Globally, patents on several well established biologic agents used to treat rheumatic diseases have already or will expire over the next few years, allowing for the availability of subsequent entry biologics (SEBs or biosimilars). The objective of this study was to identify gaps in knowledge and attitudes towards SEBs among Canadian rheumatologists. Eighty-one rheumatologists completed the survey and were included in the analysis (22 % of the 369 who were contacted). We found that one third of physicians (31 %) were familiar with SEBs and that physicians with greater than 20 years of practice were significantly more likely to be familiar or very familiar with SEBs compared to respondents with less than 10 years or 10-20 years of experience (OR 11.1, 95 % CI: 2.1-55.5, p = 0.004 and OR 4.5, 95 % CI: 1.2-16.2, p = 0.023, respectively). A third (32 %) of physicians agreed or strongly agreed that they would be comfortable with indication extrapolation. Most respondents (88 %) would feel concerned or very concerned if a pharmacist had the ability to substitute a biologic drug for an SEB without the physician's approval. This survey was the first study that evaluated the position of rheumatologists on key areas surrounding SEBs from a nationwide Canadian perspective. Current physician attitudes and perceptions of SEBs can inform future educational initiatives and highlight important issues for payers, policy makers, and other stakeholders.
FIGURE 1 Molecular size comparison of a small molecule drug (Aspirin) to 3 different classes of biologics* *Relative molecular masses are shown in parentheses. Images: Molecule of the month, adapted with permission from the RCSB Protein Data Bank website, with attributions to David Goodsell. 3
The human glycoprotein MUC1 mucin plays a critical role in cancer progression. Breast, ovarian, and colon cancer cells often display unique cell-surface antigens corresponding to aberrantly glycosylated forms of the MUC1 tandem repeat. In this report, 15 N-and 13 C-labeled forms of a recombinant MUC1 construct containing five tandem repeats were used as substrates to define the order and kinetics of addition of N-acetylgalactosamine (GalNAc) moieties by a recombinant active form of the human enzyme UDPGalNAc:polypeptide N-acetylgalactosaminyltransferase I (ppGalNAc-T1; residues 40-559). Heteronuclear NMR experiments were performed to assign resonances associated with the two serines (Ser5 and Ser15) and three threonines (Thr6, Thr14, and Thr19) present in the 20-residue long MUC1 repeat. The kinetics and order of addition of GalNAc moieties (Tn antigen) on the MUC1 construct by human ppGalNAc-T1 were subsequently dissected by NMR spectroscopy. Threonine 14 was shown to be rapidly glycosylated by ppGalNAc-T1 with an initial rate of 25 µM/min, followed by Thr6 (8.6 µM/min). The enzyme also modified Ser5 at a slower rate (1.7 µM/min), an event that started only after the glycosylation of Thr14 and Thr6 side chains was mostly completed. Ser15 and Thr19 remained unglycosylated by ppGalNAc-T1. Corresponding O-glycosylation sites within all five tandem repeats were simultaneously modified by ppGalNAc-T1, suggesting that each repeat behaves as an independent substrate unit. This study demonstrated that the hydroxyl oxygens of Thr14 and to a lesser extent Thr 6 represent the two dominant substrates modified by ppGalNAc-T1 within the context of a complex MUC1 peptide substrate. More importantly, the availability of defined isotopically labelled MUC1 glycopeptide substrates and the relative simplicity of their NMR spectra will facilitate the analysis of other transferases within the O-glycosylation pathways and the rational design of tumor-associated MUC1 antigens.Golgi-resident glycosyltransferases are responsible for the attachment of O-linked oligosaccharide chains to serine and threonine residues of proteins. The initial step in the O-glycosylation pathway involves the transfer of an Nacetylgalactosamine (GalNAc) 1 residue from UDP-GalNAc to a protein. This event is catalyzed by a family of enzymes, the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-transferases) (1), of which there are at least 14 isoforms in humans alone (2). These ppGalNActransferases are differentially expressed, in terms of development and tissue distribution (3). The most frequently studied substrate for this class of enzymes is the 20-amino acid long tandem repeat of human mucin MUC1, a glycoprotein that is found on the surfaces of most epithelial cells. Specifically, the extracellular domain of MUC1 consists primarily of a variable number (40-100) of tandem repeats with the sequence PAPGSTAPPAHGVTSAPDTR. This sequence has five potential O-glycosylation sites (three threonine and two serine residues). Interestingly...
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