RÉSUMÉ
Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor-specific CD8+ T cells and their recruitment to tumor microenvironment. However, cDC1s are often underrepresented in the microenvironment. Systemic administration of Fms-like tyrosine kinase 3 ligand, a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to cDC1 expansion in the periphery and recruitment into the microenvironment. FLT3 pathway stimulation using GS-3583, a novel FLT3 agonistic Fc fusion protein, has the potential to promote T-cell mediated antitumor activity. This was a first-in-human, placebo-controlled study of GS-3583 in healthy participants to evaluate the safety, pharmacokinetics (PK), and pharmacodynamic (PD) of escalating single doses (75-2000 µg) of GS-3583. Each dose cohort enrolled 8-12 healthy participants who received GS-3583 or placebo as single IV infusion at 3:1 ratio. As part of the PD evaluation, the changes in the number of cDC1 cells were investigated. GS-3583 was well-tolerated in healthy participants up to the highest evaluated dose (2000 µg). There have been no serious or grade III or higher adverse events. PK analysis suggested a dose-dependent increase in GS-3583 exposure with target-mediated disposition characteristics at low doses. PD analysis shows that administration of GS-3583 resulted in transient, dose-dependent increases in cDC1 cells that returned to baseline within 3 weeks of drug administration. The pharmacokinetics and pharmacodynamics of GS-3583 following single dosing were characterized in this study which enabled subsequent phase Ib assessments in patients with advanced solid tumors.
Sujet(s)
Volontaires sains , Fragments Fc des immunoglobulines , Protéines de fusion recombinantes , Tyrosine kinase-3 de type fms , Humains , Adulte , Mâle , Femelle , Adulte d'âge moyen , Protéines de fusion recombinantes/pharmacocinétique , Protéines de fusion recombinantes/administration et posologie , Protéines de fusion recombinantes/effets indésirables , Protéines de fusion recombinantes/pharmacologie , Tyrosine kinase-3 de type fms/antagonistes et inhibiteurs , Jeune adulte , Fragments Fc des immunoglobulines/administration et posologie , Fragments Fc des immunoglobulines/pharmacologie , Fragments Fc des immunoglobulines/effets indésirables , Relation dose-effet des médicaments , Cellules dendritiques/effets des médicaments et des substances chimiques , Cellules dendritiques/immunologie , Méthode en double aveugle , Perfusions veineusesRÉSUMÉ
Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer's disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aß pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder.
Sujet(s)
Maladie d'Alzheimer , Encéphale , , Animaux , Femelle , Humains , Mâle , Souris , Administration par voie nasale , Maladie d'Alzheimer/traitement médicamenteux , Maladie d'Alzheimer/métabolisme , Précurseur de la protéine bêta-amyloïde/génétique , Barrière hémato-encéphalique/métabolisme , Barrière hémato-encéphalique/effets des médicaments et des substances chimiques , Encéphale/métabolisme , Encéphale/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Exénatide , Fragments Fc des immunoglobulines/administration et posologie , Incrétines , Souris transgéniques , Préséniline-1/génétique , Protéines de fusion recombinantes/administration et posologie , Protéines de fusion recombinantes/pharmacocinétique , /pharmacocinétiqueRÉSUMÉ
OBJECTIVE: This prospective study aimed to describe the clinical course in terms of glycemic outcomes, body weight, and adverse events during the first 12 weeks following a switch from glucagon-like peptide-1 receptor agonists (GLP-1 RAs) directly to tirzepatide 5 mg. METHODS: Participants were ≥18 years with type 2 diabetes (T2D), glycated hemoglobin (HbA1c) ≥6.5% to ≤9.0%, body mass index ≥25 kg/m2 and were on a stable treatment dose of GLP-1 RAs (liraglutide every day [1.2, 1.8 mg], semaglutide once-weekly [0.5, 1.0, 2.0 mg], or dulaglutide once-weekly [0.75, 1.5, 3.0, and 4.5 mg]) for ≥3 months at baseline. The primary end point was HbA1c change from baseline at week 12. Secondary end points included change from baseline in fasting serum glucose, body weight, and glucose assessed by continuous glucose monitoring. Safety was also assessed. RESULTS: Participants were 58.3 years on average, with baseline HbA1c 7.39%, body mass index 35.18 kg/m2, T2D duration around 12.4 years, and included 55% females. Semaglutide (55%) and dulaglutide (42%) were the most commonly used GLP-1 RAs at baseline with semaglutide 1.0 mg and dulaglutide 1.5 mg being the most common treatment doses. At week 12, mean HbA1c changed from baseline by -0.43%, fasting serum glucose by -7.83 mg/dL, and body weight by -2.15 kg (all P < .01). Glycemic outcomes and body weight improved in participants in all baseline GLP-1 RA subgroups. Twenty participants (13.2%) developed gastrointestinal events. Three (2%) participants discontinued tirzepatide due to adverse events. There were no severe hypoglycemic events or deaths. CONCLUSION: In this prospective study, when people with T2D on stable GLP-1 RA treatment were switched directly to tirzepatide 5 mg, they experienced improved glycemic outcomes and additional weight reduction with an acceptable risk of adverse gastrointestinal events over 12 weeks.
