83 results on '"Wyant, T"'
Search Results
2. 1141PD - CA-170, a first in class oral small molecule dual inhibitor of immune checkpoints PD-L1 and VISTA, demonstrates tumor growth inhibition in pre-clinical models and promotes T cell activation in Phase 1 study
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Powderly, J., Patel, M.R., Lee, J.J., Brody, J., Meric-Bernstam, F., Hamilton, E., Ponce Aix, S., Garcia-Corbacho, J., Bang, Y-J., Ahn, M-J., Rha, S.Y., Kim, K-P., Gil Martin, M., Wang, H., Lazorchak, A., Wyant, T., Ma, A., Agarwal, S., Tuck, D., and Daud, A.
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- 2017
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3. Operational modelling of preventive maintenance of a production plant
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Christer, A.H., Wang, Wenbin, Baker, R.D., Sharp, J., Wyant, T., Martin, H.H., and Operations Planning Acc. & Control
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In this paper we describe a case study carried out at a local company which manufactures copper products. The study addresses the imptementing of Planned Prevenlive Maintenance (P M) of an Extrusion Press, a key capita/ machine in the company. Using the Delay Time Modelling Technique, the model parameter values are estimatedfrom subjective data obtained through a questionnaire survey, and a goodness of fit test is proposed to assess the model fit. As aresult of the model test, revised parameter values are obtained in termsof the "best" model fit. Based upon the results of data analysis and delay time modelling, improved P M policy and procedures have been proposed to increase the effectiveness and efficiency of PM These proposals have been generally accepted by the company. The results are highlighted
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- 1995
4. O-0009 - Phase I Study of the Investigational Anti-Guanylyl Cyclase C (GCC) Antibody-Drug Conjugate (ADC) Mln0264 in Adult Patients with Advanced Gastrointestinal Malignancies Expressing GCC
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Faris, J.E., Cruz, C., Almhanna, K., Messersmith, W., Rodon, J., Ryan, D.P., Jung, J.A., Fasanmade, A., Wyant, T., and Kalebic, T.
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- 2014
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5. DOP058 Pharmacokinetic and pharmacodynamic relationship and immunogenicity of vedolizumab in adults with inflammatory bowel disease: Additional results from the GEMINI 1 and 2 studies
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Rosario, M., Wyant, T., Milch, C., Parikh, A., Feagan, B., Sandborn, W.J., Yang, H., and Fox, I.
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- 2014
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6. P592 A phase 1, double-blind placebo-controlled single-dose study to determine the immune response to systemic and mucosal antigenic challenge in the presence of vedolizumab
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Wyant, T., Leach, T., Sankoh, S., Wang, Y., Paolino, J., Feagan, B., and Parikh, A.
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- 2013
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7. P025 Vedolizumab does not affect the suppressive activity of gut-homing T regulatory cells
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Fedyk, E.R., Yang, L.-L., Wyant, T., and Kadambi, V.J.
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- 2013
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8. 329 The Investigational Drug MLN0264 First-in-human, First in Class ADC Targeting GCC: Phase I Dose-escalation Study and Supportive Scientific Rationale
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Veiby, P., Zhang, J., Yang, J., McDonald, A., Fasanmade, A., Wyant, T., Almhanna, K., and Kalebic, T.
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- 2012
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9. Tqm In Maintenance To Improve Manufacturing Performance.
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Sharp, J.M., Irani, Z.N., Wyant, T., and Firth, N.
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- 1997
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10. MLN3897 plus methotrexate in patients with rheumatoid arthritis: Safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study.
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Vergunst CE, Gerlag DM, von Moltke L, Karol M, Wyant T, Chi X, Matzkin E, Leach T, and Tak PP
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OBJECTIVE: To assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of the CC chemokine receptor CCR1 antagonist MLN3897 in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX). METHODS: In this phase IIa, proof-of-concept study, patients meeting the American College of Rheumatology (ACR) criteria for RA who had been taking MTX for >/=6 months with evidence of active disease were randomly assigned to receive either 10 mg oral MLN3897 or matching placebo once daily for 12 weeks (days 1-83) while continuing to receive MTX once a week. Clinical assessments, safety monitoring, and sampling for pharmacokinetic and pharmacodynamic analyses were performed throughout the study. The primary efficacy end point was the difference in the percentage of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) on day 84 in the MLN3897-treated group compared with that in the placebo-treated group. RESULTS: MLN3897 was well tolerated, with no evidence of systemic immunosuppression. In the intent-to-treat population, there was no significant difference in day 84 ACR20 response rates between MLN3897-treated patients and placebo-treated patients (35% versus 33%, respectively; P = 0.72). Results were similar for the per-protocol population. Pharmacokinetic analyses demonstrated no interactions between MLN3897 and MTX. MLN3897 was associated with a high degree of CCR1 occupancy (>/=90% on days 28, 56, and 84 in 82% of patients, by macrophage inflammatory protein 1alpha internalization assay). CONCLUSION: MLN3897 at a concentration of 10 mg once daily had no discernible activity in patients with RA who were also receiving MTX. The results suggest that CCR1 antagonism is unlikely to be a viable strategy for the treatment of RA when used in isolation at the receptor occupancy levels reached in this study. [ABSTRACT FROM AUTHOR]
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- 2009
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11. 943b Induction Therapy for Ulcerative Colitis: Results of GEMINI I, a Randomized, Placebo-Controlled, Double-Blind, Multicenter Phase 3 Trial
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Feagan, B.G., Rutgeerts, P.J., Sands, B.E., Colombel, J., Sandborn, W.J., Hanauer, S.B., Van Assche, G.A., Axler, J., Kim, H., Danese, S., Fox, I., Milch, C., Sankoh, S., Wyant, T., Xu, J., and Parikh, A.
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- 2012
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12. Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial.
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Vergunst CE, Gerlag DM, Lopatinskaya L, Klareskog L, Smith MD, van den Bosch F, Dinant HJ, Lee Y, Wyant T, Jacobson EW, Baeten D, and Tak PP
- Abstract
OBJECTIVE: CCR2 is a chemokine receptor expressed by monocytes, macrophages, and a subset of T cells. Its ligand, CCL2 (monocyte chemotactic protein 1), is abundantly present in the synovium of patients with rheumatoid arthritis (RA). Blocking CCR2 prevents CCL2-mediated chemotaxis in vitro and modulates arthritis in animal models of RA. In this study we examined the effects of CCR2 blockade on synovial inflammation in RA. METHODS: The study was designed as a phase IIa clinical trial with a human CCR2 blocking antibody (MLN1202) in patients with active RA. Thirty-two patients received 3 infusions, over a period of 6 weeks, with either placebo (n = 9) or anti-CCR2 monoclonal antibody at 0.5 mg/kg (n = 7), 1.5 mg/kg (n = 7), or 4.0 mg/kg (n = 9). Safety was monitored with laboratory tests, immunotoxicity assessments, and documenting of adverse events, and European League Against Rheumatism and American College of Rheumatology response criteria were used to assess clinical improvement. Synovial tissue was obtained at baseline and after 43 days of treatment, for pharmacodynamic analysis using immunohistochemistry and digital image analysis. The Kruskal-Wallis test was used to compare groups, and the Wilcoxon signed rank test was used to assess changes within the groups. RESULTS: All patients completed the study. Treatment with CCR2 blocking antibody reduced the levels of free CCR2 on CD14+ monocytes by at least 57% and up to 94% (P < 0.001), demonstrating the biologic activity of the compound. However, there was no reduction in the levels or expression of any of the synovial biomarkers. Accordingly, no clinical improvement was observed. CONCLUSION: Treatment with anti-CCR2 blocking antibody did not result in amelioration of synovial inflammation in active RA. The results do not support the notion that blockade of CCR2 may be sufficient to induce clinical improvement in RA. [ABSTRACT FROM AUTHOR]
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- 2008
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13. P234 Vedolizumab does not reduce the CD4+:CD8+ ratio in the CSF of healthy volunteers
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Milch, C., Wyant, T., Xu, J., Kent, W., Berger, J., and Fox, I.H.
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- 2012
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14. P019 Internalization of the vedolizumab/α4β7 complex and kinetics of restoring functional activity
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Yang, L.-L., Fedyk, E., and Wyant, T.
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- 2012
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15. using network analysis on a learning sequence.
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Wood, A. and Wyant, T. G.
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ENGINEERING education ,PROFESSIONAL education ,VOCATIONAL education ,TECHNICAL education ,CAREER development ,MANUFACTURING processes ,TECHNOLOGY - Abstract
The article presents a structure of engineering craft courses, consisting of an engineering syllabus applicable to engineering crafts. The article adds that engineering craft courses are courses of technical education for craft trainees. These courses have been designed for trainees in engineering and allied trades who are receiving industrial training based on the craft training recommendations of the Engineering, Electricity Supply, Iron and Steel and Shipbuilding Industry Training Boards. In 1969, the eight Joint Advisory Committees of the Council of Technical Examining Bodies (CTEB) devised a new structure of engineering craft courses, consisting of a common engineering syllabus comprising the basic elements applicable to a number of engineering crafts, plus an appropriate complementary element biased towards a particular trade, As an example, the basic element could be: A. General Engineering and its complement; C. Mechanical; D. Electrical; or E. Fabrication and Welding. Thus the combination A+C would produce a course with a Mechanical Bias, A+E a Fabrication and Welding Bias.
