Strategies for Modulation of Pharmacokinetics of Recombinant Therapeutic Proteins | SpringerLink
Freeman, Czajkowsky, D. De Vos, A. DeFrees, S. Dumont, J.
New Research In
Economides, A. Egrie, J. Elliott, S. Fares, F. Fee, C. Flintegaard, T.
Frejd, F. Gaberc-Porekar, V. Drug Discovery Dev. Geething, N. Graham, L. Drug Delivery Rev. Harris, J. Drug Discovery , , vol. Hedayati, M. Hershfield, M.
Hinton, P. Hoffman, H. Huang, C. Huang, Y. Kinstler, O. Kontermann, R. Kozlovski, A. Controlled Release , , vol. Kuhn, N. Kuo, T. Kuter, D. Lapolt, P. Lee, S. Mannucci, P. Haemostasis , , vol. Matzuk, M. Melder, R.
BMS345 Therapeutic Proteins (8)
Mendler, C. Mero, A. Metzner, H. Monfardini, C. Morath, V. Morell, A. Nucci, M. Nygren, P. Pascal, V. Pasut, G. Peppel, K. Peters, R. Peters, T. Podusta, V. Roopenian, D. Rosenstock, J. Schellenberger, V.
- Graphical abstract.
- Israels Wine Renaissance Celebrates 30th Year.
- Fix Any NICD Dewalt Battery dw965 dw9050 dw907k-2 18v 12v 24v.
- The 1900 Olympic Games: Complete Results for All Competitors in All Events with Commentary: Complete Results for All Competitors in All Events, with Commentary ... Games: Results of the Early Modern Olympics)?
Schlapschy, M. Schlesinger, P. Sherman, M. Shimamoto, G. Sleep, D. Blood samples were collected into heparinized tubes through submandibular cheek pouch bleeds. Comparison between multiple groups was analyzed for statistical significance using a one-way ANOVA and Bonferroni post-test. All statistical analysis was performed in Prism 5 GraphPad Software on untransformed data. To test the hypothesis that proteins modified with an IgG binding peptide results in half-life extension, we fused the 13 amino acid FcIII sequence  separated by a short, flexible Gly 4 Ser linker to the C-terminus of a model fluorescent protein, monomeric Katushka  mKate Figure 1a.
The standards include thyroglobulin kDa, gamma-globulin kDa, ovalbumin 44 kDa, myoglobin 17 kDa, and vitamin B12 1. The data shown are the mean and error bars indicate s. Our results contrast that of Sakamoto et al. It is difficult to determine with confidence the reason for the difference in reactivity observed between our study and that of Sakamoto et al. SA tetramer staining is a common technique used to detect low affinity interactions by increasing the avidity of the binding ligand.
Therefore, it is possible that FcIII reacts weakly with mouse IgG but is not detectable under the assay conditions we used in this study. To further confirm species specificity and quantify binding we measured binding kinetics by surface plasmon resonance SPR.
- BMS345 Therapeutic Proteins (8);
- Strategies for Modulation of Pharmacokinetics of Recombinant Therapeutic Proteins;
- Educare al plurilinguismo. Riflessioni didattiche, pedagogiche e linguistiche: Riflessioni didattiche, pedagogiche e linguistiche (Lingua, traduzione e didattica) (Italian Edition).
- La Nueva Dieta HCG (Spanish Edition).
- People also read.
- Yew: A Mountain Medium Ghost Story (The Mountain Medium Chronicles Book 7).
Therefore, in addition to extending the half-life of protein cargo, the IgGBP also has the potential for use as an antagonist of the IgG-FcRn interaction to treat IgG-mediated autoimmune diseases, as can alternative inhibitors of the IgG-FcRn axis  —  , however this would need to be validated experimentally.
This supports the hypothesis that engineering proteins to interact with serum IgG through a short, C-terminal peptide extension enables prolonged blood circulation. The termini of a number of therapeutically relevant protein drugs and imaging agents are amenable for genetic modification  ; therefore, IgGBP fusion may be a general strategy to improve protein half-life with minimal modification size and complexity. The plasma clearance of hIgG1 are similar in the single agent and co-dose conditions indicating that mKate-IgGBP does not alter the elimination of hIgG1 under the dosing conditions used in this study Figure 5c.
Thus, both single agent and co-administration of mKate-IgGBP results in a significant extension of protein half-life. We describe a simple approach to substantially improve protein half-life without the necessity to increase molecular weight by engineering serum IgG binding using a low molecular weight IgG-Fc binding peptide fused to the C-terminus of a model protein. The half-life extensions obtained by IgGBP fusion are similar to that reported by Mark Dennis and co-workers who identified peptides that bind with high affinity to serum albumin and constructed albumin binding peptide-protein fusions to increase the serum half-life of Fab fragments.
Our results provide additional evidence to support the concept of targeting abundant serum proteins, such as IgG and albumin, to increase protein half-life. The IgGBP fusion approach promoted herein buttresses the foundation for this half-life extension strategy that may improve the drug-like properties of numerous rapidly eliminated therapeutic proteins, macromolecule drugs, or drug carriers. Figures S1—S7. Figure S1. Figure S2. Solid lines represent data fit to a one-site log IC 50 model in Prism. Figure S3. Unmodified mKate does not bind immobilized mouse, rat, or human IgG at concentrations up to nM e.
All data were baseline-adjusted and reference cell-subtracted. Figure S4. Figure S5. Figure S6. Blood was collected at various time points into heparized tubes and the plasma clearance of labeled mIgG1 was determined via fluorometry. Figure S7. Blood was collected at various time points into heparized tubes and the plasma clearance of labeled protein was determined via fluorometry based on the intrinsic far-red fluorescent properties of mKate.
Dashed lines represent the data fit to a semi-log line model in Prism and the half-life shown in the figure was calculated as described in the Supplementary Methods. LOQ, limit of quantification. Analyzed the data: JTS. Browse Subject Areas?
Related Therapeutic Proteins: Strategies to Modulate Their Plasma Half-lives
Copyright 2019 - All Right Reserved