Pharmacokinetic Comparability of a Biosimilar Trastuzumab Anticipated from Its Physicochemical and Biological Characterization

Abstract

Comparability between a biosimilar and its reference product requires the evaluation of critical quality attributes that may impact on its pharmacological response. Herein we present a physicochemical characterization of a biosimilar trastuzumab focused on the attributes related to the pharmacokinetic response. Capillary isoelectrofocusing (cIEF) and cation exchange chromatography (CEX) were used to evaluate charge heterogeneity; glycosylation profiles were assessed through hydrophilic interaction liquid chromatography (HILIC); aggregates content was evaluated through size exclusion chromatography (SEC) while binding affinity to FcRn was evaluated using isothermal titration calorimetry (ITC). The biosimilar trastuzumab and its reference product exhibited a high degree of similarity for the evaluated attributes. In regard to the pharmacokinetic parameters, randomized, double blind, and two-arm parallel and prospective study was employed after the administration of a single intravenous dose in healthy volunteers. No significant differences were found between the pharmacokinetic profiles of both products. Our results confirm that similarity of the critical quality attributes between a biosimilar product, obtained from a different manufacturing process, and the reference product resulted in comparable pharmacokinetic profiles, diminishing the uncertainty related to the biosimilar's safety and efficacy.

Successful Application of CuAAC Click Reaction in Constructing 64Cu-Labeled Antibody Conjugates for Immuno-PET Imaging

“…Thus, although the tumor uptake signals of conjugate 9 are high in PET images obtained at 24 h (Figure a), a substantial level of background noise interferes with the signals over the whole body, with significant uptakes in the blood (heart), liver, spleen, and bladder. Due to the long biological half-life of trastuzumab, − the tumor-to-background ratios did not improve much until 48 h (Figure b). When whole-body activities of the mice were measured, only 16 and 31% of the injected activity of conjugate 9 were excreted from the body by 24 and 48 h, respectively (Figure S35).…”

Comparison of Strategies in Development and Manufacturing of Low Viscosity, Ultra-High Concentration Formulation for IgG1 Antibody

“…Miao et al 30 in their work on concentration/diafiltration for antibodies demonstrated low histidine concentration in retentate because of repulsive charge interactions between positively-charged histidine molecules and positively-charged protein molecules. Miranda et al 31 demonstrated that IgG1 has an isoelectric point of 8.7. Based on observations of Stoner et al 32 and Teerters et al 33 it can be concluded that, histidine with isoelectric point of 7.6 will be positively charge at pH 6.0.…”

Investigation of native and aggregated therapeutic proteins in human plasma with asymmetrical flow field-flow fractionation and mass spectrometry

“…The monoclonal antibody trastuzumab was supplied by Bernt Nilsson (Lund University, Sweden) [39,40] at a stock concentration of 8.4 mg/mL in a buffer with 25 mM sodium phosphate buffer, 25 mM sodium acetate, and 120 mM NaCl at pH 6.2. Trastuzumab has a molecular weight of 148,300 Da and an isoelectric point of 8.7 [41]. Tris hydrochloride (molecular biology grade, ≥99%), 1,4-dithiothreitol (Ellman′s reagent, ≥97%), iodoacetamide (BioUltra, ≥99%), sodium deoxycholate (≥97%), trypsin porcine (MS grade), plasma (human, P9523), and trifluoroacetic acid (HPLC grade, > 99%) were purchased from Sigma-Aldrich (St. Louis, MO, USA).…”