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- 1970
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16. P164 - Clinical pharmacology of vedolizumab (MLN0002) in patients with active ulcerative colitis
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Scholz, C., Wyant, T., Leach, T., Sankoh, S., Mould, D.R., Patella, M., Parikh, A., Fox, I., and von Moltke, L.
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- 2009
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17. P130 - Gastrointestinal selectivity of vedolizumab (MLN0002), a humanized monoclonal antibody to α 4β 7 integrin
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Parikh, A., Fedyk, E., Soler, D., Wyant, T., Kadambi, V., Leach, T., Milch, C., and Fox, I.
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- 2009
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18. An integrated approach of maintenance tools and techniques to improve manufacturing performance
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Wyant, T and Sharp, JM
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In todays competitive markets with increasing demands on manufacturers\ud to produce quality products to tight deadlines, the availability of\ud manufacturing plant and equipment is of prime importance.\ud Traditionally, maintenance has often been considered as a second line\ud function and non-productive. However, an effective maintenance\ud activity can contribute to plant availability and reliability leading\ud to increased production efficiency and consequently to company\ud profitability.\ud This Thesis is concerned with adopting an integrated approach to\ud implementing maintenance tools and techniques and describes the\ud definition, implementation and consolidation of these within a\ud traditional factory environment in order to increase manufacturing\ud performance.\ud The tools and techniques implemented include re-organisation of the\ud maintenance department to adopt a customer focused team based\ud approach, preventive maintenance improvements, implementation of\ud various condition monitoring techniques including vibration analysis,\ud oil monitoring, thermography and the introduction of in-house\ud monitoring methods as well as the introduction of a computerised\ud maintenance management system.\ud As a result of implementing these tools and techniques the company has\ud seen dramatic improvements. These improvements have realised savings\ud in excess of £ 220,000 with opportunity costs in excess of\ud £ 1,500,000. Condition monitoring tools allowed the company to meet a\ud 50% increase in production during 1995, with an effect on pre-tax\ud profit in the region of 50%.\ud The results obtained emphasise the importance of an effective\ud maintenance strategy to the manufacturing operation. As well as this\ud its importance to the business as a whole, making it a key business\ud activity.
19. Oilspill risk analysis for the Western Gulf of Alaska (Kodiak Island) Outer Continental Shelf lease area
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Wyant, T
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- 1977
20. Vedolizumab Immunogenicity With Long-Term or Interrupted Treatment of Patients With Inflammatory Bowel Disease.
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Wyant T, Yang L, Lirio RA, and Rosario M
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- Adult, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Colitis, Ulcerative drug therapy, Crohn Disease drug therapy, Drug Administration Schedule, Female, Gastrointestinal Agents administration & dosage, Gastrointestinal Agents adverse effects, Humans, Male, Middle Aged, Antibodies, Monoclonal, Humanized immunology, Antibodies, Monoclonal, Humanized therapeutic use, Gastrointestinal Agents therapeutic use, Inflammatory Bowel Diseases drug therapy
- Abstract
Patients in the GEMINI 1 or 2 study (NCT00790933; Eudra CT2008-002784-14) with ulcerative colitis or Crohn disease had low immunogenicity rates after vedolizumab treatment for up to 52 weeks. We report immunogenicity rates from the GEMINI long-term safety (LTS) study using a new drug-tolerant electrochemiluminescence assay, including analyses in patients who received continuous vedolizumab induction and maintenance in GEMINI 1 or 2 and long term safety, or vedolizumab induction and placebo maintenance in GEMINI 1 or 2 followed by re-treatment in long term safety (treatment interruption). Patients were enrolled in GEMINI long term safety from GEMINI 1, 2, or 3, or as de novo vedolizumab-treated patients; all received vedolizumab 300 mg intravenously every 4 weeks. Vedolizumab antidrug antibody (ADA) status was determined by electrochemiluminescence assay; ADA-positive samples were characterized by neutralizing activity. Vedolizumab ADA data were available for 1753 patients: 1513 continuously treated with vedolizumab before/during GEMINI long term safety, 240 re-treated after treatment interruption. Among continuously treated patients, 36 (2.4%) were ADA positive (15 persistently, 20 neutralizing ADA positive). Among re-treated patients, 53 (22.1%) were ADA positive (42 persistently, 40 neutralizing ADA positive). Longitudinal immunogenicity rates increased during placebo maintenance (19.4% at week 52), then decreased in GEMINI long term safety to rates (0 at the final visit) similar to continuously treated patients. ADA positivity was 1.1% vs 2.5% (continuous treatment) and 23.1% vs 22.0% (re-treatment) among patients with and without infusion-related reactions, respectively. Long-term vedolizumab treatment was associated with generally low immunogenicity rates; vedolizumab-re-treated patients had higher rates during placebo maintenance, which decreased during re-treatment. No relationship was observed between immunogenicity and infusion-related reactions., (© 2021 Takeda. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
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- 2021
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21. Comparison of the ELISA and ECL Assay for Vedolizumab Anti-drug Antibodies: Assessing the Impact on Pharmacokinetics and Safety Outcomes of the Phase 3 GEMINI Trials.
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Wyant T, Yang L, and Rosario M
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- Adolescent, Adult, Aged, Antibodies, Monoclonal, Humanized pharmacokinetics, Biological Products pharmacokinetics, Biological Variation, Population, Clinical Trials, Phase III as Topic, Colitis, Ulcerative blood, Colitis, Ulcerative drug therapy, Colitis, Ulcerative immunology, Crohn Disease blood, Crohn Disease drug therapy, Crohn Disease immunology, Enzyme-Linked Immunosorbent Assay methods, Female, Humans, Luminescent Measurements methods, Male, Middle Aged, Randomized Controlled Trials as Topic, Young Adult, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Neutralizing isolation & purification, Biological Products adverse effects, Drug Monitoring methods
- Abstract
Vedolizumab immunogenicity has been assessed using an enzyme-linked immunosorbent assay (ELISA) with a ~ 0.5 μg/mL drug interference, which may underestimate on-drug immunogenicity. We aimed to compare immunogenicity results between ELISA and the new drug-tolerant electrochemiluminescence (ECL) assay (and the two versions of neutralizing assays, drug-sensitive versus drug-tolerant). The ECL assay drug tolerance is ~ 100 times higher than that of the ELISA (≥ 50 μg/mL vs. 0.5 μg/mL with a 500 ng/mL positive control), and assay sensitivity is < 5 ng/mL for both assays. Vedolizumab immunogenicity was assessed in 2000 GEMINI 1 and 2 patients originally tested by ELISA and retested by ECL assay. Anti-drug antibody (ADA) impact on infusion-related reactions and pharmacokinetics (PK) was examined using descriptive statistics and population PK analyses. By ECL assay, 6% (86/1427) of patients treated with vedolizumab as induction and maintenance therapy tested ADA-positive. Of these, 20 patients were persistently positive and 56 had neutralizing antibodies. By ELISA, 4% (56/1434) of these patients were ADA-positive, 9 were persistently positive, and 33 had neutralizing antibodies. Among 61 patients with infusion-related reactions, 6 (10%) were ADA-positive (2 persistently positive) by ECL assay. By ELISA, 3 (5%) patients were both ADA-positive and persistently positive. Most results (96%) were similar with both assays. In the updated population PK model, ADA-positive status was estimated to increase vedolizumab linear clearance by a factor of 1.10 (95% credible interval 1.03-1.17), which is consistent with previous reports. The impact of ADA on safety and PK modeling remained generally consistent using either ELISA or ECL assay. ClinicalTrials.gov: NCT00783718 and NCT00783692.
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- 2020
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22. Fecal Calprotectin Responses Following Induction Therapy With Vedolizumab in Moderate to Severe Ulcerative Colitis: A Post Hoc Analysis of GEMINI 1.
