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Oss, Netherlands

Van Koppen C.J.,MSD NV Organon | De Gooyer M.E.,MSD NV Organon | Plate R.,MSD NV Organon | Conti P.,MSD NV Organon | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

TheTSH receptor (TSHR) on orbital fibroblasts (OF) is a proposed target of the autoimmune attack in Graves' ophthalmopathy. In the present study, we tested whether the novel low-molecularweight (LMW) TSHR antagonist Org-274179-0 inhibits cAMP production induced by rhTSH, Graves' disease IgG (GD-IgG), or M22 (a potent human monoclonal TSHRstimulating antibody) in cultured and differentiated OF from Graves' ophthalmopathy patients. cAMP production significantly increased after incubation either with 10 mU/ml rhTSH (3-fold; P≤ 0.05), 1 mg/ml GD-IgG (2-fold; P≤ 0.05), or 500 ng/ml M22 (5-fold; P ≤ 0.05). Incubation with the LMW TSHR antagonist dose dependently inhibited rhTSH, GD-IgG as well as the M22-induced cAMP production at nanomolar concentrations; complete blockade was affected at 10-6 m. Our results suggest that GD-IgG- and M22-induced cAMP production in differentiated OF is exclusively mediated via the TSHR because it can be completely blocked by the LMWTSHR antagonist, Org 274179-0. Copyright © 2012 by The Endocrine Society.

Miltenburg A.M.M.,MSD NV Organon | Prohn M.,MSD NV Organon | van Kuijk J.H.M.,MSD NV Organon | Tiessen R.G.,PRA International | And 2 more authors.
British Journal of Clinical Pharmacology | Year: 2013

Aim: Conjugation to antithrombin III ATIII-binding pentasaccharides has been proposed as a novel method to extend the half-life of therapeutic proteins. We aim to validate this technological concept in man by performing a first-in-human study using CarboCarrier® insulin (SCH 900948) as an example. A rising single dose phase 1 study was performed assessing safety, tolerability, pharmacokinetics and relative bioactivity of CarboCarrier® insulin. Safety, tolerability and pharmacokinetics (PK) of single doses of CarboCarrier® insulin in healthy volunteers were explored, and the dose-response relationship and relative bioactivity of CarboCarrier® insulin in subjects with type 2 diabetes were investigated. Methods: After an overnight fast, subjects were randomized to a treatment sequence. PK and pharmacodynamic (glucose, insulin and C-peptide) samples were obtained for up to 72h post-dose. Effects of CarboCarrier® insulin were compared with those of NPH-insulin. Results: CarboCarrier® insulin was safe and well-tolerated and no consistent pattern of adverse events occurred. CarboCarrier® insulin exposure (Cmax and AUC) increased proportionally with dose. The mean terminal elimination half-life ranged between 3.11 and 5.28h. All CarboCarrier® insulin dose groups showed decreases in the mean change from baseline of plasma glucose concentrations compared with the placebo group. Conclusions: CarboCarrier® insulin is pharmacologically active showing features of insulin action in man. The elimination half-life of the molecule was clearly extended compared with endogenous insulin, indicating that conjugation to ATIII-binding pentasaccharides is a viable approach to extend the half-life of therapeutic proteins in humans. This is an important step towards validation of the CarboCarrier® technology by making use of CarboCarrier® insulin as an example. © 2012 The British Pharmacological Society.

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