Sujet(s)
Glycémie , Diabète de type 2 , , Peptides glucagon-like , Hypoglycémiants , Fragments Fc des immunoglobulines , Adulte , Sujet âgé , Femelle , Humains , Mâle , Adulte d'âge moyen , Glycémie/effets des médicaments et des substances chimiques , Glycémie/analyse , Poids/effets des médicaments et des substances chimiques , Diabète de type 2/traitement médicamenteux , Diabète de type 2/sang , Substitution de médicament , Peptide gastrointestinal , /administration et posologie , /effets indésirables , Récepteur du peptide-2 similaire au glucagon , Peptides glucagon-like/analogues et dérivés , Peptides glucagon-like/administration et posologie , Peptides glucagon-like/usage thérapeutique , Peptides glucagon-like/effets indésirables , Hémoglobine glyquée/analyse , Hypoglycémiants/administration et posologie , Hypoglycémiants/usage thérapeutique , Hypoglycémiants/effets indésirables , Fragments Fc des immunoglobulines/administration et posologie , Fragments Fc des immunoglobulines/usage thérapeutique , Fragments Fc des immunoglobulines/effets indésirables , Liraglutide/administration et posologie , Liraglutide/usage thérapeutique , Liraglutide/effets indésirables , Études prospectives , Protéines de fusion recombinantes/administration et posologie , Protéines de fusion recombinantes/usage thérapeutique , Protéines de fusion recombinantes/effets indésirablesRÉSUMÉ
AIM: To assess the efficacy and safety of dulaglutide 1.5 mg versus dulaglutide 0.75 mg in Japanese participants with type 2 diabetes (T2D). MATERIALS AND METHODS: A Phase 3, multicentre, randomized, double-blind, parallel-group study was conducted in Japanese participants aged ≥20 years, with T2D for ≥6 months and inadequate glycaemic control, while on a single oral antihyperglycaemic medication (NCT04809220). The primary objective was to evaluate superiority of dulaglutide 1.5 mg versus dulaglutide 0.75 mg measured by mean change in glycated haemoglobin (HbA1c) from baseline to 26 weeks. Other efficacy and safety endpoints were evaluated at 26 and 52 weeks. All statistical analyses were conducted using the intention-to-treat population. RESULTS: Overall, 591 participants were randomized to once-weekly dulaglutide 1.5 mg or 0.75 mg. At Week 26, dulaglutide 1.5 mg was superior to dulaglutide 0.75 mg in HbA1c reduction from baseline (least squares mean [LSM] difference -0.29% [95% confidence interval {CI} -0.43, -0.14]). At Week 52, the dulaglutide 1.5-mg arm had a significantly greater proportion of participants who achieved HbA1c <7.0% (46.3% vs. 38.5%; p = 0.03) and showed significantly greater reduction in fasting serum glucose (LSM difference -9.4 mg/dL [95% CI -14.4, -4.3]; p < 0.001) versus the dulaglutide 0.75-mg arm. No statistically significant change in body weight was observed in either treatment arm. Overall, 442 participants (75.4%) experienced treatment emergent adverse events (TEAEs). Constipation (11.3%), diarrhoea (9.6%) and pyrexia (9.0%) were the most commonly reported TEAEs. CONCLUSIONS: Dulaglutide 1.5 mg once weekly demonstrated superior glycaemic control versus dulaglutide 0.75 mg once weekly, with comparable safety and tolerability, in Japanese people with T2D.
Sujet(s)
Glycémie , Diabète de type 2 , Peptides glucagon-like , Hémoglobine glyquée , Hypoglycémiants , Fragments Fc des immunoglobulines , Protéines de fusion recombinantes , Humains , Diabète de type 2/traitement médicamenteux , Diabète de type 2/sang , Protéines de fusion recombinantes/administration et posologie , Protéines de fusion recombinantes/effets indésirables , Protéines de fusion recombinantes/usage thérapeutique , Fragments Fc des immunoglobulines/effets indésirables , Fragments Fc des immunoglobulines/administration et posologie , Fragments Fc des immunoglobulines/usage thérapeutique , Peptides glucagon-like/analogues et dérivés , Peptides glucagon-like/administration et posologie , Peptides glucagon-like/effets indésirables , Peptides glucagon-like/usage thérapeutique , Mâle , Adulte d'âge moyen , Femelle , Méthode en double aveugle , Hypoglycémiants/administration et posologie , Hypoglycémiants/effets indésirables , Hypoglycémiants/usage thérapeutique , Hémoglobine glyquée/métabolisme , Hémoglobine glyquée/analyse , Japon , Sujet âgé , Glycémie/effets des médicaments et des substances chimiques , Glycémie/métabolisme , Résultat thérapeutique , Adulte , Hypoglycémie/induit chimiquement , Hypoglycémie/épidémiologie , Calendrier d'administration des médicaments , Peuples d'Asie de l'EstRÉSUMÉ
This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar HEC14028 compared to reference Trulicity® (dulaglutide) in healthy male Chinese subjects. This study was a single-center, randomized, open, single-dose, parallel-controlled comparative Phase I clinical trial, including a screening period of up to 14 days, a 17-day observation period after administration, and a 7-day safety follow-up period. A total of 68 healthy male subjects were randomly assigned (1:1) to the test group (HEC14028) and the reference group (dulaglutide) (single 0.75 mg abdominal subcutaneous dose). The primary objective was to evaluate the pharmacokinetic characteristics of HEC14028 and compare the pharmacokinetic similarities between HEC14028 and dulaglutide. The primary PK endpoints were maximum plasma concentration (Cmax) and area under the blood concentration-time curve from zero time to the estimated infinite time (AUC0-∞). The study results showed that HEC14028 and dulaglutide were pharmacokinetically equivalent: 90% confidence interval (CI) of Cmax and AUC0-∞ geometric mean ratios were 102.9%-122.0% and 97.1%-116.9%, respectively, which were both within the range of 80.00%-125.00%. No grade 3 or above treatment emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to withdrawal from the trial, or TEAEs leading to death were reported in this study. Both HEC14028 and dulaglutide showed good and similar safety profiles, and no incremental immunogenicity was observed in subjects receiving HEC14028 and dulaglutide.
