Follow‐up of antibodies to growth hormone in 210 growth hormone‐deficient children treated with different commercial preparations

Pirazzoli, P; Cacciari, E; Mandini, M; Cicognani, Alessandro; Zucchini, Stefano; Sganga, T; Capelli, M.

doi:10.1111/j.1651-2227.1995.tb13539.x

Cited by 18 publications

(11 citation statements)

References 13 publications

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“…In this work, we analyzed the impact of aggregates on DC, as these professional antigen‐presenting cells are known to have a crucial role in adaptive immune responses. We chose three protein models to generate aggregates that we next characterized: recombinant hGH, for which ADA formation has been reported in 1–75% of treated patients, 29 , 30 , 31 a serum‐purified human IgG1 and a chimeric antibody, Rituximab, that showed clinical immunogenicity in rheumatoid arthritis patients 32 , 33 . We then showed that aggregates were able to induce moDC maturation, evidenced by key surface markers increase, and by cytokines and chemokines production.…”

Section: Discussionmentioning

confidence: 99%

Effect of growth hormone and IgG aggregates on dendritic cells activation and T‐cells polarization

et al. 2016

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Patients treated with therapeutic biological products (BP) frequently develop anti-drug antibodies (ADA) with potential neutralizing capacities leading to loss of clinical response or serious side effects. BP aggregates have been suggested to promote immunogenicity, thus enhancing ADA production. Dendritic cells (DC) are key effectors in T-cell and B-cell fates, and the subsequent generation of immunogenicity. The objective of this work was to determine if BP aggregates can participate to DC maturation and T-cell activation. We compared aggregates from three different proteins: human growth hormone (hGH), Rituximab, a chimeric anti-CD20 antibody and a serum-purified human IgG1. All three proteins underwent a stir stress, generating comparable populations of aggregated particles. Maturation of human monocyte-derived DC (moDC) upon exposure to native BPs or aggregates was evaluated in vitro. Results showed that hGH aggregates induced an increased expression of moDC co-stimulation markers, and augmented levels of IL-6, IL-8, IL-12p40, CCL2, CCL3, CCL4 and CXCL10. Both antibodies aggregates were also able to modify DC phenotype, but cytokine and chemokine productions were seen only with IL-6, IL-8, IL-12p40 and CXCL10. Aggregates-treated moDC enhanced allogenic T-cell proliferation and cytokines production, suggesting Th1 polarization with hGH, and mixed T-cell responses with antibodies aggregates. These results showed that BP aggregates provoked DC maturation, thus driving adaptive T-cell responses and polarization.

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Section: Discussionmentioning

confidence: 99%

Effect of growth hormone and IgG aggregates on dendritic cells activation and T‐cells polarization

et al. 2016

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“…In humans, GH therapy has been variably reported to initiate an immune response between 1 to 75 % of patients [6][7][8][9][10][11][12][13][14][15][16], and the degree of immune response is due to the source of the GH, its purity and the formulation [4]. The presence of anti-GH antibodies did not appear to have a detrimental effect on the therapeutic efficacy of GH in most of these cases.…”

Section: Table 2 Immunogenicity Results For Gh-lrv2 Gh-lrv3 and Hghmentioning

confidence: 99%

“…In 30-60 % of patients, antibodies against pituitary-derived human GH were detected, and in 5 % of treated patients, these antibodies blocked the therapeutic activity of GH [5]. Antibody formation to GH has been reported in 1-75 % of patients treated with recombinant human GH [6][7][8][9][10][11][12][13][14][15][16], but these antibodies have not been inhibitory or harmful. Antibodies are found whether GH is produced in Escherichia coli or mammalian cells [15].…”

Section: Introductionmentioning

confidence: 99%

“…Antibody formation to GH has been reported in 1-75 % of patients treated with recombinant human GH [6][7][8][9][10][11][12][13][14][15][16], but these antibodies have not been inhibitory or harmful. Antibodies are found whether GH is produced in Escherichia coli or mammalian cells [15]. Antibody formation probably relates to a small amount of denatured GH in the preparation [17], although antibody production is generally greater with pituitary-derived GH and recombinant GH with an N-terminal methionine residue; recent studies suggest similar immunogenicity when GH is presented in a depot preparation [18].…”

Section: Introductionmentioning

confidence: 99%

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Immunogenicity, toxicology, pharmacokinetics and pharmacodynamics of growth hormone ligand–receptor fusions

et al. 2010

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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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“…In such a case the increased immunogenicity was indicated to be the main reason of in vivo growth hormone inactivity. 25 Dose-related adverse events associated to the systemic administration of proteins and peptides represent another restriction to their clinical application. Most physiological proteins do not normally circulate through the body to reach their target cell or tissue; rather, they are frequently synthesised at local sites where they act and degrade without reaching appreciable systemic levels.…”

Section: Main Problems To Protein Deliverymentioning

confidence: 99%

Nanotechnologies in Protein Delivery

Salmaso¹,

Bersani²,

Semenzato³

et al. 2006

j nanosci nanotechnol

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The growth rate for biotech drugs, namely proteins, peptides, and oligonucleotides, is dictated by the parallel progresses in biotechnology and nanotechnology. Actually, biotechnology techniques have expanded enormously the arsenal of therapeutically useful peptides and proteins making these products of primary interest for future pharmaceutical market. Nevertheless, the exploitation of protein and peptide drugs is strictly related to the development of innovative delivery systems which should provide for controlled, prolonged, or targeted delivery, improved stability during storage and delivery, reduced adverse effects, increased bioavailability, improved patient compliance and allow for administration through the desired route and cope with cost-containment therapeutic protocols. Colloidal formulations ideally possess the physicochemical and biopharmaceutical requisites for protein delivery. Pharmaceutical nanotechnology is a tool of techniques applied to design, develop and produce these systems. It involves the investigation of innovative materials and production procedures for preparation of a variety of nanosized dosage forms, which range from solid nanoparticles to soluble bioconjugates. The research and development of innovative tailor made protein delivery systems, which must be designed according to the drug candidate pharmacological and physicochemical properties, is one of the primary aim of modern pharmaceutical technology. Therefore, as an unmet need exists for technologies that combine innovative drug delivery solutions, a close un-prejudicial interaction between academic and industrial researchers as well as business thought leaders is required.

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Follow‐up of antibodies to growth hormone in 210 growth hormone‐deficient children treated with different commercial preparations

Cited by 18 publications

References 13 publications

Effect of growth hormone and IgG aggregates on dendritic cells activation and T‐cells polarization

Effect of growth hormone and IgG aggregates on dendritic cells activation and T‐cells polarization

Immunogenicity, toxicology, pharmacokinetics and pharmacodynamics of growth hormone ligand–receptor fusions

Nanotechnologies in Protein Delivery

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