scholarly journals Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kevin J. Roberts ◽  
Marion F. Cubitt ◽  
Timothy M. Carlton ◽  
Lurdes Rodrigues-Duarte ◽  
Luana Maggiore ◽  
...  
Keyword(s):  
Oral Administration ◽  
Single Molecule ◽  
Ex Vivo ◽  
Oral Treatment ◽  
Complete Separation ◽  
Preclinical Development ◽  
Specific Domain ◽  
Domain Antibody ◽  
Inflammatory Bowel ◽  
Further Development

AbstractAnti-TNFα and anti-IL-23 antibodies are highly effective therapies for Crohn’s disease or ulcerative colitis in a proportion of patients. V56B2 is a novel bispecific domain antibody in which a llama-derived IL-23p19-specific domain antibody, humanised and engineered for intestinal protease resistance, V900, was combined with a previously-described TNFα-specific domain antibody, V565. V56B2 contains a central protease-labile linker to create a single molecule for oral administration. Incubation of V56B2 with trypsin or human faecal supernatant resulted in a complete separation of the V565 and V900 monomers without loss of neutralising potency. Following oral administration of V900 and V565 in mice, high levels of each domain antibody were detected in the faeces, demonstrating stability in the intestinal milieu. In ex vivo cultures of colonic biopsies from IBD patients, treatment with V565 or V900 inhibited tissue phosphoprotein levels and with a combination of the two, inhibition was even greater. These results support further development of V56B2 as an oral therapy for IBD with improved safety and efficacy in a greater proportion of patients as well as greater convenience for patients compared with traditional monoclonal antibody therapies.

scholarly journals Oral Anti-Tumour Necrosis Factor Domain Antibody V565 Provides High Intestinal Concentrations, and Reduces Markers of Inflammation in Ulcerative Colitis Patients

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Suhail Nurbhai ◽  
Kevin J. Roberts ◽  
Timothy M. Carlton ◽  
Luana Maggiore ◽  
Marion F. Cubitt ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Oral Administration ◽  
Oral Treatment ◽  
Inflammatory Cells ◽  
Single Domain Antibody ◽  
Oral Dosing ◽  
Markers Of Inflammation ◽  
Domain Antibody ◽  
Enteric Coated ◽  
Terminal Ileostomy

Abstract V565 is an engineered TNFα-neutralising single domain antibody formulated into enteric coated mini-tablets to enable release in the intestine after oral administration as a possible oral treatment for inflammatory bowel disease (IBD). Following oral administration, ileal recovery of V565 was investigated in four patients with terminal ileostomy. Intestinal and systemic pharmacokinetics were measured in six patients with Crohn’s disease and evidence of target engagement assessed in five patients with ulcerative colitis. Following oral administration, V565 was detected at micromolar concentrations in ileal fluid from the ileostomy patients and in stools of the Crohn’s patients. In four of the five ulcerative colitis patients, biopsies taken after 7d dosing demonstrated V565 in the lamina propria with co-immunostaining on CD3+ T-lymphocytes and CD14+ macrophages. Phosphorylation of signalling proteins in biopsies taken after 7d oral dosing was decreased by approximately 50%. In conclusion, enteric coating of V565 mini-tablets provided protection in the stomach with gradual release in intestinal regions affected by IBD. Immunostaining revealed V565 tissue penetration and association with inflammatory cells, while decreased phosphoproteins after 7d oral dosing was consistent with V565-TNFα engagement and neutralising activity. Overall these results are encouraging for the clinical utility of V565 in the treatment of IBD.

Pharmacokinetics and Safety Assessment of Anti-HIV Dapivirine Vaginal Microbicide Rings with Multiple Dosing

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Ex Vivo ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Vaginal Ring ◽  
Vaginal Fluid ◽  
Cervical Tissue ◽  
Double Blind ◽  
Group A ◽  
Group B ◽  
Anti Hiv

Objectives: Self-administered vaginal rings are a promising method for delivery of topical anti-HIV microbicidesand might offer an adherence advantage over daily or coitally-dependent dosage forms such as gels. This trialassessed the safety and pharmacokinetic aspects of the Dapivirine Vaginal Ring-004 when worn as multiple rings oversequential periods of ring use by healthy, sexually-active, HIV-negative women.Methods: This double-blind trial was conducted among 48 women (18-40 years). Participants were randomlyassigned to two groups (A or B) and received (3:1) either the dapivirine or a placebo vaginal ring. Group A used tworings over a 56-day period and Group B used three rings over a 57-day period. Safety evaluations were conductedthroughout the trial. Dapivirine concentrations were measured in plasma, vaginal fluid and cervical tissue samplescollected during and after the 56 days (Group A) or 57 days (Group B) of vaginal ring use.Results: Ring-004 was safe and well tolerated in all participants. The pharmacokinetic profile demonstrated arapid increase in plasma and vaginal fluid concentrations and achieved concentrations in vaginal fluids and cervicaltissue well above the in vitro IC99 in cervical tissue (3.3 ng/mL) that were sustained for a 28 to 35-day ring use period(approximately 3000 times higher in vaginal fluids and 14 -1000 times higher in cervical tissue). Drug levels wereassociated with significant inhibitory activity of genital secretions against HIV ex vivo, a biomarker of pharmacodynamics.Individual plasma dapivirine concentrations did not exceed 553 pg/mL and were well below plasma concentrations atthe maximum tolerated dose for oral treatment (mean Cmax 2286 ng/mL).Conclusions: The consecutive use of several rings over a period of up to 57 days was safe and well tolerated, andPK data indicate that a single Ring-004 is likely to be protective for at least 35 days.