Sujet(s)
Produits pharmaceutiques biosimilaires , Peptides glucagon-like , Volontaires sains , Fragments Fc des immunoglobulines , Protéines de fusion recombinantes , Adolescent , Adulte , Humains , Mâle , Adulte d'âge moyen , Jeune adulte , Aire sous la courbe , Asiatiques , Produits pharmaceutiques biosimilaires/pharmacocinétique , Produits pharmaceutiques biosimilaires/administration et posologie , Produits pharmaceutiques biosimilaires/effets indésirables , Chine , Peuples d'Asie de l'Est , Peptides glucagon-like/pharmacocinétique , Peptides glucagon-like/analogues et dérivés , Peptides glucagon-like/administration et posologie , Peptides glucagon-like/effets indésirables , Hypoglycémiants/pharmacocinétique , Hypoglycémiants/administration et posologie , Hypoglycémiants/effets indésirables , Fragments Fc des immunoglobulines/administration et posologie , Fragments Fc des immunoglobulines/effets indésirables , Fragments Fc des immunoglobulines/immunologie , Injections sous-cutanées , Protéines de fusion recombinantes/pharmacocinétique , Protéines de fusion recombinantes/administration et posologie , Protéines de fusion recombinantes/effets indésirables , Équivalence thérapeutiqueRÉSUMÉ
PURPOSE: GS-3583, an FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDC) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and promote T cell-mediated antitumor activity in cancer patients. This phase Ib open-label study assessed GS-3583 in adults with advanced solid tumors. PATIENTS AND METHODS: Multiple escalating doses of GS-3583 (standard 3+3 design) were administered intravenously on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle for up to 52 weeks. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 at each dose level. RESULTS: Thirteen participants enrolled in four dose-escalation cohorts, after which the study was terminated following safety review. Median (range) age was 71 (44-79), and 7 (54%) participants were male. There were no DLTs. Seven participants had grade ≥3 AEs; 2 participants had grade 5 AEs, including a second primary malignancy (acute myeloid leukemia) considered treatment-related. Dose-dependent increase in GS-3583 serum exposure was observed in the dose range of 2-20 mg with GS-3583 accumulation at higher dose levels. Expansions of cDCs occurred at all four doses with a dose-dependent trend in the durability of the cDC expansion. CONCLUSIONS: GS-3583 was relatively well tolerated and induced dose-dependent expansion of cDCs in the periphery of patients with advanced solid tumors. However, development of a second primary malignancy provides a cautionary tale for the FLT3 agonist mechanism. See related commentary by Raeder and Drazer, p. 2857.
Sujet(s)
Tumeurs , Protéines de fusion recombinantes , Tyrosine kinase-3 de type fms , Humains , Mâle , Tumeurs/traitement médicamenteux , Tumeurs/anatomopathologie , Femelle , Adulte d'âge moyen , Sujet âgé , Adulte , Tyrosine kinase-3 de type fms/antagonistes et inhibiteurs , Protéines de fusion recombinantes/administration et posologie , Protéines de fusion recombinantes/effets indésirables , Protéines de fusion recombinantes/usage thérapeutique , Dose maximale tolérée , Fragments Fc des immunoglobulines/effets indésirables , Fragments Fc des immunoglobulines/administration et posologie , Fragments Fc des immunoglobulines/usage thérapeutique , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/effets indésirables , Antinéoplasiques/administration et posologie , Résultat thérapeutiqueRÉSUMÉ
INTRODUCCIÓN: La miastenia gravis es un trastorno neuromuscular autoinmune caracterizada por una debilidad motora fluctuante que afecta a los músculos oculares, bulbares, de las extremidades y/o respiratorios.1 La debilidad se debe a un ataque inmunológico mediado por anticuerpos dirigido a proteínas de la membrana post-sináptica de la unión neuromuscular, como los receptores de acetilcolina o proteínas asociadas a receptores. La miastenia gravis generalizada es trastorno crónico y de baja incidencia que se manifiesta predominantemente por debilidad generalizada del músculo esquelético y debilidad inducida por el ejercicio. 1,2 Entre el 80 y 90 % de las personas con miastenia gravis tienen autoanticuerpos contra el receptor de acetilcolina (AChR) detectables en el suero, y se cree que estos anticuerpos desempeñan un papel central en el mecanismo patogénico de la enfermedad.1 A nivel celular, los anticuerpos AChR causan disfunción en la unión neuromuscular al bloquear la unión de ACh al AChR, entrecruzar e internalizar los AChR y activar la destrucción de AChR mediada por el complemento. Se cree que existe una asociación entre la presencia de anticuerpo AChR y la gravedad de los síntomas clínicos de la miastenia gravis, sin embargo, su correlación todavía no está demostrada. TECNOLOGÍA: Efgartigimod alfa (Vyvgart®) es una molécula de fragmento Fc de anticuerpo IgG diseñada para promover la degradación de autoanticuerpos IgG.3 Se administra por via intravenosa a una dosis de 10 mg/kg administrados durante una hora una vez a la semana durante 4 semanas. En personas que pesan 120 kg o más, la dosis recomendada es de 1.200 mg (3 viales). En la actualidad la administración subcutánea del fármaco se encuentra en estudio. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de efgartigimod alfa (Vyvgart®) en adultos con miastenia gravis generalizada. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. La fecha de búsqueda de información fue hasta el 11 de noviembre de 2023. Para la búsqueda en Pubmed se utilizó la siguiente estrategia de búsqueda: efgartigimod alfa [Supplementary Concept] OR efgartigimod alfa [tiab] OR Vyvgart[tiab]. RECOMENDACIONES: No se hallaron guías de práctica clínica actualizadas en Argentina y en el Mundo que recomienden la tecnología en la indicación evaluada, como tampoco es mencionada en el Consenso Internacional para el manejo de la Miastenia Gravis publicado en 2021.14 El Instituto Nacional para la Excelencia en Salud y Atención (NICE, sus siglas del inglés National Institute for Health and Care Excellence) de Reino Undo y la Agencia Canadiense de Medicamentos y Tecnologías en Salud (CADTH, su sigla del inglés Canadian Agency for Drugs and Technologies in Health) recientemente han comenzado a evaluar la tecnología en la indicación evaluada. CONCLUSIONES: La evidencia que sustenta la aprobación de comercialización por parte de los Estados Unidos y Europa de efgartigimod alfa como complemento a la terapia estándar para el tratamiento de adultos con miastenia gravis generalizada que tienen anticuerpos AChR positivos, se basa en un único ensayo clínico aleatorizado de fase III frente a placebo. No se hallaron estudios que comparen efgartigimod alfa frente a otras alternativas farmacológicas disponibles para la enfermedad, como tampoco frente a otros biológicos no disponibles en Argentina. El estudio identificado demostró que los adultos con miastenia gravis generalizada que tienen anticuerpos AChR positivos y reciben un primer ciclo de tratamiento con efgartigimod alfa, en complemento a la terápia estándar, alcanzan mejorías clinicamente significativas para puntuaciones específicas de la patología frente a placebo al corto plazo. No se hallaron estudios publicados que reporten sobre si estos beneficios se mantienen en el tiempo, sin embargo, existe un estudio en curso sin datos publicados aún que podría responder esta pregunta. No se hallaron guías de práctica clínica actualizadas ni evaluaciones económicas en Argentina y en el Mundo que mencionen la tecnología en la indicación evaluada. Según los precios de adquisición relevados, el costo de un ciclo con el fármaco sería de aproximadamente USD 51.201, 28 (ARS 17.915.328 noviembre/23).