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Reinisch W, Bressler B, Curtis R, Parikh A, Yang H, Rosario M, Røseth A, Danese S, Feagan B, Sands BE, Ginsburg P, Dassopoulos T, Lewis J, Xu J, and Wyant T
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- Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized therapeutic use, Colitis, Ulcerative pathology, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prognosis, ROC Curve, Remission Induction, Young Adult, Biomarkers metabolism, Colitis, Ulcerative drug therapy, Colitis, Ulcerative metabolism, Feces chemistry, Gastrointestinal Agents therapeutic use, Leukocyte L1 Antigen Complex metabolism, Severity of Illness Index
- Abstract
Background: In patients with ulcerative colitis (UC), fecal calprotectin (FC) concentrations correlate with endoscopic inflammation evidence. This study investigated the effect of vedolizumab induction on FC concentrations and whether FC concentrations could be a reliable surrogate measure of disease status., Methods: Data from the placebo-controlled, phase 3 trial GEMINI 1 were used to evaluate week-6 relationships between outcomes (including clinical remission, mucosal healing [MH], and endoscopic remission) and both absolute FC concentration values and relative FC concentration changes from baseline (%FC0-6). Sensitivity and specificity were calculated by cross-tabulation; the value of week-6 FC concentration as surrogate biomarker was measured with Youden J statistic computed for various cut points., Results: GEMINI 1 induction phase enrolled 895 patients. Fecal calprotectin concentration decreases were deeper in patients with clinical remission, MH, and/or endoscopic remission than in patients without. The best week-6 indicator of clinical or endoscopic remission in this data set was absolute FC concentration ≤150 µg/g. The surrogate biomarker values (based on areas under the curve) for the best-performing cut points (FC0-6 reduction >90%, FC ≤150 µg/g) were fair (range, 0.70-0.77, total population). More patients met the ≤150 µg/g cut point with vedolizumab than with placebo. Baseline FC concentrations were not correlated with clinical outcomes., Conclusions: Fecal calprotectin concentration reductions were greater with vedolizumab induction than with placebo. Week-6 FC concentrations had only fair surrogate biomarker value for endoscopic status. Our data suggest that, while FC may reflect inflammatory burden, FC concentration after vedolizumab induction may not be a robust biomarker of mucosal inflammation., (© 2018 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)
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- 2019
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23. A monomethyl auristatin E-conjugated antibody to guanylyl cyclase C is cytotoxic to target-expressing cells in vitro and in vivo.
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Gallery M, Zhang J, Bradley DP, Brauer P, Cvet D, Estevam J, Danaee H, Greenfield E, Li P, Manfredi M, Loke HK, Rabino C, Stringer B, Williamson M, Wyant T, Yang J, Zhu Q, Abu-Yousif A, and Veiby OP
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- Animals, Antibodies, Monoclonal metabolism, Antibodies, Monoclonal, Humanized, Blotting, Western, Colorectal Neoplasms enzymology, Colorectal Neoplasms pathology, Female, HEK293 Cells, Humans, Intestinal Mucosa enzymology, Mice, Mice, SCID, Receptors, Enterotoxin genetics, Receptors, Enterotoxin metabolism, Reverse Transcriptase Polymerase Chain Reaction, Xenograft Model Antitumor Assays, Antibodies, Monoclonal immunology, Immunoconjugates pharmacology, Oligopeptides metabolism, Receptors, Enterotoxin immunology
- Abstract
Guanylyl cyclase C (GCC) is a cell-surface protein that is expressed by normal intestinal epithelial cells, more than 95% of metastatic colorectal cancers (mCRC), and the majority of gastric and pancreatic cancers. Due to strict apical localization, systemically delivered GCC-targeting agents should not reach GCC in normal intestinal tissue, while accessing antigen in tumor. We generated an investigational antibody-drug conjugate (TAK-264, formerly MLN0264) comprising a fully human anti-GCC monoclonal antibody conjugated to monomethyl auristatin E via a protease-cleavable peptide linker. TAK-264 specifically bound, was internalized by, and killed GCC-expressing cells in vitro in an antigen-density-dependent manner. In GCC-expressing xenograft models with similar GCC expression levels/patterns observed in human mCRC samples, TAK-264 induced cell death, leading to tumor regressions and long-term tumor growth inhibition. TAK-264 antitumor activity was generally antigen-density-dependent, although some GCC-expressing tumors were refractory to TAK-264-targeted high local concentrations of payload. These data support further evaluation of TAK-264 in the treatment of GCC-expressing tumors.
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- 2018
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24. Consistent expression of guanylyl cyclase-C in primary and metastatic gastrointestinal cancers.
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Danaee H, Kalebic T, Wyant T, Fassan M, Mescoli C, Gao F, Trepicchio WL, and Rugge M
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- Adenocarcinoma enzymology, Adenocarcinoma pathology, Humans, Neoplasm Metastasis, Gastrointestinal Neoplasms enzymology, Gastrointestinal Neoplasms pathology, Receptors, Enterotoxin metabolism
- Abstract
Background: The transmembrane receptor guanylate cyclase-C (GCC) has been found to be expressed in colorectal cancers. However, limited data are available on GCC protein expression in non-colorectal gastrointestinal tumors and few studies have reported whether GCC protein expression was consistently preserved in synchronous primary and metastatic cancer tissues., Methods: GCC protein status was assessed by immunohistochemistry in tumor specimens from individuals (n = 627) with gastrointestinal tumors, including esophageal (n = 130), gastric (n = 276), pancreatic (n = 136), and colorectal (n = 85) primary and metastatic tumors. Tissue specimens consisted of tissue microarrays containing esophageal, gastric, pancreatic tumors, and whole-slide tissue sections from colorectal cancer patients with matching primary and metastatic tumors., Result: Among the evaluated esophageal, gastric, and pancreatic tumors, the frequency of GCC positivity at the protein level ranged from 59% to 68%. GCC was consistently expressed in primary and matched/synchronous metastatic lesions of colorectal cancer tissues derived from the same patients., Conclusion: This observational study demonstrated the protein expression of GCC across various gastrointestinal malignancies. In all cancer histotypes, GCC protein localization was observed predominantly in the cytoplasm compared to the membrane region of tumor cells. Consistent immunohistochemistry detection of GCC protein expression in primary colorectal cancers and in their matched liver metastases suggests that the expression of GCC is maintained throughout the process of tumor progression and formation of metastatic disease.
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- 2017
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25. A Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Vedolizumab.
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Rosario M, Dirks NL, Milch C, Parikh A, Bargfrede M, Wyant T, Fedyk E, and Fox I
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- Antibodies, Monoclonal, Humanized blood, Antibodies, Monoclonal, Humanized pharmacology, Colitis, Ulcerative blood, Colitis, Ulcerative drug therapy, Crohn Disease blood, Crohn Disease drug therapy, Drug Interactions, Gastrointestinal Agents blood, Gastrointestinal Agents immunology, Gastrointestinal Agents pharmacokinetics, Gastrointestinal Agents pharmacology, Humans, Remission Induction, Antibodies, Monoclonal, Humanized immunology, Antibodies, Monoclonal, Humanized pharmacokinetics
- Abstract
Vedolizumab is a humanized anti-α
4 β7 integrin monoclonal antibody that selectively blocks trafficking of memory T cells to inflamed gut tissue by inhibiting the α4 β7 -mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interaction. Approved for treating patients with moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), vedolizumab is administered as a 300 mg intravenous infusion. Vedolizumab undergoes a rapid, saturable, non-linear, target-mediated elimination process at low concentrations and a slower, linear, non-specific elimination process at higher concentrations. At therapeutic concentrations, vedolizumab primarily undergoes linear elimination. From population pharmacokinetic modeling, the vedolizumab terminal elimination half-life (t½ β) was estimated to be 25.5 days; linear clearance (CLL ) was similar for patients with UC (0.159 L/day) and CD (0.155 L/day). Extreme low albumin concentrations and extreme high body weight values were potentially clinically important predictors of vedolizumab CLL . Other factors, including concomitant therapy use (methotrexate, azathioprine, mercaptopurine, or aminosalicylates) or prior tumor necrosis factor-α (TNF-α) antagonist use, had no clinically relevant effects on CLL . A positive exposure-efficacy relationship for clinical remission and clinical response was apparent for vedolizumab induction therapy in patients with UC or CD. On average, patients with higher albumin, lower fecal calprotectin (UC only), lower C-reactive protein (CD only), and no prior TNF-α antagonist use had a higher probability of remission. Off drug, 10% of patients with UC or CD were positive for anti-drug antibodies. This article provides a comprehensive review of the clinical pharmacokinetics, pharmacodynamics, exposure-efficacy relationships, and immunogenicity of vedolizumab.- Published
- 2017
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26. Safety Culture: Establishing Processes to Support Trust and Accountability for Risk Reduction .
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Wyant T
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- Awareness, Humans, Workforce, Oncology Nursing, Organizational Culture, Patient Safety, Risk Reduction Behavior, Social Responsibility, Trust
- Abstract
Oncology nurses are tasked with developing skills that enable vigilant risk surveillance through situational awareness. However, care distractions, task interruptions, increased workloads, and time constraints are common challenges that compete with the ability to provide optimal safe care. A commitment to safety is a professional and organizational expectation, and being empowered to overcome safety-related challenges necessitates multilevel and interprofessional accountability. .
- Published
- 2017
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27. An Overview of the Mechanism of Action of the Monoclonal Antibody Vedolizumab.