scholarly journals Phenotypical and Functional Characteristics of Human Regulatory T Cells during Ex Vivo Maturation from CD4+ T Lymphocytes

2021 ◽  
Vol 11 (13) ◽  
pp. 5776
Author(s):  
Varvara G. Blinova ◽  
Natalia S. Novachly ◽  
Sofya N. Gippius ◽  
Abdullah Hilal ◽  
Yulia A. Gladilina ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Ex Vivo ◽  
Pcr Analysis ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Inflammatory Reactions ◽  
Effector Cells ◽  
Cycle Regulation ◽  
Further Development

Regulatory T cells (Tregs) participate in the negative regulation of inflammatory reactions by suppressing effector cells. In a number of autoimmune disorders, the suppressive function and/or the number of Tregs is compromised. The lack of active functioning Tregs can be restored with adoptive transfer of expanded ex vivo autologous Tregs. In our study, we traced the differentiation and maturation of Tregs CD4+CD25+FoxP3+CD127low over 7 days of cultivation from initial CD4+ T cells under ex vivo conditions. The resulting ex vivo expanded cell population (eTregs) demonstrated the immune profile of Tregs with an increased capacity to suppress the proliferation of target effector cells. The expression of the FoxP3 gene was upregulated within the time of expansion and was associated with gradual demethylation in the promotor region of the T cell-specific demethylation region. Real-time RT-PCR analysis revealed changes in the expression profile of genes involved in cell cycle regulation. In addition to FOXP3, the cells displayed elevated mRNA levels of Ikaros zinc finger transcription factors and the main telomerase catalytic subunit hTERT. Alternative splicing of FoxP3, hTERT and IKZF family members was demonstrated to be involved in eTreg maturation. Our data indicate that expanded ex vivo eTregs develop a Treg-specific phenotype and functional suppressive activity. We suggest that eTregs are not just expanded but transformed cells with enhanced capacities of immune suppression. Our findings may influence further development of cell immunosuppressive therapy based on regulatory T cells.

scholarly journals Plasma profile of cimicoxib in sheep after oral administration at two different rates

2017 ◽  
Vol 20 (3) ◽  
pp. 535-538
Author(s):  
A. Di Salvo ◽  
M. Giorgi ◽  
H.K. Lee ◽  
C. Vercelli ◽  
F. Rueca ◽  
...  
Keyword(s):  
Oral Administration ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Individual Variability ◽  
Maximum Plasma ◽  
Dose Rates ◽  
Single Oral Administration ◽  
Concentration Peak ◽  
Value Range ◽  
Slow Absorption

Abstract Sheep are often subjected to painful procedures and thus they need to be treated with analgesics. Nevertheless, knowledges about pharmacokinetic features of these drugs in this species are poor. The aim of this study was to evaluate plasma behaviour of cimicoxib in sheep after a single oral administration at two different dose rates (4 and 6 mg/kg). Maximum plasma concentrations of cimicoxib were equal to 273.78 (median value; range 189.00-567.32) and 565.01 (range 308.27-822.59) ng/mL after treatment with 4 and 6 mg/kg, respectively. The time of maximum concentration (Tmax) was achieved between 4 and 10 hours following treatment at the lower dose, and between 6 and 10 hours after the administration of the higher dose, with one sheep achieving the concentration peak at 0.75 hours. The slow absorption and the great individual variability in plasma concentration, probably due to ruminal effects, suggest that cimicoxib is not suitable for oral treatment in sheep.

scholarly journals Ex vivo response to mucosal bacteria and muramyl dipeptide in inflammatory bowel disease

2016 ◽  
Vol 22 (44) ◽  
pp. 9734
Author(s):  
Claudia Loganes ◽  
Erica Valencic ◽  
Alessia Pin ◽  
Elisa Marini ◽  
Stefano Martelossi ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Ex Vivo ◽  
Muramyl Dipeptide ◽  
Inflammatory Bowel

scholarly journals Pomalidomide-Dexamethasone in the Management of Heavily Pretreated Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Claudio Cerchione ◽  
Lucio Catalano ◽  
Davide Nappi ◽  
Anna Emanuele Pareto ◽  
Gerardo Musuraca ◽  
...  
Keyword(s):  
Oral Administration ◽  
Oral Treatment ◽  
Novel Agents ◽  
Hematologic Toxicity ◽  
Salvage Regimen ◽  
Good Compliance ◽  
Impressive Result ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3