Sujet(s)
Humains , Fragments Fc des immunoglobulines/administration et posologie , Myasthénie/traitement médicamenteux , Argentine , Efficacité en Santé Publique , Analyse coût-bénéficeRÉSUMÉ
BACKGROUND: The incidence of type 2 diabetes mellitus is increasing among youths. Once-weekly treatment with dulaglutide, a glucagon-like peptide-1 receptor agonist, may have efficacy with regard to glycemic control in youths with type 2 diabetes. METHODS: In a double-blind, placebo-controlled, 26-week trial, we randomly assigned participants (10 to <18 years of age; body-mass index [BMI], >85th percentile) being treated with lifestyle modifications alone or with metformin, with or without basal insulin, in a 1:1:1 ratio to receive once-weekly subcutaneous injections of placebo, dulaglutide at a dose of 0.75 mg, or dulaglutide at a dose of 1.5 mg. Participants were then included in a 26-week open-label extension study in which those who had received placebo began receiving dulaglutide at a weekly dose of 0.75 mg. The primary end point was the change from baseline in the glycated hemoglobin level at 26 weeks. Secondary end points included a glycated hemoglobin level of less than 7.0% and changes from baseline in the fasting glucose concentration and BMI. Safety was also assessed. RESULTS: A total of 154 participants underwent randomization. At 26 weeks, the mean glycated hemoglobin level had increased in the placebo group (0.6 percentage points) and had decreased in the dulaglutide groups (-0.6 percentage points in the 0.75-mg group and -0.9 percentage points in the 1.5-mg group, P<0.001 for both comparisons vs. placebo). At 26 weeks, a higher percentage of participants in the pooled dulaglutide groups than in the placebo group had a glycated hemoglobin level of less than 7.0% (51% vs. 14%, P<0.001). The fasting glucose concentration increased in the placebo group (17.1 mg per deciliter) and decreased in the pooled dulaglutide groups (-18.9 mg per deciliter, P<0.001), and there were no between-group differences in the change in BMI. The incidence of gastrointestinal adverse events was higher with dulaglutide therapy than with placebo. The safety profile of dulaglutide was consistent with that reported in adults. CONCLUSIONS: Treatment with dulaglutide at a once-weekly dose of 0.75 mg or 1.5 mg was superior to placebo in improving glycemic control through 26 weeks among youths with type 2 diabetes who were being treated with or without metformin or basal insulin, without an effect on BMI. (Funded by Eli Lilly; AWARD-PEDS ClinicalTrials.gov number, NCT02963766.).
Sujet(s)
Diabète de type 2 , Hypoglycémiants , Adolescent , Glycémie/effets des médicaments et des substances chimiques , Enfant , Diabète de type 2/sang , Diabète de type 2/traitement médicamenteux , Méthode en double aveugle , Peptides glucagon-like/analogues et dérivés , Hémoglobine glyquée/analyse , Humains , Hypoglycémiants/administration et posologie , Hypoglycémiants/usage thérapeutique , Fragments Fc des immunoglobulines/administration et posologie , Fragments Fc des immunoglobulines/usage thérapeutique , Injections sous-cutanées , Insulines/usage thérapeutique , Metformine/usage thérapeutique , Protéines de fusion recombinantes/administration et posologie , Protéines de fusion recombinantes/usage thérapeutique , Résultat thérapeutiqueRÉSUMÉ
CONTEXT: Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating triglycerides and lipoprotein markers and improved markers of beta-cell function and insulin resistance (IR), effects only partially attributable to weight loss. OBJECTIVE: Assess plasma metabolome changes mediated by tirzepatide. DESIGN: Phase 2b trial participants were randomly assigned to receive weekly subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks. Post hoc exploratory metabolomics and lipidomics analyses were performed. SETTING: Post hoc analysis. PARTICIPANTS: 259 subjects with T2D. INTERVENTION(S): Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or placebo. MAIN OUTCOME MEASURE(S): Changes in metabolite levels in response to tirzepatide were assessed against baseline levels, dulaglutide, and placebo using multiplicity correction. RESULTS: At 26 weeks, a higher dose tirzepatide modulated a cluster of metabolites and lipids associated with IR, obesity, and future T2D risk. Branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts such as 2-hydroxybutyrate decreased compared to baseline and placebo. Changes were significantly larger with tirzepatide compared with dulaglutide and directly proportional to reductions of HbA1c, homeostatic model assessment 2-IR indices, and proinsulin levels. Proportional to metabolite changes, triglycerides and diglycerides were lowered significantly compared to baseline, dulaglutide, and placebo, with a bias toward shorter and highly saturated species. CONCLUSIONS: Tirzepatide reduces body weight and improves glycemic control and uniquely modulates metabolites associated with T2D risk and metabolic dysregulation in a direction consistent with improved metabolic health.
