SummaryBackgroundVedolizumab, an anti‐α4β7 integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing.AimsTo characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic–pharmacodynamic relationship using population modelling.MethodsData from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data.ResultsVedolizumab pharmacokinetics was described by a 2‐compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half‐life of vedolizumab was 25.5 days; linear clearance (CLL) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution (V c) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (%CV) were 35% for CLL and 19% for V c; residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CLL.ConclusionsPopulation pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2); NCT01224171 (GEMINI 3).
Type 1 cell-mediated immunity might play an important role in protection from typhoid fever. We evaluated whether immunization with Salmonella enterica serovar Typhi (S. Typhi) strain CVD 908-htrA (a ΔaroC ΔaroD ΔhtrA mutant), a leading live oral typhoid vaccine candidate, elicits specific CD4+ and CD8+ S. Typhi immune responses. Potent CTL responses and IFN-γ secretion by CD8+ T cells were detected following immunization with CVD 908-htrA in high (4.5 × 108 CFU) and low (5 × 107 CFU) dosages. S. Typhi-specific CTL were observed in six of eight vaccinees (four high and two low dose) after immunization. Mean increases in the frequency of IFN-γ spot-forming cells (SFC) in the presence of S. Typhi-infected targets were 221 ± 41 SFC/106 PBMC and 233 ± 87 SFC/106 PBMC, in the high and low dose groups, respectively. Strong CD4+ T cell responses were also observed. Increases in the IFN-γ production to soluble S. Typhi flagella (STF) occurred in 82 and 38% of the volunteers who received the high and low doses, respectively. Robust correlations were observed between volunteers that responded with IFN-γ SFC to stimulation with S. Typhi-infected cells and IFN-γ released in response to stimulation with STF Ags (r = 0.822, p < 0.001) and between CTL and IFN-γ production to STF (r = 0.818, p = 0.013). These data demonstrating the concomitant induction of both CD4- and CD8-mediated CMI are consistent with a significant role for type 1 immunity in controlling typhoid infection and support the continuing evaluation of CVD 908-htrA as a typhoid vaccine candidate.
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.Chemokines control the directed movement of cells expressing matching receptors (1,2). Chemokine receptor CCR2 is mainly expressed on monocytes and a subset of T cells, implying that ligands of CCR2 may attract these cell types (3). CCR2 has 5 known ligands, This publication reflects only the authors' views. The European Community is not liable for any use that may be made of the information herein.
Salmonella enterica serovar Typhi strain CVD 908-htrA is a live attenuated strain which may be useful as an improved oral typhoid vaccine and as a vector for cloned genes of other pathogens. We conducted a phase 2 trial in which 80 healthy adults received one of two dosage levels of CVD 908-htrA in a double-blind, placebocontrolled, crossover study. There were no differences in the rates of side effects among volunteers who received high-dose vaccine (4.5 ؋ 10 8 CFU), lower-dose vaccine (5 ؋ 10 7 CFU), or placebo in the 21 days after vaccination, although recipients of high-dose vaccine (8%) had more frequent diarrhea than placebo recipients (0%) in the first 7 days. Seventy-seven percent and 46% of recipients of high-and lower-dose vaccines, respectively, briefly excreted vaccine organisms in their stools. All blood cultures were negative. Antibody-secreting cells producing antilipopolysaccharide (LPS) immunoglobulin A (IgA) were detected in 100 and 92% of recipients of high-and lower-dose vaccines, respectively. Almost half the volunteers developed serum anti-LPS IgG. Lymphocyte proliferation and gamma interferon production against serovar Typhi antigens occurred in a significant proportion of vaccinees. This phase 2 study supports the further development of CVD 908-htrA as a single-dose vaccine against typhoid fever and as a possible live vector for oral delivery of other vaccine antigens.Attenuated Salmonella enterica serovar Typhi oral vaccine Ty21a (7) and parenteral purified Vi polysaccharide vaccine (1, 13) have replaced parenteral killed whole-cell vaccine as the recommended prophylaxis against typhoid fever. However, both of these vaccines have disadvantages. The Vi vaccine is T-cell independent and so does not stimulate helper T cells that could enhance and broaden the immune response and elicit immunologic memory. Ty21a requires three or four doses for optimal immunogenicity.A single-dose, oral serovar Typhi vaccine strain is highly desirable. Moreover, such a strain would also be a promising vector for the delivery of heterologous cloned antigens (2,6,8,9,22,25). One strategy for attenuating salmonellae has been to introduce defined deletions into the genes encoding enzymes of the aromatic amino acid biosynthesis pathway, thereby rendering the bacteria auxotrophic for para-aminobenzoic acid (PABA) and dihydroxybenzoate (DHB) (10). These are substrates that the organism cannot scavenge in sufficient quantities in mammalian tissues to sustain growth. Such aro deletion mutants of S. enterica serovar Typhimurium are safe and immunogenic as live oral vaccines in mice and cattle (4,10,12,19). Analogous auxotrophic mutants of serovar Typhi have been prepared as typhoid vaccines and vaccine vectors for humans.In recent studies, vaccine strain CVD 908, a derivative of wild-type strain Ty2 harboring deletion mutations in aroC and in aroD, has been evaluated with adult volunteers. CVD 908 was well tolerated and highly immunogenic when given to volunteers in phase 1 studies after having been freshly harvested f...
The cytokine production patterns of human peripheral blood mononuclear cells (PBMC) in response to Salmonella typhiflagella (STF) were examined in culture supernatants of PBMC stimulated with STF. Consistent with previous findings in volunteers vaccinated with aroC aroD deletion mutants of S. typhi, PBMC from volunteers immunized with the licensed live Ty21a S. typhi vaccine secreted gamma interferon following exposure to STF. Stimulation with STF induced rapid de novo synthesis of tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β), followed by IL-6 and IL-10. Trypsin treatment of STF abrogated their effects, while polymyxin B had no effect. Intracellular cytokine measurements of STF-stimulated PBMC revealed the existence of monocyte subpopulations that produce only TNF-α, IL-1β or both cytokines. Moreover, STF markedly decreased the percentage of CD14+cells. These data demonstrate that STF are powerful monocyte activators which may have important implications for vaccine development and for understanding the pathogenesis of S. typhi infection.
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