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Wyant T, Fedyk E, and Abhyankar B
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- Animals, Antibodies, Monoclonal, Humanized therapeutic use, Humans, Immunologic Factors therapeutic use, Intestinal Mucosa drug effects, Leukocytes drug effects, Antibodies, Monoclonal, Humanized pharmacology, Colitis, Ulcerative drug therapy, Crohn Disease drug therapy, Immunologic Factors pharmacology
- Abstract
Vedolizumab is a novel therapeutic monoclonal antibody recently approved for the treatment of moderately to severely active ulcerative colitis and Crohn's disease in adults who have failed at least one conventional therapy. An integrin antagonist, vedolizumab binds to the α
4 β7 integrin which is expressed specifically by a subset of gastrointestinal-homing T lymphocytes. The binding of α4 β7 integrin to mucosal addressin cell adhesion molecule-1 expressed on the surface of mucosal endothelial cells is a crucial component of the gut-selective homing mechanism for lymphocytes.In contrast, other monoclonal antibodies approved for the treatment of inflammatory bowel diseases, such as tumour necrosis factor α antagonists and the integrin antagonist natalizumab, act systemically or on multiple targets to reduce inflammation.The unique gut selectivity of vedolizumab may contribute to the favourable benefit-risk profile observed in vedolizumab clinical trials. In this review, we summarise data from the preclinical development of vedolizumab and describe the current understanding of the mechanism of action as it relates to other biological therapies for inflammatory bowel disease., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)- Published
- 2016
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28. Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers.
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Rosario M, Wyant T, Leach T, Sankoh S, Scholz C, Parikh A, Fox I, and Feagan BG
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- Adult, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized pharmacokinetics, Double-Blind Method, Female, Half-Life, Humans, Infusions, Intravenous, Male, Middle Aged, Young Adult, Antibodies, Monoclonal, Humanized administration & dosage
- Abstract
Background and Objectives: Vedolizumab, a humanized monoclonal antibody against the α
4 β7 integrin, is indicated for treatment of moderately to severely active ulcerative colitis or Crohn's disease. In this placebo-controlled, double-blind, randomized, single ascending-dose study, the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab were evaluated in healthy volunteers., Methods: Forty-nine participants (in five cohorts) were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of either vedolizumab (0.2, 0.5, 2.0, 6.0, or 10.0 mg/kg) or placebo. Blood samples were collected for measurement of vedolizumab serum concentrations and α4 β7 saturation on peripheral blood lymphocytes by vedolizumab. Pharmacokinetic parameters were computed using a non-compartmental approach. Adverse events were monitored., Results: Vedolizumab maximum observed serum concentration (Cmax ) demonstrated dose proportionality over the dose range tested. Greater than dose-proportional increases in area under the serum concentration-time curve from time 0 to infinity (AUC0-inf ) and shorter terminal elimination half-life (t1/2 ) were observed from 0.2 to 2.0 mg/kg, suggestive of nonlinear pharmacokinetics at lower doses. At doses higher than 2.0 mg/kg, these parameters increased dose proportionally. Saturation of α4 β7 was at or near maximal levels (>90 %) at all doses and time points when vedolizumab was measurable in serum. A total of 21 of 39 (54 %) vedolizumab-treated participants were anti-drug antibody (ADA) positive, and 11 (28 %) were persistently ADA positive. Overall, no adverse event signals, including serious infections or malignancies, were apparent., Conclusions: Vedolizumab exhibited target-mediated disposition, characterized by a rapid, saturable, nonlinear elimination process at low concentrations and a slower linear elimination process at higher concentrations. Nearly complete α4 β7 saturation was observed at all doses. A single intravenous infusion of vedolizumab was well tolerated by healthy volunteers.- Published
- 2016
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29. Partnering to promote safety in the nursing profession.
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Wyant T
- Subjects
- Humans, Organizational Culture, Organizational Objectives, Societies, Nursing, United States, Nurse's Role, Patient Care Team organization & administration, Patient Safety
- Published
- 2016
30. Phase I Study of the Investigational Anti-Guanylyl Cyclase Antibody-Drug Conjugate TAK-264 (MLN0264) in Adult Patients with Advanced Gastrointestinal Malignancies.
- Author
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Almhanna K, Kalebic T, Cruz C, Faris JE, Ryan DP, Jung J, Wyant T, Fasanmade AA, Messersmith W, and Rodon J
- Subjects
- Adenocarcinoma pathology, Adult, Aged, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents adverse effects, Dose-Response Relationship, Drug, Female, Gastrointestinal Neoplasms pathology, Guanylate Cyclase immunology, Humans, Immunoconjugates adverse effects, Male, Middle Aged, Oligopeptides adverse effects, Oligopeptides therapeutic use, Adenocarcinoma drug therapy, Antineoplastic Agents therapeutic use, Gastrointestinal Neoplasms drug therapy, Guanylate Cyclase antagonists & inhibitors, Immunoconjugates therapeutic use, Maximum Tolerated Dose
- Abstract
Purpose: To assess the safety, tolerability, and preliminary antitumor activity of the investigational anti-guanylyl cyclase C (GCC) antibody-drug conjugate TAK-264 (formerly MLN0264) in adult patients with advanced gastrointestinal malignancies., Experimental Design: Adult patients with GCC-expressing gastrointestinal malignancies (H-score ≥ 10) were eligible for inclusion. TAK-264 was administered as a 30-minute intravenous infusion once every 3 weeks for up to 17 cycles. Dose escalation proceeded using a Bayesian continual reassessment method. At the maximum tolerated dose (MTD), 25 patients with metastatic colorectal cancer were enrolled in a prespecified dose expansion cohort., Results: Forty-one patients were enrolled, including 35 (85%) with metastatic colorectal cancer. During dose escalation (0.3-2.4 mg/kg), four of 19 patients experienced dose-limiting toxicities of grade 4 neutropenia; the MTD was determined as 1.8 mg/kg. Patients received a median of two cycles of TAK-264 (range, 1-12); nine received ≥four cycles. Common drug-related adverse events (AEs) included nausea and decreased appetite (each 41%), fatigue (32%), diarrhea, anemia, alopecia, and neutropenia (each 27%); grade ≥3 AEs included neutropenia (22%), hypokalemia, and febrile neutropenia (each 7%). Peripheral neuropathy was reported in four (10%) patients. Pharmacokinetic data showed approximately dose proportional systemic exposure and a mean plasma half-life of around 4 days, supporting the dosing schedule. Overall, 39 patients were response-evaluable; three experienced durable stable disease; and one with gastric adenocarcinoma had a partial response. GCC expression did not appear to correlate with treatment duration., Conclusions: These findings suggest that TAK-264 has a manageable safety profile, with preliminary evidence of potential antitumor activity in specific gastrointestinal malignancies. Further investigation is underway. Clin Cancer Res; 22(20); 5049-57. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
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31. Be a Leader by Cultivating a Culture of Safety.
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Wyant T
- Subjects
- Humans, Accident Prevention standards, Nurse's Role, Nursing Care standards, Patient Safety standards, Practice Guidelines as Topic
- Published
- 2016
32. Recommendations for the development and validation of flow cytometry-based receptor occupancy assays.
- Author
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Green CL, Stewart JJ, Högerkorp CM, Lackey A, Jones N, Liang M, Xu Y, Ferbas J, Moulard M, Czechowska K, Mc Closkey TW, van der Strate BW, Wilkins DE, Lanham D, Wyant T, and Litwin V
- Subjects
- Antibodies, Monoclonal therapeutic use, Fluorescent Dyes therapeutic use, Humans, Antibodies, Monoclonal immunology, Drug Discovery, Flow Cytometry
- Abstract
Receptor occupancy measurements demonstrate the binding of a biotherapeutic agent to its extra-cellular target and represent an integral component of the pharmacodynamic (PD) portfolio utilized to advance the development and commercialization of a therapeutic agent. Coupled with traditional pharmacokinetic (PK) assessments derived from serum drug concentration, receptor occupancy data can be used to model PK/PD relationships and validate dose selection decisions throughout the drug development lifecycle. Receptor occupancy assays can be even more challenging to develop than other flow cytometric methods (e.g. surface immunophenotyping). In addition to typical considerations regarding stability of the cell type of interest, stability of the target-bound therapeutic agent and stability of the target receptor must be taken into account. Reagent selection is also challenging as reagents need to be evaluated for the potential to compete with the therapeutic agent and bind with comparable affinity. This article provides technical guidance for the development and validation of cytometry-based receptor occupancy assays., (© 2016 International Clinical Cytometry Society.)
- Published
- 2016
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33. Role of receptor occupancy assays by flow cytometry in drug development.