Sujet(s)
Diabète de type 2/traitement médicamenteux , Peptide gastrointestinal/administration et posologie , Hypoglycémiants/administration et posologie , Adulte , Sujet âgé , Glycémie/analyse , Glycémie/métabolisme , Diabète de type 2/sang , Diabète de type 2/métabolisme , Femelle , Peptide gastrointestinal/effets indésirables , Peptide gastrointestinal/métabolisme , Glucagon-like peptide 1/métabolisme , Récepteur du peptide-1 similaire au glucagon/agonistes , Récepteur du peptide-1 similaire au glucagon/métabolisme , Peptides glucagon-like/administration et posologie , Peptides glucagon-like/effets indésirables , Peptides glucagon-like/analogues et dérivés , Hémoglobine glyquée/analyse , Humains , Hypoglycémiants/effets indésirables , Fragments Fc des immunoglobulines/administration et posologie , Fragments Fc des immunoglobulines/effets indésirables , Injections sous-cutanées , Mâle , Métabolomique , Adulte d'âge moyen , Récepteur hormone gastrointestinale/agonistes , Récepteur hormone gastrointestinale/métabolisme , Protéines de fusion recombinantes/administration et posologie , Protéines de fusion recombinantes/effets indésirables , Triglycéride/sang , Triglycéride/métabolisme , Perte de poids/effets des médicaments et des substances chimiques , Jeune adulteRÉSUMÉ
BACKGROUND: Both innate and adaptive immune responses are important components of anticancer immunity. The CD47-SIRPα interaction could represent an important pathway used by tumour cells to evade immune surveillance. We aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and anticancer activity of evorpacept (also known as ALX148), a high-affinity CD47-blocking protein with an inactive IgG Fc region in patients with solid tumours. METHODS: We did a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study at nine hospitals and one clinic in the USA and Korea. Eligible patients for the dose-escalation and safety lead-in phases were aged 18 years or older with histological or cytological diagnosis of advanced or metastatic solid tumours with no available standard therapy, measurable or unmeasurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. In the dose-escalation phase, which used a 3 + 3 design, patients received intravenous evorpacept at either 0·3, 1, 3, or 10 mg/kg once per week in 21-day cycles, or 30 mg/kg once every other week in 28-day cycles. In the safety lead-in phase, patients were given the maximum tolerable dose of evorpacept from the dose-escalation phase plus either intravenous pembrolizumab (200 mg administered once every 3 weeks) or intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks). In the dose-expansion phase, additional patients aged 18 years or older with second-line or later-line advanced malignancies were enrolled into three parallel cohorts: those with head and neck squamous cell carcinoma (HNSCC) and those with non-small-cell lung cancer (NSCLC) were given the maximum tolerated dose of evorpacept plus intravenous pembrolizumab (200 mg administered once every 3 weeks), and patients with HER2-positive gastric or gastroesophageal junction cancer were given the maximum tolerated dose of evorpacept plus intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks) until disease progression, voluntary withdrawal from the study, or unacceptable toxicity. The primary endpoint was the maximum tolerated dose of evorpacept administered as a single agent and in combination with pembrolizumab or trastuzumab, measured by the occurrence of dose-limiting toxicities during the first cycle, and was assessed in all patients who had received at least one dose of evorpacept. Secondary outcomes included the safety, tolerability, and antitumour activity of evorpacept, alone or in combination with pembrolizumab or trastuzumab. The primary outcome, safety, and tolerability were assessed in all patients who had received at least one dose of evorpacept, and antitumour activity was assessed in those who recieved at least one dose of study treatment and underwent at least one post-baseline tumor assessment. This trial is registered with ClinicalTrials.gov, NCT03013218. FINDINGS: Between March 6, 2017, and Feb 21, 2019, 110 patients received single-agent evorpacept (n=28), evorpacept plus pembrolizumab (n=52), or evorpacept plus trastuzumab (n=30), and were included in the safety analysis. Median follow-up was 29·1 months (95% CI not calculable [NC]-NC) in the single-agent cohort, 27·0 months (25·1-28·8) in the evorpacept plus pembrolizumab cohort, and 32·7 months (27·0-32·7) in the evorpacept plus trastuzumab cohort. Two (7%) dose-limiting toxicities in the first cycle were reported in patients who received single-agent evorpacept; neutropenia with an associated infection in one patient with gastroesophageal junction cancer who received 3 mg/kg once per week, and thrombocytopenia with associated bleeding in one patient with pancreatic cancer who received 30 mg/kg once every other week. No maximum tolerated dose was reached; the maximum administered doses were 10 mg/kg once per week or 30 mg/kg once every other week. The 10 mg/kg once per week dose was used in the expansion cohorts in combination with pembrolizumab or trastuzumab. The most common grade 3 or worse treatment-related adverse events were thrombocytopenia with single-agent evorpacept (two [7%] patients) and evorpacept plus pembrolizumab (two [4%]), and thrombocytopenia (two [7%]) and neutropenia (two [7%]) with evorpacept plus trastuzumab. In patients who received single-agent evorpacept, four treatment-related serious adverse events were reported. Five serious treatment-related adverse events related to evorpacept plus pembrolizumab were reported, and one serious adverse event related to evorpacept plus trastuzumab was reported. In response-evaluable patients in the dose-escalation phase (n=15) receiving single-agent evorpacept once per week, four (27%) had a best overall response of stable disease (two received 0·3 mg/kg, one received 3 mg/kg, and one received 10 mg/kg); in the 11 patients who received single-agent evorpacept at the highest dose of 30 mg/kg once every other week, two (18%) had stable disease. In the dose-expansion cohort, overall responses were recorded in four (20·0%; 95% CI 5·7-43·7) of 20 patients with HNSCC who received evorpacept plus pembrolizumab, in one (5·0%; 0·1-24·9) of 20 patients with NSCLC who received evorpacept plus pembrolizumab, and in four (21·1%; 6·1-45·6) of 19 patients with gastric or gastroesophageal junction cancer who received evorpacept plus trastuzumab. INTERPRETATION: The safety findings support the use of evorpacept in combination with pembrolizumab or trastuzumab for patients with advanced solid tumours. Preliminary antitumour activity results support future investigation of evorpacept combined with pembrolizumab or trastuzumab in patients with HNSCC, gastric or gastroesophageal junction cancer, and NSCLC. FUNDING: ALX Oncology.