RESUMEN
Current factor VIII (FVIII) products display a half-life (t(1/2)) of â¼ 8-12 hours, requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG(1) to extend circulating rFVIII t(1/2). This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc. Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc. Most adverse events were unrelated to study drug. None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors. Across dose levels, compared with rFVIII, rFVIIIFc showed 1.54- to 1.70-fold longer elimination t(1/2), 1.49- to 1.56-fold lower clearance, and 1.48- to 1.56-fold higher total systemic exposure. rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries. Time to 1% FVIII activity above baseline was â¼ 1.53- to 1.68-fold longer than rFVIII across dose levels. Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII. Thus, rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www.clinicaltrials.gov as NCT01027377.
Asunto(s)
Factor VIII/farmacocinética , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Receptores Fc/uso terapéutico , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto , Relación Dosis-Respuesta a Droga , Factor VIII/administración & dosificación , Factor VIII/efectos adversos , Semivida , Hemofilia A/sangre , Hemofilia A/metabolismo , Humanos , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Bombas de Infusión , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Receptores Fc/administración & dosificación , Receptores Fc/metabolismo , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Factores de Tiempo , Adulto Joven , Factor de von Willebrand/análisisRESUMEN
BACKGROUND: MD-7246, a delayed-release formulation of linaclotide, is designed to target the ileocaecal junction and caecum with the aim of relieving abdominal pain independently of bowel function. AIMS: To evaluate the efficacy, safety and dose-response of MD-7246 in patients with irritable bowel syndrome with diarrhoea (IBS-D). METHODS: A randomised, double-blind, phase 2 clinical trial enrolled adult patients with IBS-D (Rome IV criteria). Patients were randomised to placebo or once-daily oral MD-7246 300, 600 or 1200 µg for 12 weeks. Abdominal and bowel symptoms were assessed daily. Key efficacy endpoints were change from baseline in abdominal pain and responder rates for a 30% reduction in abdominal pain in 6/12 weeks. Additional abdominal pain responder and exploratory bowel function endpoints were also assessed. RESULTS: Among the 388 randomised patients, there was no significant difference in mean change from baseline in abdominal pain between the MD-7246 300 µg, 600 µg and 1200 µg groups and placebo (-1.93, -1.58, -1.95 and - 2.01, respectively; p > 0.05 for each group vs placebo). The abdominal pain responder rates in the MD-7246 groups were similar to or lower than those in the placebo group. All doses of MD-7246 had a minimal effect on bowel function and were generally well tolerated. CONCLUSIONS: MD-7246 at the doses studied did not improve abdominal pain relative to placebo in an IBS-D patient population. Similarly, most additional efficacy endpoints showed no improvement with MD-7246 relative to placebo.
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Síndrome del Colon Irritable , Adulto , Humanos , Síndrome del Colon Irritable/complicaciones , Síndrome del Colon Irritable/tratamiento farmacológico , Estreñimiento/tratamiento farmacológico , Resultado del Tratamiento , Diarrea/tratamiento farmacológico , Dolor Abdominal/tratamiento farmacológico , Dolor Abdominal/diagnóstico , Método Doble CiegoRESUMEN
We assessed the efficacy of a culturally competent outreach model with promotoras in raising the coronavirus disease 2019 (COVID-19) first-dose vaccination rates in Chicago's at-risk ZIP codes from February through May 2021. Utilizing community members from within target communities may reduce barriers, increase vaccination rates, and enhance COVID-19 prevention.
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COVID-19 , Humanos , COVID-19/prevención & control , Relaciones Comunidad-Institución , Hospitales Comunitarios , VacunaciónRESUMEN
The coronavirus disease 2019 (COVID-19) pandemic has disproportionately impacted Black, indigenous, and people of color (BIPOC). Equitable access to therapeutics is key to addressing health disparities. We established a monoclonal infusion program in the emergency department of a safety-net hospital. Our program successfully reached underserved BIPOC communities and was sustained throughout the pandemic.
Asunto(s)
Anticuerpos Monoclonales , COVID-19 , Humanos , Anticuerpos Monoclonales/uso terapéutico , COVID-19/terapia , Servicio de Urgencia en Hospital , Estudios de Factibilidad , Pandemias/prevención & control , Poblaciones Vulnerables , Accesibilidad a los Servicios de Salud , Disparidades en Atención de SaludRESUMEN
T cell-stimulating cytokines and immune checkpoint inhibitors (ICI) are an ideal combination for increasing response rates of cancer immunotherapy. However, the results of clinical trials have not been satisfying. It is important to understand the mechanism of synergy between these two therapeutic modalities. Here, through integrated analysis of multiple single-cell RNA sequencing (scRNA-seq) datasets of human tumor-infiltrating immune cells, we demonstrate that IL21 is produced by tumor-associated T follicular helper cells and hyperactivated/exhausted CXCL13+CD4+ T cells in the human tumor microenvironment (TME). In the mouse model, the hyperactivated/exhausted CD4+ T cell-derived IL21 enhances the helper function of CD4+ T cells that boost CD8+ T cell-mediated immune responses during PD-1 blockade immunotherapy. In addition, we demonstrated that IL21's antitumor activity did not require T-cell trafficking. Using scRNA-seq analysis of the whole tumor-infiltrating immune cells, we demonstrated that IL21 treatment in combination with anti-PD-1 blockade synergistically drives tumor antigen-specific CD8+ T cells to undergo clonal expansion and differentiate toward the hyperactive/exhausted functional state in the TME. In addition, IL21 treatment and anti-PD-1 blockade synergistically promote dendritic cell (DC) activation and maturation to mature DC as well as monocyte to type 1 macrophage (M1) differentiation in the TME. Furthermore, the combined treatment reprograms the immune cellular network by reshaping cell-cell communication in the TME. Our study establishes unique mechanisms of synergy between IL21 and PD-1-based ICI in the TME through the coordinated promotion of type 1 immune responses. Significance: This study reveals how cytokine and checkpoint inhibitor therapy can be combined to increase the efficacy of cancer immunotherapy.