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Stewart JJ, Green CL, Jones N, Liang M, Xu Y, Wilkins DE, Moulard M, Czechowska K, Lanham D, McCloskey TW, Ferbas J, van der Strate BW, Högerkorp CM, Wyant T, Lackey A, and Litwin V
- Subjects
- Antibodies therapeutic use, Flow Cytometry trends, Humans, Antibodies immunology, Drug Discovery, Flow Cytometry methods
- Abstract
The measurement of the binding of a biotherapeutic to its cellular target, receptor occupancy (RO), is increasingly important in development of biologically-based therapeutic agents. Receptor occupancy (RO) assays by flow cytometry describe the qualitative and/or quantitative assessment of the binding of a therapeutic agent to its cell surface target. Such RO assays can be as simple as measuring the number of cell surface receptors bound by an antireceptor therapeutic agent or can be designed to address more complicated scenarios such as internalization or shedding events once a receptor engages the administered therapeutic agent. Data generated from RO assays can also be used to model whether given doses of an experimental therapeutic agent and their administration schedules lead to predicted levels of receptor occupancy and whether the receptor is modulated (up or down) on cells engaged by the therapeutic agent. There are a variety of approaches that can be used when undertaking RO assays and with the ability to measure distinct subsets in heterogeneous populations, flow cytometry is ideally suited to RO measurements. This article highlights the importance of RO assays on the flow cytometric platform in the development of biotherapeutic agents., (© 2016 The Authors Cytometry Part B: Clinical Cytometry Published by Wiley Periodicals, Inc.)
- Published
- 2016
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34. Development and validation of receptor occupancy pharmacodynamic assays used in the clinical development of the monoclonal antibody vedolizumab.
- Author
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Wyant T, Estevam J, Yang L, and Rosario M
- Subjects
- Adaptor Proteins, Signal Transducing, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal immunology, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized immunology, Biomarkers blood, Cell Adhesion immunology, Cell Adhesion Molecules, Colitis, Ulcerative blood, Colitis, Ulcerative immunology, Humans, Immunoglobulins blood, Immunoglobulins immunology, Integrins immunology, Integrins metabolism, Lymphocytes immunology, Mucoproteins blood, Mucoproteins immunology, Patients, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins blood, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins immunology, Colitis, Ulcerative drug therapy, Flow Cytometry, Immunoglobulins isolation & purification, Mucoproteins isolation & purification, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins isolation & purification
- Abstract
Background: Vedolizumab is a monoclonal antibody approved for use in ulcerative colitis and Crohn's disease. By specifically binding to α4 β7 integrin, vedolizumab prevents trafficking of lymphocytes to the gut, thereby interfering with disease pathology. During the clinical development program, the pharmacodynamic effect of vedolizumab was evaluated by 2 flow cytometry receptor occupancy assays: act-1 (ACT-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Here we describe the development and validation of these assays., Methods: The ACT-1 assay is a receptor occupancy free-site assay that uses a monoclonal antibody with the same binding epitope as vedolizumab to detect free (unbound) sites on α4 β7 integrin. The MAdCAM-1 assay used a soluble version of the natural ligand for α4 β7 integrin to detect free sites. The assays were validated using a fit-for-purpose approach throughout the clinical development of vedolizumab., Results: Both the ACT-1 assay and the MAdCAM-1 assay demonstrated acceptable reproducibility and repeatability. The assays were sufficiently stable to allow for clinical use. During clinical testing the assays demonstrated that vedolizumab was able to saturate peripheral cells at all doses tested., Conclusions: Two pharmacodynamic receptor occupancy assays were developed and validated to assess the effect of vedolizumab on peripheral blood cells. The results of these assays demonstrated the practical use of flow cytometry to examine pharmacodynamic response in clinical trials., (© 2015 International Clinical Cytometry Society.)
- Published
- 2016
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35. Understanding the Supersensitive Anti-Drug Antibody Assay: Unexpected High Anti-Drug Antibody Incidence and Its Clinical Relevance.
- Author
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Song S, Yang L, Trepicchio WL, and Wyant T
- Subjects
- Antibodies blood, Humans, Reproducibility of Results, Sensitivity and Specificity, Antibodies immunology, Biological Products adverse effects, Biological Products immunology, Immunoassay methods, Pharmaceutical Preparations
- Abstract
Numbers of biotherapeutic products in development have increased over past decade. Despite providing significant benefits to patients with unmet needs, almost all protein-based biotherapeutics could induce unwanted immunogenicity, which result in a loss of efficacy and/or increase the risk of adverse reactions, such as infusion reactions, anaphylaxis, and even life-threatening response to endogenous proteins. Recognizing these possibilities, regulatory agencies request that immunogenicity be assessed as part of the approval process for biotherapeutics. Great efforts have been made to reduce drug immunogenicity through protein engineering. Accordingly the immunogenicity incidence has been reduced from around 80% in murine derived products to 0-10% in fully human products. However, recent improvements in immunogenicity assays have led to unexpectedly high immunogenicity rates, even in fully human products, leading to new challenges in assessing immunogenicity and its clinical relevance. These new immunogenicity assays are becoming supersensitive and able to detect more of anti-drug antibodies (ADA) than with earlier assays. This paper intends to review and discuss our understanding of the supersensitive ADA assay and the unexpected high ADA incidence and its potential clinical relevance.
- Published
- 2016
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36. Recommendations for adaptation and validation of commercial kits for biomarker quantification in drug development.
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Khan MU, Bowsher RR, Cameron M, Devanarayan V, Keller S, King L, Lee J, Morimoto A, Rhyne P, Stephen L, Wu Y, Wyant T, and Lachno DR
- Subjects
- Calibration, Government Regulation, Guidelines as Topic, Humans, Reagent Kits, Diagnostic, Biomarkers analysis, Drug Discovery methods, Immunoassay standards
- Abstract
Increasingly, commercial immunoassay kits are used to support drug discovery and development. Longitudinally consistent kit performance is crucial, but the degree to which kits and reagents are characterized by manufacturers is not standardized, nor are the approaches by users to adapt them and evaluate their performance through validation prior to use. These factors can negatively impact data quality. This paper offers a systematic approach to assessment, method adaptation and validation of commercial immunoassay kits for quantification of biomarkers in drug development, expanding upon previous publications and guidance. These recommendations aim to standardize and harmonize user practices, contributing to reliable biomarker data from commercial immunoassays, thus, enabling properly informed decisions during drug development.
- Published
- 2015
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37. Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results.
- Author
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Wyant T, Leach T, Sankoh S, Wang Y, Paolino J, Pasetti MF, Feagan BG, and Parikh A
- Subjects
- Adult, Double-Blind Method, Female, Hepatitis B Vaccines immunology, Humans, Immunization, Male, Young Adult, Antibodies, Monoclonal, Humanized pharmacology, Antibody Formation drug effects, Gastrointestinal Tract drug effects, Gastrointestinal Tract immunology
- Abstract
Objective: The α4β7 integrin monoclonal antibody vedolizumab is hypothesised to be gut selective. Effects of vedolizumab on immune responses to parenterally or enterally administered antigens were investigated., Design: In this randomised, double-blind, placebo-controlled, phase I trial, healthy participants received a single intravenous dose of vedolizumab 750 mg (n=64) or placebo (n=63). After 4 days, participants began intramuscular hepatitis B vaccine (HBV; days 4, 32, 60) and oral cholera vaccine (OCV; days 4, 18) regimens. The study was designed to demonstrate a 15% non-inferiority margin for the between-group difference in the primary end point: percentage of participants with HBV seroconversion at day 74 (serum hepatitis B surface antigen (HBs) antibody titre ≥10 IU/L). OCV seroconversion at day 74 (>4-fold increase in serum cholera toxin (CT) antibodies) was a secondary end point., Results: A total of 56 (90.3%) placebo-treated and 54 (88.5%) vedolizumab-treated participants responded to HBV. Geometric mean anti-HBs titres were similar for placebo (114.4 IU/L) and vedolizumab (129.6 IU/L) at day 74. A total of 60 (96.8%) placebo-treated and 52 (82.5%) vedolizumab-treated participants responded to OCV at day 74. Geometric mean anti-CT IgG levels were higher for placebo than for vedolizumab at day 74 (9210.08 vs. 3007.8 ELISA Units (EU)/mL) and day 32 (11629.3 vs. 1575.4 EU/mL). Anti-CT IgA results were similar. Adverse events were consistent with previous experience. One serious adverse event (spontaneous abortion) was reported for placebo., Conclusions: Vedolizumab did not alter the response to parenterally administered antigens but reduced the response to oral antigens, demonstrating its gut-selective mechanism of action., Trial Registration Number: NCT Number: 01981616; EudraCT Number: 2011-001874-24., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Published
- 2015
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38. Interaction of Prevotella intermedia strain 17 leucine-rich repeat domain protein AdpF with eukaryotic cells promotes bacterial internalization.