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Tumeurs/traitement médicamenteux , Sujet âgé , Anticorps monoclonaux humanisés/administration et posologie , Femelle , Études de suivi , Humains , Fragments Fc des immunoglobulines/administration et posologie , Mâle , Dose maximale tolérée , Adulte d'âge moyen , Tumeurs/anatomopathologie , Pronostic , Trastuzumab/administration et posologieRÉSUMÉ
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by joint inflammation, synovial hyperplasia, cartilage degeneration, bone erosion, and pannus. Immunoglobulin D (IgD) plays an important role in autoimmune diseases although the content of it in vivo is low. Increased concentrations of anti-IgD autoantibodies have been detected in many RA patients. IgD-Fc-Ig fusion protein is constructed by connecting human IgD Fc domain and IgG1 Fc domain, which specifically block the IgD/ IgDR pathway and regulate the function of cells expressing IgDR to treat RA. The expression levels of Wnt5A and Frizzled 5 are higher in RA synovial tissue specimens. The complex of Wnt5A-Fzd5-LRP5/6-CTHRC1 promotes the expression of hypoxia inducible factor-1α by activating nuclear factor kappa-B (NF-κB), leading to high expression of VEGF and participating in angiogenesis. VEGF is the strongest angiogenic factor found so far. Here, we aimed to explore whether IgD participates in synovitis by binding to IgDR and regulating the activation of Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway in fibroblast synovial cells (FLSs), whether IgD-Fc-Ig fusion protein inhibits VEGF production in FLS of CIA and explore mechanism. We found that IgDR is expressed on MH7A and FLS. IgD promotes VEGF expression by activating Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway in MH7A and FLS. After activation of Fzd5 with Wnt5A, IgD-Fc-Ig reduced VEGF-A level in the culture supernatant of MH7A stimulation by IgD. The expressions of CTHRC1, Fzd5, p-P65 and VEGF in MH7A and FLSs were down-regulated after IgD-Fc-Ig treatment. IgD-Fc-Ig suppressed the combination of CTHRC1 and Fzd5 as well. By using the animal model, we demonstrated that IgD-Fc-Ig suppress ankle CTHRC1 and Fzd5 production resulted in inhibition of index of joint inflammation of CIA rats, which were consistent with vitro results. Conclusively, IgD-Fc-Ig inhibits IgD and Wnt5A-induced angiogenesis and joint inflammation by suppressing the combination of CTHRC1 and Fzd5. Our results show that IgD-Fc-Ig exerts its suppressive effect on IgD and Wnt5A by Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway.
Sujet(s)
Arthrite expérimentale/immunologie , Immunoglobuline D/métabolisme , Protéines de fusion recombinantes/administration et posologie , Membrane synoviale/anatomopathologie , Synovite/immunologie , Protéine Wnt-5a/antagonistes et inhibiteurs , Animaux , Arthrite expérimentale/traitement médicamenteux , Arthrite expérimentale/anatomopathologie , Collagène/administration et posologie , Collagène/immunologie , Fibroblastes , Récepteurs Frizzled/métabolisme , Glycoprotéines/métabolisme , Humains , Immunoglobuline D/administration et posologie , Immunoglobuline D/génétique , Fragments Fc des immunoglobulines/administration et posologie , Fragments Fc des immunoglobulines/génétique , Mâle , Facteur de transcription NF-kappa B/métabolisme , Rats , Protéines de fusion recombinantes/génétique , Transduction du signal/effets des médicaments et des substances chimiques , Transduction du signal/immunologie , Membrane synoviale/effets des médicaments et des substances chimiques , Membrane synoviale/immunologie , Cellules synoviales , Synovite/traitement médicamenteux , Synovite/anatomopathologie , Protéine Wnt-5a/métabolismeRÉSUMÉ
Dulaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effects on muscle wasting due to aging are poorly understood. In the current study, we investigated the therapeutic potential and underlying mechanism of dulaglutide in muscle wasting in aged mice. Dulaglutide improved muscle mass and strength in aged mice. Histological analysis revealed that the cross-sectional area of the tibialis anterior (TA) in the dulaglutide-treated group was thicker than that in the vehicle group. Moreover, dulaglutide increased the shift toward middle and large-sized fibers in both young and aged mice compared to the vehicle. Dulaglutide increased myofiber type I and type IIa in young (18.5% and 8.2%) and aged (1.8% and 19.7%) mice, respectively, compared to the vehicle group. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, decreased but increased by dulaglutide in aged mice. The expression of atrophic factors such as myostatin, atrogin-1, and muscle RING-finger protein-1 was decreased in aged mice, whereas that of the myogenic factor, MyoD, was increased in both young and aged mice following dulaglutide treatment. In aged mice, optic atrophy-1 (OPA-1) protein was decreased, whereas Toll-like receptor-9 (TLR-9) and its targeting inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]) were elevated in the TA and quadriceps (QD) muscles. In contrast, dulaglutide administration reversed this expression pattern, thereby significantly attenuating the expression of inflammatory cytokines in aged mice. These data suggest that dulaglutide may exert beneficial effects in the treatment of muscle wasting due to aging.
