precise, time-saving, simple, and robust. The validated bioassay could be qualified for bioactivity determination during the research, development, and manufacture of rhGH-Fc, and other LAGH formulations.
Highlights
Growth hormone (GH), known as somatotropin, is pituitary-derived anabolic hormone that regulates a number of metabolic processes involved in growth and development [1,2]
Upon binding to the GH receptor, the GH-associated janus kinase 2 (JAK2) tyrosine kinase is activated, and the signaling proteins to GH receptor (GHR)–JAK2 complexes are recruited by phosphorylated tyrosines and subsequently induce signal transducers and activators of transcription (STAT), mitogen-activated protein kinases (MAPK), and phosphatidylinositol 3 kinase (PI3K) intracellular signaling pathways [3,4]
The two cell lines were evaluated for luciferase activity after Recombinant human GH (rhGH)-Fc stimulation
Summary
Growth hormone (GH), known as somatotropin, is pituitary-derived anabolic hormone that regulates a number of metabolic processes involved in growth and development [1,2]. Long-acting growth hormone (LAGH) formulations with extended half-lives have been developed to improve adherence and simplify dosing schedules, which were existing disadvantages of rhGH [6,8,9,10,11,12,13]. The bioassay for rhGH bioactivity highly relies on in vivo rat weight gain, as described in the US Pharmacopeia and the Chinese Pharmacopoeia, and it is time-consuming, expensive, and imprecise. The development of an animal-free bioassay with a low coefficient of variation (CV) that is time-saving and simple to carry out needs to be explored to facilitate the determination of bioactivity for LAGH formulations. We develop a cell-based bioassay to determine the bioactivity of therapeutic rhGH-Fc using.
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