- Author
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Sengupta D, Kang DJ, Anaya-Bergman C, Wyant T, Ghosh AK, Miyazaki H, and Lewis JP
- Subjects
- Analysis of Variance, Fibroblasts microbiology, Fibronectins metabolism, Gene Expression Regulation, Bacterial, HeLa Cells microbiology, Humans, Leucine-Rich Repeat Proteins, Prevotella intermedia genetics, Prevotella intermedia pathogenicity, Bacterial Proteins physiology, Eukaryotic Cells microbiology, Prevotella intermedia physiology, Proteins physiology
- Abstract
Prevotella intermedia is an oral bacterium implicated in a variety of oral diseases. Although internalization of this bacterium by nonphagocytic host cells is well established, the molecular players mediating the process are not well known. Here, the properties of a leucine-rich repeat (LRR) domain protein, designated AdpF, are described. This protein contains a leucine-rich region composed of 663 amino acid residues, and molecular modeling shows that it folds into a classical curved solenoid structure. The cell surface localization of recombinant AdpF (rAdpF) was confirmed by electron and confocal microscopy analyses. The recombinant form of this protein bound fibronectin in a dose-dependent manner. Furthermore, the protein was internalized by host cells, with the majority of the process accomplished within 30 min. The internalization of rAdpF was inhibited by nystatin, cytochalasin, latrunculin, nocodazole, and wortmannin, indicating that microtubules, microfilaments, and signal transduction are required for the invasion. It is noteworthy that preincubation of eukaryotic cells with AdpF increased P. intermedia 17 internalization by 5- and 10-fold for HeLa and NIH 3T3 fibroblast cell lines, respectively. The addition of the rAdpF protein was also very effective in inducing bacterial internalization into the oral epithelial cell line HN4, as well as into primary cells, including human oral keratinocytes (HOKs) and human umbilical vein endothelial cells (HUVECs). Finally, cells exposed to P. intermedia 17 internalized the bacteria more readily upon reinfection. Taken together, our data demonstrate that rAdpF plays a role in the internalization of P. intermedia 17 by a variety of host cells.
- Published
- 2014
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39. Vedolizumab, a monoclonal antibody to the gut homing α4β7 integrin, does not affect cerebrospinal fluid T-lymphocyte immunophenotype.
- Author
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Milch C, Wyant T, Xu J, Parikh A, Kent W, Fox I, and Berger J
- Subjects
- Adult, Antibodies, Monoclonal, Humanized blood, Antigens, CD metabolism, Female, Humans, Male, Young Adult, Antibodies, Monoclonal, Humanized pharmacology, Cerebrospinal Fluid cytology, Integrins immunology, T-Lymphocytes drug effects
- Abstract
Vedolizumab, a gut-homing α4β7 integrin antagonist, has demonstrated efficacy in ulcerative colitis and Crohn's disease. Development of progressive multifocal leukoencephalopathy, a serious brain infection associated with natalizumab (an α4β7 and α4β1 integrin antagonist), has raised concern that vedolizumab may convey a similar risk. Natalizumab is believed to impair central nervous system immune surveillance by affecting cerebrospinal fluid (CSF) lymphocyte counts and the CD4:CD8 ratio. To determine if vedolizumab elicits similar effects, we examined CSF of healthy volunteers by flow cytometry for T-lymphocyte surface markers 5 weeks after administration of intravenous vedolizumab 450 mg. No significant changes were observed in CSF T-lymphocyte populations., (© 2013. Published by Elsevier B.V. All rights reserved.)
- Published
- 2013
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40. In vitro assessment of the effects of vedolizumab binding on peripheral blood lymphocytes.
- Author
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Wyant T, Yang L, and Fedyk E
- Subjects
- Animals, Anti-Inflammatory Agents metabolism, Anti-Inflammatory Agents pharmacology, Antibodies, Monoclonal, Humanized metabolism, Flow Cytometry, Humans, In Vitro Techniques, Integrins metabolism, Mice, Protein Binding, Antibodies, Monoclonal, Humanized pharmacology, Lymphocytes drug effects, Lymphocytes metabolism
- Abstract
Vedolizumab (VDZ) is a humanized monoclonal antibody in development for the treatment of inflammatory bowel disease. VDZ binds to the α4β7 integrin complex and inhibits its binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), thus preventing lymphocyte extravasation to gut mucosal tissues. To understand whether VDZ has additional effects that may affect its overall safety as a therapeutic molecule, we examined other potential actions of VDZ. In vitro assays with human peripheral blood lymphocytes demonstrated that VDZ fails to elicit cytotoxicity, lymphocyte activation, and cytokine production from memory T lymphocytes and does not interfere with the suppressive ability of regulatory T cells. Furthermore, we demonstrated that VDZ induces internalization of α4β7 and that the integrin is rapidly re-expressed and fully functional after VDZ withdrawal. These studies provide insight into the mechanisms underlying the observed safety profile of VDZ in clinical trials.
- Published
- 2013
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41. Vedolizumab as induction and maintenance therapy for ulcerative colitis.
- Author
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Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, Van Assche G, Axler J, Kim HJ, Danese S, Fox I, Milch C, Sankoh S, Wyant T, Xu J, and Parikh A
- Subjects
- Adult, Aged, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized pharmacokinetics, Double-Blind Method, Drug Administration Schedule, Drug Therapy, Combination, Female, Glucocorticoids therapeutic use, Humans, Immunosuppressive Agents therapeutic use, Induction Chemotherapy, Integrins antagonists & inhibitors, Maintenance Chemotherapy, Male, Middle Aged, Antibodies, Monoclonal, Humanized therapeutic use, Colitis, Ulcerative drug therapy, Integrins immunology
- Abstract
Background: Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis., Methods: We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1., Results: Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P<0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups., Conclusions: Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).
- Published
- 2013
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42. Antagonizing the α4β1 integrin, but not α4β7, inhibits leukocytic infiltration of the central nervous system in rhesus monkey experimental autoimmune encephalomyelitis.
- Author
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Haanstra KG, Hofman SO, Lopes Estêvão DM, Blezer EL, Bauer J, Yang LL, Wyant T, Csizmadia V, 't Hart BA, and Fedyk ER
- Subjects
- Animals, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized immunology, Cell Movement drug effects, Cell Movement immunology, Central Nervous System drug effects, Central Nervous System pathology, Encephalomyelitis, Autoimmune, Experimental drug therapy, Encephalomyelitis, Autoimmune, Experimental metabolism, Encephalomyelitis, Autoimmune, Experimental pathology, Humans, Immunologic Surveillance drug effects, Injections, Intravenous, Integrin alpha4beta1 immunology, Macaca mulatta, Myelin-Oligodendrocyte Glycoprotein administration & dosage, Myelin-Oligodendrocyte Glycoprotein immunology, Natalizumab, Organ Specificity, Placebos, Protein Isoforms antagonists & inhibitors, Protein Isoforms immunology, Recombinant Proteins administration & dosage, Recombinant Proteins immunology, T-Lymphocytes drug effects, T-Lymphocytes pathology, Autoimmunity drug effects, Cell Migration Inhibition immunology, Central Nervous System immunology, Encephalomyelitis, Autoimmune, Experimental immunology, Integrin alpha4beta1 antagonists & inhibitors, T-Lymphocytes immunology
- Abstract
The immune system is characterized by the preferential migration of lymphocytes through specific tissues (i.e., tissue tropism). Tissue tropism is mediated, in part, by the α(4) integrins expressed by T lymphocytes. The α(4)β(1) integrin mediates migration of memory T lymphocytes into the CNS, whereas the α(4)β(7) integrin mediates migration preferentially into gastrointestinal tissue. This paradigm was established primarily from investigations in rodents; thus, the objective of this investigation was to determine if blocking the α(4)β(7) integrin exclusively would affect migration of T lymphocytes into the CNS of primates. The effects of the dual α(4)β(1) and α(4)β(7) antagonist natalizumab were compared with those of the α(4)β(7) antagonist vedolizumab on experimental autoimmune encephalomyelitis in the rhesus monkey. Animals received an initial i.v. bolus of placebo, natalizumab (30 mg/kg), or vedolizumab (30 mg/kg) before intracutaneous immunization with recombinant human myelin oligodendrocyte glycoprotein and then Ab once weekly thereafter. Natalizumab prevented CNS inflammation and demyelination significantly (p < 0.05), compared with time-matched placebo control animals, whereas vedolizumab did not inhibit these effects, despite saturating the α(4)β(7) integrin in each animal for the duration of the investigation. These results demonstrate that blocking α(4)β(7) exclusively does not inhibit immune surveillance of the CNS in primates.
- Published
- 2013
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43. Exclusive antagonism of the α4 β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates.