Sujet(s)
Vieillissement/métabolisme , Peptides glucagon-like/analogues et dérivés , Fragments Fc des immunoglobulines/administration et posologie , Muscles squelettiques/physiopathologie , Protéines de fusion recombinantes/administration et posologie , Sarcopénie/traitement médicamenteux , Sarcopénie/immunologie , Récepteur-9 de type Toll-like/immunologie , Vieillissement/effets des médicaments et des substances chimiques , Vieillissement/génétique , Animaux , dGTPases/génétique , dGTPases/immunologie , Peptides glucagon-like/administration et posologie , Humains , Hypoglycémiants/administration et posologie , Interleukine-6/génétique , Interleukine-6/immunologie , Mâle , Souris , Protéines du muscle/génétique , Protéines du muscle/immunologie , Muscles squelettiques/effets des médicaments et des substances chimiques , Muscles squelettiques/immunologie , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes/génétique , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes/immunologie , SKP cullin F-box protein ligases/génétique , SKP cullin F-box protein ligases/immunologie , Sarcopénie/étiologie , Sarcopénie/génétique , Transduction du signal/effets des médicaments et des substances chimiques , Récepteur-9 de type Toll-like/génétique , Facteur de nécrose tumorale alpha/génétique , Facteur de nécrose tumorale alpha/immunologieSujet(s)
Diabète de type 2/traitement médicamenteux , Récepteur du peptide-1 similaire au glucagon/agonistes , Peptides glucagon-like/analogues et dérivés , Fragments Fc des immunoglobulines/usage thérapeutique , Protéines de fusion recombinantes/usage thérapeutique , Inhibiteurs du cotransporteur sodium-glucose de type 2/usage thérapeutique , Association de médicaments , Peptides glucagon-like/administration et posologie , Peptides glucagon-like/usage thérapeutique , Humains , Hypoglycémiants/administration et posologie , Hypoglycémiants/usage thérapeutique , Fragments Fc des immunoglobulines/administration et posologie , Metformine/administration et posologie , Metformine/usage thérapeutique , Mesures des résultats rapportés par les patients , Essais contrôlés randomisés comme sujet , Protéines de fusion recombinantes/administration et posologie , Inhibiteurs du cotransporteur sodium-glucose de type 2/administration et posologie , Résultat thérapeutiqueRÉSUMÉ
BACKGROUND: Alpha-1 antitrypsin (AAT) is a major serine protease inhibitor. AAT deficiency (AATD) is a genetic disorder characterized by early-onset severe emphysema. In well-selected AATD patients, therapy with plasma-derived AAT (pAAT), "augmentation therapy", provides modest clinical improvement but is perceived as cumbersome with weekly intravenous infusions. Using mouse models of emphysema, we compared the effects of a recombinant AAT-IgG1 Fc-fusion protein (AAT-Fc), which is expected to have a longer half-life following infusion, to those of pAAT. METHODS: In an elastase model of emphysema, mice received a single intratracheal instillation of porcine pancreatic elastase (PPE) or human leucocyte elastase (hLE). AAT-Fc, pAAT, or vehicle was administered intraperitoneally 1 day prior to or 3 weeks following elastase instillation. Lung function and histology assessments were performed at 7 and 32 days after elastase instillation. In a cigarette smoke (CS) model of emphysema, mice were exposed to CS daily, 5 days a week, for 6 months and AAT-Fc, pAAT, or vehicle were administered every 10 days during the last 3 months of CS exposure. Assessments were performed 3 days after the last CS exposure. Immune responses to lung elastin peptide (EP) and the effects of AAT-Fc or pAAT treatment on dendritic cell (DC) function were determined ex vivo. RESULTS: Both elastase instillation and CS exposure triggered emphysema-like alveolar enlargement, increased lung compliance, and increased markers of inflammation compared to controls. Administration of AAT-Fc either prior to or following elastase instillation or during CS exposure provided greater protection than pAAT against alveolar enlargement, lung dysfunction, and airway inflammation. When challenged ex vivo with EP, spleen mononuclear cells from elastase-exposed mice exhibited dose-dependent production of IFNγ and IL-17, suggesting immune reactivity. In co-culture experiments with splenic CD4+ T cells isolated from elastase-exposed mice, AAT-Fc treatment prior to EP-priming of bone marrow-derived dendritic cells inhibited the production of IFNγ and IL-17. CONCLUSIONS: Compared to pAAT, AAT-Fc more effectively prevented or attenuated elastase- and CS-induced models of emphysema. These effects were associated with immunomodulatory effects on DC activity. AAT-Fc may provide a therapeutic option to individuals with AATD- and CS-induced emphysema.
Sujet(s)
Fragments Fc des immunoglobulines/administration et posologie , Exposition par inhalation/effets indésirables , Pancreatic elastase/toxicité , Emphysème pulmonaire/induit chimiquement , Emphysème pulmonaire/traitement médicamenteux , Protéines de fusion recombinantes/administration et posologie , Fumée/effets indésirables , alpha-1-Antitrypsine/administration et posologie , Animaux , Femelle , Humains , Mâle , Souris , Souris de lignée C57BL , Pancreatic elastase/administration et posologie , Emphysème pulmonaire/immunologie , Suidae , NicotianaRÉSUMÉ
Introduction: Beta-thalassemia is an autosomal recessive hereditary anemia characterized by reduced or absent ß-globin chain synthesis, affecting about 60,000 people peryear. Management for ß-thalassemia major includes regular blood transfusions followed by iron chelating therapy and drug targeting ineffective erythropoiesis.Areas covered: The safety of licensed drugs for the management of ß-thalassemia is reviewed, using evidence from clinical trials and observational research. Such drugs include the iron chelators and the erythrocyte maturation agent luspatercept. The safety of emerging treatment, such as hydroxyurea and thalidomide is also reviewed.Expert opinion: Beta-thalassemia is arare disease, and is not surprising that there are limited studies investigating the safety of drugs used in this disease. Indeed, although observational studies are the main source of drug safety information in areal-world setting, only eleven studies were identified for iron-chelators and none of these estimated the risk of agiven safety outcome. Future work should aim to better leverage existing sources of real-world datato investigate drug safety in thalassemia.
Sujet(s)
Récepteur activine, type 2/effets indésirables , Fragments Fc des immunoglobulines/effets indésirables , Agents chélateurs du fer/effets indésirables , Protéines de fusion recombinantes/effets indésirables , bêta-Thalassémie/traitement médicamenteux , Récepteur activine, type 2/administration et posologie , Antianémiques/administration et posologie , Antianémiques/effets indésirables , Humains , Hydroxy-urée/administration et posologie , Hydroxy-urée/effets indésirables , Fragments Fc des immunoglobulines/administration et posologie , Agents chélateurs du fer/administration et posologie , Protéines de fusion recombinantes/administration et posologie , Thalidomide/administration et posologie , Thalidomide/effets indésirables , bêta-Thalassémie/physiopathologieRÉSUMÉ
Recombinant factor VIII Fc fusion protein (rFVIIIFc) has been indicated for adults and children with hemophilia A. The objective of this article was to build a population pharmacokinetic (PK) model using adult and pediatric data sets and explore relevant dosing scenarios across all ages. The activity-time profiles of rFVIIIFc from 3 clinical studies (all trials registered at https://www.clinicaltrials.gov: NCT01027377, NCT01181128, and NCT01458106) were characterized, and covariates that determine variability of rFVIIIFc PK in children and adults were identified and implemented. Data sets were pooled to estimate population PK parameters. Simulations were conducted to generate activity-time profiles at steady state (SS). The proportion of subjects maintaining SS trough >1 and >3 IU/dL and time >10 IU/dL were estimated. The rFVIIIFc model was a two-compartment model that identified weight and von Willebrand factor as significant covariates. Model-predicted SS peaks and troughs of rFVIIIFc activity-time profiles confirmed the necessity of modifying dosing in pediatric subjects. The model also predicted that the average subject in the adult and adolescent group dosed with 40 IU/kg every 2 days maintained factor VIII activity >10 IU/dL for the entire duration. Children aged <6 years and aged 6 to <12 years receiving this dose maintained factor VIII activity of >10 IU/dL for nearly two-thirds and three-quarters of their time, respectively. In conclusion, these population PK analyses characterize activity-time profiles for rFVIIIFc among pediatric and adult subjects. The model was used for simulation of clinically relevant dosing scenarios, which can provide better protection and better clinical outcomes.