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Linfocitos T CD8-positivos , Microambiente Tumoral , Animales , Ratones , Humanos , Interleucinas/farmacología , Inmunoterapia/métodos , CitocinasRESUMEN
BACKGROUND: Non-antiviral therapeutic options are required for the treatment of hospitalised patients with COVID-19. CD24Fc is an immunomodulator with potential to reduce the exaggerated inflammatory response to tissue injuries. We aimed to evaluate the safety and efficacy of CD24Fc in hospitalised adults with COVID-19 receiving oxygen support. METHODS: We conducted a randomised, double-blind, placebo-controlled, phase 3 study at nine medical centres in the USA. Hospitalised patients (age ≥18 years) with confirmed SARS-CoV-2 infection who were receiving oxygen support and standard of care were randomly assigned (1:1) by site-stratified block randomisation to receive a single intravenous infusion of CD24Fc 480 mg or placebo. The study funder, investigators, and patients were masked to treatment group assignment. The primary endpoint was time to clinical improvement over 28 days, defined as time that elapsed between a baseline National Institute of Allergy and Infectious Diseases ordinal scale score of 2-4 and reaching a score of 5 or higher or hospital discharge. The prespecified primary interim analysis was done when 146 participants reached the time to clinical improvement endpoint. Efficacy was assessed in the intention-to-treat population. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT04317040. FINDINGS: Between April 24 and Sept 22, 2020, 243 hospitalised patients were assessed for eligibility and 234 were enrolled and randomly assigned to receive CD24Fc (n=116) or placebo (n=118). The prespecified interim analysis was done when 146 participants reached the time to clinical improvement endpoint among 197 randomised participants. In the interim analysis, the 28-day clinical improvement rate was 82% (81 of 99) for CD24Fc versus 66% (65 of 98) for placebo; median time to clinical improvement was 6·0 days (95% CI 5·0-8·0) in the CD24Fc group versus 10·0 days (7·0-15·0) in the placebo group (hazard ratio [HR] 1·61, 95% CI 1·16-2·23; log-rank p=0·0028, which crossed the prespecified efficacy boundary [α=0·0147]). 37 participants were randomly assigned after the interim analysis data cutoff date; among the 234 randomised participants, median time to clinical improvement was 6·0 days (95% CI 5·0-9·0) in the CD24Fc group versus 10·5 days (7·0-15·0) in the placebo group (HR 1·40, 95% CI 1·02-1·92; log-rank p=0·037). The proportion of participants with disease progression within 28 days was 19% (22 of 116) in the CD24Fc group versus 31% (36 of 118) in the placebo group (HR 0·56, 95% CI 0·33-0·95; unadjusted p=0·031). The incidences of adverse events and serious adverse events were similar in both groups. No treatment-related adverse events were observed. INTERPRETATION: CD24Fc is generally well tolerated and accelerates clinical improvement of hospitalised patients with COVID-19 who are receiving oxygen support. These data suggest that targeting inflammation in response to tissue injuries might provide a therapeutic option for patients hospitalised with COVID-19. FUNDING: Merck & Co, National Cancer Institute, OncoImmune.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Adolescente , Adulto , Método Doble Ciego , Humanos , Factores Inmunológicos/efectos adversos , Oxígeno , SARS-CoV-2 , Resultado del TratamientoRESUMEN
Kinases represent an important class of targets for pharmaceutical drug development. Microfluidic devices capable of running kinase assays with either an on-chip or an off-chip enzymatic reaction have been developed. For the on-chip assay, reagent addition, mixing, enzymatic reaction, and electrophoretic separation and detection of substrate and product all take place in the channels of the microfluidic chip. For the off-chip assay, the reaction takes place in a microtiter plate, whereas the electrophoretic separation and detection of substrate and product take place in the channels of the chip. To probe differences between the on-chip and off-chip assays, a panel of commercially available kinase inhibitors was assayed at 10 microM against cyclic AMP-dependent protein kinase A, glycogen synthase kinase 3beta, mitogen- and stress-activated protein kinase, and Akt1 using both the off-chip and on-chip assays. Good correlation was observed between inhibition measured by the two methods, with most of the differences in measured inhibition being attributed to compound solubility and enzyme concentration effects. Microfluidic devices represent an attractive platform for kinase assays due to high data quality and the possibility of on-chip assay integration, leading to reagent and labor savings.