- Author
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Fedyk ER, Wyant T, Yang LL, Csizmadia V, Burke K, Yang H, and Kadambi VJ
- Subjects
- Animals, Female, Gastrointestinal Tract immunology, Gastrointestinal Tract metabolism, Inflammatory Bowel Diseases immunology, Inflammatory Bowel Diseases metabolism, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Leukocytes immunology, Leukocytes metabolism, Macaca fascicularis, Male, Natalizumab, T-Lymphocytes, Helper-Inducer drug effects, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer metabolism, Antibodies, Monoclonal, Humanized therapeutic use, Gastrointestinal Tract drug effects, Inflammatory Bowel Diseases drug therapy, Integrins antagonists & inhibitors, Intestinal Mucosa drug effects, Leukocytes drug effects
- Abstract
Background: Biological therapies that antagonize specific molecules have demonstrated efficacy in inflammatory bowel diseases, but infections resulting from systemic immunosuppression underscore the need for safer therapies. The objective of this investigation was to determine if antagonism of the α(4) β(7) integrin would exclusively yield gut-selective antiinflammatory activity in primates., Methods: A series of experiments were conducted to investigate potential intra- and extraintestinal effects in healthy nonhuman primates dosed repeatedly with the α(4) β(7) -exclusive antagonist vedolizumab (former versions: MLN0002, MLN02, LDP-02) for 4, 13, and 26 weeks., Results: No adverse clinical effects of vedolizumab were observed in healthy cynomolgus monkeys up to the highest doses tested (100 mg/kg). Histomorphologic analyses indicated a reduction in the frequency of leukocytes in gastrointestinal tissue, but not other organs. A significant (P < 0.05) decrease in the frequency of β 7+ lymphocytes in gastrointestinal tissues corresponded to a significant (P < 0.05) increase in α(4) β 7+ memory helper T lymphocytes in peripheral blood. This elevation was specific to α(4) β 7+ memory helper T lymphocytes; levels of other leukocyte subsets remained unaffected. Systemic opportunistic infections were not observed, and vedolizumab did not inhibit adaptive or innate immune responses systemically., Conclusions: These data demonstrate that blocking the α(4) β(7) integrin exclusively yields gut-selective antiinflammatory activity in primates., (Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.)
- Published
- 2012
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44. Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study.
- Author
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Parikh A, Leach T, Wyant T, Scholz C, Sankoh S, Mould DR, Ponich T, Fox I, and Feagan BG
- Subjects
- Adolescent, Adult, Aged, Colitis, Ulcerative immunology, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Prognosis, Tissue Distribution, Young Adult, Antibodies, Monoclonal, Humanized pharmacokinetics, Antibodies, Monoclonal, Humanized therapeutic use, Colitis, Ulcerative drug therapy
- Abstract
Background: Vedolizumab is a gut-selective biologic that has shown efficacy in ulcerative colitis (UC) and Crohn's disease (CD). We studied the pharmacokinetics, pharmacodynamics, safety, tolerability, and efficacy of a new formulation of vedolizumab produced by an improved manufacturing process., Methods: UC patients were randomized to receive vedolizumab (2, 6, or 10 mg/kg) or placebo on days 1, 15, 29, and 85. Safety, pharmacokinetics, pharmacodynamics, and immunogenicity evaluations were performed at multiple timepoints through day 253. Partial Mayo Scores and fecal calprotectin levels were used to assess efficacy., Results: In all, 46 patients (9 placebo, 37 vedolizumab) received at least one dose of study medication. The vedolizumab serum concentration declined monoexponentially until concentrations reached 1-10 μg/mL, and then fell nonlinearly. Vedolizumab maximum serum concentration (C(max) ) and area under the curve (AUC) increased approximately proportionally as a function of dose. Vedolizumab maximally saturated α(4) β(7) receptors on peripheral serum lymphocytes at all measurable serum concentrations. Vedolizumab was well tolerated, with no deaths and no adverse events leading to discontinuation. At every assessment from day 29 through day 253, over 50% of vedolizumab-treated patients were in clinical response, while placebo response rates generally ranged between 22% and 33%. Vedolizumab treatment reduced fecal calprotectin levels compared with placebo., Conclusions: Vedolizumab demonstrated dose-proportional pharmacokinetics and maximally saturated α(4) β(7) receptors over the tested dose range. Multiple dosing up to 10 mg/kg was well tolerated. Over the course of follow-up a greater proportion of patients treated with vedolizumab were in clinical response than those who were assigned to placebo., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)
- Published
- 2012
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45. The capsule of Porphyromonas gingivalis leads to a reduction in the host inflammatory response, evasion of phagocytosis, and increase in virulence.
- Author
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Singh A, Wyant T, Anaya-Bergman C, Aduse-Opoku J, Brunner J, Laine ML, Curtis MA, and Lewis JP
- Subjects
- Animals, Bacterial Capsules immunology, Dendritic Cells microbiology, Macrophages microbiology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Porphyromonas gingivalis cytology, Virulence, Bacterial Capsules physiology, Bacteroidaceae Infections microbiology, Inflammation microbiology, Phagocytosis physiology, Porphyromonas gingivalis immunology, Porphyromonas gingivalis pathogenicity
- Abstract
Periodontal disease is a chronic oral inflammatory disease that is triggered by bacteria such as Porphyromonas gingivalis. P. gingivalis strains exhibit great heterogeneity, with some strains being encapsulated while others are nonencapsulated. Although the encapsulated strains have been shown to be more virulent in a mouse abscess model, so far the role of the capsule in P. gingivalis interactions with host cells is not well understood and its role in virulence has not been defined. Here, we investigated the contribution of the capsule to triggering a host response following microbial infection, as well as its protective role following bacterial internalization by host phagocytic cells with subsequent killing, using the encapsulated P. gingivalis strain W50 and its isogenic nonencapsulated mutant, PgC. Our study shows significant time-dependent upregulation of the expression of various groups of genes in macrophages challenged with both the encapsulated and nonencapsulated P. gingivalis strains. However, cells infected with the nonencapsulated strain showed significantly higher upregulation of 9 and 29 genes at 1 h and 8 h postinfection, respectively, than cells infected with the encapsulated strain. Among the genes highly upregulated by the nonencapsulated PgC strain were ones coding for cytokines and chemokines. Maturation markers were induced at a 2-fold higher rate in dendritic cells challenged with the nonencapsulated strain for 4 h than in dendritic cells challenged with the encapsulated strain. The rates of phagocytosis of the nonencapsulated P. gingivalis strain by both macrophages and dendritic cells were 4.5-fold and 7-fold higher, respectively, than the rates of phagocytosis of the encapsulated strain. On the contrary, the survival of the nonencapsulated P. gingivalis strain was drastically reduced compared to the survival of the encapsulated strain. Finally, the encapsulated strain exhibited greater virulence in a mouse abscess model. Our results indicate that the P. gingivalis capsule plays an important role in aiding evasion of host immune system activation, promoting survival of the bacterium within host cells, and increasing virulence. As such, it is a major virulence determinant of P. gingivalis.
- Published
- 2011
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46. Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region.
- Author
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Gilbert J, Lekstrom-Himes J, Donaldson D, Lee Y, Hu M, Xu J, Wyant T, and Davidson M
- Subjects
- Antibodies, Monoclonal, Humanized, Biomarkers metabolism, Double-Blind Method, Female, Genotype, Humans, Male, Middle Aged, Placebos, Promoter Regions, Genetic, Risk Factors, Statistics, Nonparametric, Antibodies, Monoclonal pharmacology, C-Reactive Protein metabolism, Chemokine CCL2 genetics, Coronary Artery Disease blood, Coronary Artery Disease genetics, Polymorphism, Single Nucleotide, Receptors, CCR2 antagonists & inhibitors
- Abstract
CC chemokine receptor 2 (CCR2), expressed on the surface of circulating monocytes, and its ligand monocyte chemoattractant protein-1 (MCP-1; also known as CC-chemokine ligand 2) are present in atherosclerotic plaques and may have important roles in endothelial monocyte recruitment and activation. MLN1202 is a highly specific humanized monoclonal antibody that interacts with CCR2 and inhibits MCP-1 binding. The aim of this randomized, double-blind, placebo-controlled study was to measure reductions in circulating levels of high-sensitivity C-reactive protein, an established biomarker of inflammation associated with coronary artery disease, on MLN1202 treatment in patients at risk for atherosclerotic cardiovascular disease (≥2 risk factors for atherosclerotic cardiovascular disease and circulating high-sensitivity C-reactive protein >3 mg/L). Additionally, patients were genotyped for the 2518 A→G polymorphism in the promoter of the MCP-1 gene to investigate the correlation between this polymorphism and reduced C-reactive protein levels with MLN1202 treatment. Patients who received MLN1202 exhibited significant decreases in high-sensitivity C-reactive protein levels, beginning at 4 weeks and continuing through 12 weeks after dosing. Patients with A/G or G/G genotypes in the MCP-1 promoter had significantly greater reductions in high-sensitivity C-reactive protein levels than patients with the wild-type A/A genotype. In conclusion, MLN1202 treatment was well tolerated in this patient population and resulted in significant reductions in high-sensitivity C-reactive protein levels., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
47. Validation of a flow cytometry based G(2)M delay cell cycle assay for use in evaluating the pharmacodynamic response to Aurora A inhibition.
