Relative energetics of fragmentation of protonated peptides are investigated by using electrospray ionization/ surface-induced dissociation (ESI/SID) tandem mass spectrometry. ESI/SID fragmentation efficiency curves (percent fragmentation versus laboratory collision energy) are presented for 20 oligopeptides and are a measure of how easily a peptide fragments. The relative positions of the ESI/SID fragmentation efficiency curves depend on several parameters which include peptide composition (e.g., presence/absence of a basic amino acid residue) and peptide size. The ESI/SID fragmentation efficiency curves, in combination with quantum chemical calculations, provide a unique approach to substantiate and refine the mobile proton model for peptide fragmentation. Selected peptides are also investigated to further test and confirm the mobile proton model; these include doubly-protonated peptides and chemically-modified peptides (i.e., acetylated and fixed-charge derivatized peptides). Doubly-protonated peptides fragment more easily than the singly-protonated forms of the same peptides, with a sequence dependence for the difference in energy required for the fragmentation of singly-vs doubly-protonated peptides. Acetylation at the amino terminus and arginine side chain leads to a decrease in basicity and a corresponding lower energy onset for fragmentation than for the unmodified form of the peptide. Fixing the site of charge by addition of trimethylammonium acetyl to the amino terminus, i.e., eliminating the mobile proton, results in a higher energy onset than that for the protonated form of the same peptide. Curves for doubly protonated peptides with two adjacent basic residues (Arg, Arg) suggest the localization of the two protons at the two basic side chains rather than at opposite termini of the peptide.
BACKGROUND & AIMS: Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. METHODS: We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 [ strongly disagree and 10 [ strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score ‡7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting. RESULTS: The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios. CONCLUSION: Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.
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