Demonstrating a powerful scale-up strategy for Biosimilar mAb in single use systems via physicochemical and functional characterization

Biosimilars have received a remarkable attention in the recent years. Due to the heterogeneity of biosimilar mAbs, they need to be well-characterized by various orthogonal techniques in order to identify their physicochemical and functional characteristics. Characterization of the post translational modifications, especially, glycosylation is vital to define the critical quality attributes (CQAs) which affect safety, efficacy and quality of drugs. In this study, we were able to manipulate the quality of the drug by using scale-up strategies for single use systems. By using ultra-performance liquid chromatography (UPLC) coupled to mass spectrometry (MS), we were able to demonstrate physicochemical similarities between innovator and its biosimilar candidate. Even the PTM (N-terminal pyroglutamic acid formation, C-terminal lysine truncation, methionine and tryptophan oxidation, asparagine deamidation, N-glycosylation and glycation) levels of two products from 3 and 200-liter single-use bioreactors were highly similar compared to the innovator. The mass spectrometry studies showed that the scale-up strategy from 3 liter to 200 liter was successful. Deconvoluted mass spectrum for intact and reduced masses (heavy and light chain) of innovator and its biosimilar candidates from different production scales were significantly similar. Oxidation was observed to be lower in 200 liter bioreactor compared to the 3 liter. The N-glycan profiles for the major and minor glycan species were highly similar compared to the originator. Aggregation level in 200 liter was slightly lower than that of the small scale production. Mass spectrometry becomes an important tool to enhance the biosimilarity to the originator in order to decrease the clinical efforts to be able to provide affordable drugs to the patients

Iodine Status in Turkish Populations and Exposure to Iodide Uptake Inhibitors

Perchlorate, nitrate, and thiocyanate are competitive inhibitors of the sodium iodide symporter of the thyroid membrane. These inhibitors can decrease iodine uptake by the symporter into the thyroid gland and may disrupt thyroid function. This study assesses iodine status and exposure to iodide uptake inhibitors of non-pregnant and non-lactating adult women living in three different cities in Turkey (Istanbul, Isparta and Kayseri). We measured iodine and iodide uptake inhibitors in 24-hr urines collected from study participants (N = 255). All three study populations were mildly iodine deficient, with median urinary iodine (UI) levels of 77.5 mu g/L in Istanbul, 58.8 mu g/L in Isparta, and 69.8 mu g/L in Kayseri. Perchlorate doses were higher in the study population (median 0.13 mu g/kg/day), compared with a reference population (median 0.059 mu g/kg/day), but lower than the U. S. EPA reference dose (0.7 mu g/kg/day). Urinary thiocyanate levels increased with increasing exposure to tobacco smoke, with non-smokers (268 mu g/L) significantly lower than light smokers (1110 mu g/L), who were significantly lower than heavy smokers (2410 mu g/L). This pilot study provides novel data indicating that study participants were moderately iodine deficient and had higher intakes of the iodide uptake inhibitor perchlorate compared with a reference population. Further investigation is needed to characterize the thyroid impact resulting from iodine deficiency coupled with exposure to iodide uptake inhibitors such as perchlorate, thiocyanate and nitrate

Use of telomerase promoter mutations to mark specific molecular subsets with reciprocal clinical behavior in IDH mutant and IDH wild-type diffuse gliomas

OBJECTIVE Recent studies have established that hemispheric diffuse gliomas may be grouped into subsets on the basis of molecular markers; these subsets are loosely correlated with the histopathological diagnosis but are strong predictors of clinical tumor behavior. Based on an analysis of molecular and clinical parameters, the authors hypothesized that mutations of the telomerase promoter (TERTp-mut) mark separate oncogenic programs among isocitrate dehydrogenase 1 and/or 2 (IDH) mutant (IDH-mut) and IDH wild-type (IDH-wt) diffuse gliomas independent of histopathology or WHO grade

Urinary thiocyanate levels increase with increasing exposure to cyanide from tobacco smoke.

<p>(CPD: cigarettes per day).</p

Median urinary levels (µg/L) and doses (µg/kg/day) iodine, perchlorate, nitrate and thiocyanate in Isparta, Istanbul and Kayseri.

<p>*Isparta lower than Kayseri, p<0.05.</p

Participant characteristics.

<p>BMI cutpoints (kg/m²): Underweight (<18.5); Normal (18.5–24.9); Overweight (25–30); Obese (>30). Smoker: total number of current smokers (light and heavy).</p

Distribution of urinary thiocyanate excretion (µg/L) for the total study population.

<p>Distribution of urinary thiocyanate excretion (µg/L) for the total study population.</p

Distribution of urinary nitrate excretion (µg/L) for the total study population.

<p>Distribution of urinary nitrate excretion (µg/L) for the total study population.</p

Scatter plot matrix showing correlations of urinary excretion of iodine and iodide uptake inhibitors (perchlorate, thiocyanate and nitrate).

<p>Scatter plot matrix showing correlations of urinary excretion of iodine and iodide uptake inhibitors (perchlorate, thiocyanate and nitrate).</p

The composition of modified UW solution used in experimental studies.

The composition of modified UW solution used in experimental studies.</p