- Author
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Estevam J, Danaee H, Liu R, Ecsedy J, Trepicchio WL, and Wyant T
- Subjects
- Anthraquinones chemistry, Aurora Kinases, Dose-Response Relationship, Drug, Flow Cytometry methods, Humans, Kinetics, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear drug effects, Protein Serine-Threonine Kinases metabolism, Reproducibility of Results, Azepines pharmacology, Cell Division drug effects, Flow Cytometry standards, G2 Phase drug effects, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrimidines pharmacology
- Abstract
Pharmacodynamic assays are important aspects for understanding molecularly targeted anticancer agents to investigate the relationship between drug concentration (pharmacokinetics) and drug "effect" or biological activity. As new drug entities are developed that affect DNA cell cycle, a pharmacodynamic assay which measures cell cycle perturbation would be a valuable clinical trial tool. During recent years, flow cytometry has established itself as a useful method to determine the relative nuclear DNA content and percentage of cycling cells of biological specimens. However to date, the analytical validation of cytometry based assays is limited and there is no suitable guidance for method validation of flow cytometry based cell cycle assays. Here we report the validation of a flow cytometry based cell cycle G(2)/M delay assay for use in evaluating the effect of investigational drug MLN8237, a small molecule inhibitor of a mitotic kinase Aurora A, for clinical trial use. The assay method was validated by examining assay robustness, repeatability, reproducibility, precision, and determining the cutoff for a true drug effect based on biostatistical analysis models. Experimental results show that the intra-assay repeatability was less than 20% with an intra-donor variability of less than 40%. The robustness of the assay was less than 30%. Since this is an ex-vivo stimulation assay, variability parameters were expected to be higher. Based on biostatistical modeling, an absolute change in %G(2)M of 5.2% (95% CI) was needed in order to detect a true drug effect. Overall, the assay demonstrated acceptable variability to warrant further in vivo testing., (Copyright © 2010 Elsevier B.V. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
48. Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the treatment of rheumatoid arthritis.
- Author
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Lebre MC, Vergunst CE, Choi IY, Aarrass S, Oliveira AS, Wyant T, Horuk R, Reedquist KA, and Tak PP
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Neutralizing therapeutic use, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid metabolism, Case-Control Studies, Chemokine CCL2 metabolism, Chemokine CCL5 metabolism, Chemotaxis drug effects, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Monocytes cytology, Monocytes drug effects, Monocytes immunology, Monocytes pathology, Phenylurea Compounds therapeutic use, Piperidines therapeutic use, Receptors, CCR1 antagonists & inhibitors, Receptors, CCR1 immunology, Receptors, CCR2 immunology, Receptors, CCR5 immunology, Synovial Fluid metabolism, Antibodies, Neutralizing immunology, Antibodies, Neutralizing pharmacology, Arthritis, Rheumatoid drug therapy, Phenylurea Compounds pharmacology, Piperidines pharmacology, Receptors, CCR antagonists & inhibitors, Receptors, CCR immunology
- Abstract
Background: The aim of this study was to provide more insight into the question as to why blockade of CCR1, CCR2, and CCR5 may have failed in clinical trials in rheumatoid arthritis (RA) patients, using an in vitro monocyte migration system model., Methodology/principal Findings: Monocytes from healthy donors (HD; n = 8) or from RA patients (for CCR2 and CCR5 antibody n = 8; for CCR1 blockade n = 13) were isolated from peripheral blood and pre-incubated with different concentrations of either anti-CCR1, anti-CCR2, or anti-CCR5 blocking antibodies (or medium or isotype controls). In addition, a small molecule CCR1 antagonist (BX471) was tested. Chemotaxis was induced by CCL2/MCP-1 (CCR2 ligand), CCL5/RANTES (CCR1 and CCR5 ligand), or by a mix of 5 RA synovial fluids (SFs), and cellular responses compared to chemotaxis in the presence of medium alone. Anti-CCR2 antibody treatment blocked CCL2/MCP-1-induced chemotaxis of both HD and RA monocytes compared to isotype control. Similarly, anti-CCR5 antibody treatment blocked CCL5/RANTES-induced chemotaxis of RA monocytes. While neither CCR2 nor CCR5 blocking antibodies were able to inhibit SF-induced monocyte chemotaxis, even when both receptors were blocked simultaneously, both anti-CCR1 antibodies and the CCR1 antagonist were able to inhibit SF-induced monocyte chemotaxis., Conclusions/significance: The RA synovial compartment contains several ligands for CCR1, CCR2, and CCR5 as well as other chemokines and receptors involved in monocyte recruitment to the site of inflammation. The results suggest that CCR2 and CCR5 are not critical for the migration of monocytes towards the synovial compartment in RA. In contrast, blockade of CCR1 may be effective. Conceivably, CCR1 blockade failed in clinical trials, not because CCR1 is not a good target, but because very high levels of receptor occupancy at all times may be needed to inhibit monocyte migration in vivo.
- Published
- 2011
- Full Text
- View/download PDF
49. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases.
- Author
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Soler D, Chapman T, Yang LL, Wyant T, Egan R, and Fedyk ER
- Subjects
- Antibodies, Monoclonal, Humanized, B-Lymphocytes drug effects, B-Lymphocytes metabolism, Basophils drug effects, Basophils metabolism, Binding, Competitive drug effects, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes metabolism, Cell Adhesion drug effects, Cell Line, Fibronectins metabolism, Humans, Immunohistochemistry, Integrin alpha4beta1 drug effects, Integrin alpha4beta1 metabolism, Integrins metabolism, Interleukin-17 metabolism, Killer Cells, Natural drug effects, Killer Cells, Natural metabolism, Leukocytes drug effects, Leukocytes metabolism, Protein Binding, T-Lymphocytes, Helper-Inducer metabolism, Vascular Cell Adhesion Molecule-1 metabolism, Antibodies, Monoclonal pharmacology, Inflammatory Bowel Diseases drug therapy, Integrins antagonists & inhibitors
- Abstract
Vedolizumab is a humanized monoclonal antibody that targets the alpha(4)beta(7) integrin exclusively, and modulates inflammation in the gastrointestinal tract without inducing the systemic immunosuppression that characterizes anti-alpha(4) chain monoclonal antibodies, such as natalizumab. This unique pharmacologic profile is largely attributable to four determinants. The first determinant is the restriction of the expression of the alpha(4)beta(7) integrin to subsets of leukocytes. Vedolizumab does not bind to the majority of memory CD4(+) T lymphocytes (60%), neutrophils, and most monocytes. The highest level of vedolizumab binding is to a subset (approximately 25%) of human peripheral blood memory CD4(+) T lymphocytes that include gut-homing interleukin 17 T-helper lymphocytes. Vedolizumab also binds to eosinophils at high levels, and to naive T-helper lymphocytes, naive and memory cytotoxic T lymphocytes, B lymphocytes, natural killer cells, and basophils at lower levels; vedolizumab binds to memory CD4(+) T and B lymphocytes with subnanomolar potency (EC(50) = 0.3-0.4 nM). The second determinant is binding specificity; vedolizumab binds exclusively to the alpha(4)beta(7) integrin, and not to the alpha(4)beta(1) and alpha(E)beta(7) integrins. The third determinant is selective antagonism; vedolizumab selectively inhibits adhesion of alpha(4)beta(7)-expressing cells to mucosal addressin cell adhesion molecule 1 (median inhibition concentration [IC(50)] = 0.02-0.06 microg/ml) and fibronectin (IC(50) = 0.02 microg/ml), but not vascular cell adhesion molecule 1. The fourth determinant is the gastrointestinal-specific tropism of the alpha(4)beta(7) integrin function. These pharmacologic properties of vedolizumab, in conjunction with the gastrointestinal tropism of alpha(4)beta(7) integrin function, may ultimately confer an improved risk-to-benefit profile for patients with inflammatory bowel diseases.
- Published
- 2009
- Full Text
- View/download PDF
50. Validation of a flow cytometry based chemokine internalization assay for use in evaluating the pharmacodynamic response to a receptor antagonist.
- Author
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Wyant T, Lackey A, and Green M
- Subjects
- Blood Cells cytology, Blood Cells metabolism, Fluorescence, Freezing, Humans, Immunologic Memory, Indicators and Reagents, Monocytes cytology, Reproducibility of Results, Solubility, Staining and Labeling, T-Lymphocytes cytology, T-Lymphocytes immunology, Titrimetry, Biological Assay methods, Chemokine CCL2 metabolism, Endocytosis, Flow Cytometry methods, Receptors, CCR2 antagonists & inhibitors
- Abstract
Pharmacodynamic assays are important in clinical trial design to investigate the relationship between drug concentration (pharmacokinetics) and drug "effect' or biological activity. Increasingly flow cytometry is being used to examine the pharmacodynamic effect of new drug entities. However, to date, the analytical validation of cytometry based assays is limited and there is no suitable guidance for method validation of flow cytometry-based pharmacodynamic assays. Here we report the validation of a flow cytometry-based chemokine internalization assay for use in evaluating the effect of a receptor antagonist in clinical trials. The assay method was validated by examining the stability of the reagent, assay robustness, sensitivity, repeatability and reproducibility precision. Experimental results show the assay reagent was stable over 26 weeks. The assay demonstrated a sensitivity to distinguish 0.005 microg/ml of a CCR2 antagonist with a %CV of 13.3%. The intra-assay repeatability was less than 15% with an inter-assay repeatability of less than 20%. In vivo study results demonstrated that the assay was consistent and a reliable measure of antagonist activity.
- Published
- 2008
- Full Text
- View/download PDF
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