Background Pomalidomide is a new generation IMID, with a very good compliance, thanks to oral administration, which can be used also in heavily pretreated patients, in a domestic setting. Aims In this retrospective observational trial, It has been evaluated efficacy and tolerance of pomalidomide plus dexamethasone (PD) as salvage regimen in heavily pretreated patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. Methods 57 patients (31 M/26 F), with rrMM, median age at diagnosis 69 years (r. 52-86), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-11), every refractory to all the drugs previously received (also Bortezomib, Thalidomide and Lenalidomide), received Pomalidomide-Dexamethasone (Pomalidomide 4 mg for 21 days, Dexamethasone 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. ISS was equally distributed, and cytogenetic at relapse was evaluable in 14 patients. All the patients had previously been treated with schedule containing bortezomib and IMIDs. 63% (36/57) had undergone at least to a single ASCT. All patients were relapsed and refractory to last therapies received before PD. Results Pomalidomide was well tolerated, with grade 3-4 transfusion-dependent anemia in 58% (33/57) of patients, 44% (23/57) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no hospitalization was required, no septic shocks were observed), 40% (23/57) grade 3-4 thrombocytopenia without hemorrhagic events and transfusion-dependence. No severe extra-hematologic toxicity was observed. According to IMWG, ORR1 (≥PR) was 47.3% (27/57: 5 CR, 11 VGPR, 7 PR, 4 MR), but, considering that we are evaluating a cohort of heavily pretreated patients, with poor prognosis, another parameter should be considered, ORR2 (≥SD), considering stable disease as a successful result in progressive MM. ORR2 was 77.1% (17 SD). These can be considered as impressive result in this subset of patients. Oral treatment gives a really good compliance, in frail and unfit patients, and response, when present, is always really fast (median time to response: 2 months (r.1-6)), median OS from diagnosis was 94 months (range 21-234), median OS from start of pomalidomide was 9 months (range 1-25). Nine patients have surprisingly achieved a notable response (3 VGPR, 4 PR, 2 MR) after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Conclusions Pomalidomide-dexamethasone has shown significant efficacy and a very good compliance, thanks to oral administration, in a particularly severe setting of heavily pretreated patients, relapsed and refractory to all available therapeutic resources, also after failure of novel agents. Disclosures Lucchesi: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.

scholarly journals Oral administration of Weissella and Pediococcus sp alleviates formalin induced inflammation in rats by Cytokine Modulation

2021 ◽  
Vol 23 (2) ◽  
pp. 95-104
Author(s):  
B. O. Oladejo ◽  
H. M. Oluwasola
Keyword(s):  
Oral Administration ◽  
Transforming Growth Factor ◽  
Oral Treatment ◽  
Diclofenac Sodium ◽  
Fermented Food ◽  
Enzyme Linked Immunosorbent Assay ◽  
Formalin Injection ◽  
Serum Samples ◽  
Pediococcus Pentosaceus ◽  
Anti Inflammatory

This study was designed to study the cytokine modulatory activity of three lactic acid bacteria (LAB) strains, Weisella cibaria II-1-59, Weisella confusa JMC 1093, and Pediococcus pentosaceus DSM20336 isolated from a Nigerian locally fermented food condiment; “iru” using paw oedema acute inflammatory model induced with 1% formalin in Wistar rats. Rats were distributed into six groups (A-F). Rats in Groups A were neither administered formalin nor treated with LAB, while Group B received formalin injection only. Rats in Groups C, D, and E were  administered formalin and were treated orally with 2 × 107 CFU/ml of Weisella cibaria II-1-59, Weisella confusa JMC 1093, and Pediococcus pentosaceus DSM20336 respectively, while Group F received diclofenac sodium treatment following administration of formalin. The dose of LAB strain used for the oral treatment was 2 × 107 CFU/ml for all the groups while the dose of diclofenac sodium used was 150 mg/kg body weight of the rats. Paw thickness (mm) was checked at t = 0, 1, 4, 8, 24, 72, 168 and 336 h. Cytokine assay for C-reactive protein (CRP), Interleukin (IL-10) and Transforming growth factor (TGF-β) was performed on serum samples of the rats using Enzyme-linked immunosorbent assay (ELISA). Oral administration of W. cibaria II-1-59 showed the best significant decrease in the paw thickness of the rats, which was followed by P. pentosaceus DSM20336 and W. confusa JMC 1093 respectively, and was shown to be statistically significant at P<0.05. There was also a significant decrease (below standard 2000 pg/ml) in the secretion of pro-inflammatory biomarker (CRP) in all LAB treated groups at 1 hour, while there was an increase in the serum levels of anti-inflammatory cytokines IL-10 and TGF- β in Groups C-E rats which was maximally increased in W. confusa JMC 1093 treated rats. This study suggests that W. cibaria II-1-59, W. confusa JMC 1093 and P. pentosaceus DSM20336 possess anti-inflammatory potentials. Keywords: Inflammation, Cytokines, Weisella, Formalin, Oedema, Pediococcus

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