Sujet(s)
Facteur VIII/pharmacocinétique , Hémophilie A/traitement médicamenteux , Protéines de fusion recombinantes/pharmacocinétique , Adolescent , Facteurs âges , Poids , Enfant , Simulation numérique , Calcul des posologies , Facteur VIII/administration et posologie , Période , Humains , Fragments Fc des immunoglobulines/administration et posologie , Mâle , Taux de clairance métabolique , Modèles biologiques , Acuité des besoins du patient , Protéines de fusion recombinantes/administration et posologie , Facteur de von Willebrand/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: The pharmacokinetic (PK) properties of extended half-life (EHL) factor VIII (FVIII) concentrates differ, leading to variation in the optimal dosing regimen for the individual patient. The aim of this study was to establish these PK differences for various EHL FVIII concentrates by in silico simulations. METHODS: FVIII level over time profiles of rFVIII-SC, BAY 81-8973, rFVIII-Fc, BAX 855, BAY 94-9027, and standard half-life (SHL) rFVIII concentrates were simulated for 1,000 severe hemophilia A patients during steady-state dosing of 40 IU/kg every 72 hours or dosing as advised in the summary of product characteristics (SmPC). RESULTS: Although the elimination half-life values were comparable for rFVIII-FC, BAX 855, and BAY 94-9027, a higher area under the curve (AUC; 2,779 IU/h/dL) for BAY 94-9027 was obtained. During steady-state dosing of 40 IU/kg every 72 hours, 58.5% (rFVIII-SC), 69.3% (BAY 81-8972), 89.0% (rFVIII-Fc), 83.9% (BAX 855), and 93.7% (BAY 94-9027) of the patients maintained a trough level of 1 IU/dL, compared with 56.0% for SHL rFVIII. Following dosing schemes described in the SmPC, between 51.0 and 65.4% or 23.2 and 31.1% of the patients maintained a target trough level of 1 IU/dL or 3 IU/dL, respectively. CONCLUSION: BAY 94-9027 showed the largest increase of AUC and best target attainment compared with SHL rFVIII, followed closely by BAX 855 and rFVIII-Fc. BAY 81-8973 and rFVIII-SC showed smaller PK improvements. Although our analyses increase insight into the PK of these FVIII concentrates, more studies evaluating the relation between factor levels and bleeding risk are needed.
Sujet(s)
Coagulants/pharmacocinétique , Facteur VIII/pharmacocinétique , Hémophilie A/traitement médicamenteux , Modèles biologiques , Polyéthylène glycols/pharmacocinétique , Protéines de fusion recombinantes/pharmacocinétique , Coagulants/administration et posologie , Simulation numérique , Calcul des posologies , Facteur VIII/administration et posologie , Période , Hémophilie A/sang , Humains , Fragments Fc des immunoglobulines/administration et posologie , Méthode de Monte Carlo , Polyéthylène glycols/administration et posologie , Protéines de fusion recombinantes/administration et posologieRÉSUMÉ
Around the world, with the availability of factor concentrates, patients with haemophilia have undergone major and minor surgeries. Inhibitor development in early postoperative period leading to inadequate factor recovery and ongoing bleeding is a nightmare for both operating surgeon as well as haematologists. We describe a case of an elderly man with mild haemophilia A, who was diagnosed with pancreatic carcinoma and underwent Whipple's procedure. After an uneventful procedure, he developed high-titre inhibitors and bleeding a week after surgery posing major challenges in his management. The case highlights the importance of experienced surgeons, trained haematologists, regular monitoring of factor assay/inhibitors, adequate factor and bypassing-agent support while performing such procedures.
Sujet(s)
Facteurs de la coagulation sanguine/antagonistes et inhibiteurs , Hémophilie A/immunologie , Tumeurs du pancréas/chirurgie , Hémorragie postopératoire/traitement médicamenteux , Sujet âgé , Production d'anticorps/immunologie , Facteurs de la coagulation sanguine/immunologie , Facteur VIII/administration et posologie , Facteur VIII/usage thérapeutique , Issue fatale , Hématologie/normes , Hémophilie A/complications , Humains , Fragments Fc des immunoglobulines/administration et posologie , Fragments Fc des immunoglobulines/usage thérapeutique , Hémorragies intracrâniennes/complications , Mâle , Tumeurs du pancréas/complications , Complications postopératoires/épidémiologie , Complications postopératoires/immunologie , Hémorragie postopératoire/étiologie , Protéines de fusion recombinantes/administration et posologie , Protéines de fusion recombinantes/usage thérapeutique , Facteurs de risque , Chirurgiens/statistiques et données numériques , Tumeurs du pancréasRÉSUMÉ
This study was conducted to establish the toxicological profile of combination treatment with therapeutic HPV DNA vaccines (GX-188E) and the long-acting form of recombinant human interleukin-7 fused with hybrid Fc (IL-7hyFc). GX-188E was administered intramuscularly by electroporation with or without IL-7hyFc intravaginally once per 2 weeks for 8 weeks (five times) in female Sprague-Dawley rats. Because up-regulation of immune responses and migration of antigen-specific T cells in cervicoviginal tissue were predicted as therapeutic effects, we distinguished adverse effects from therapeutic effects based on the severity of the systemic immune response, reversibility of lymphoid tissue changes, target tissue damage, and off-target immune responses. We observed that the number of neutrophils was increased, and the number of lymphocytes was decreased in the blood. Further, myofiber degeneration, necrosis, fibroplasia, and cell infiltration were observed at the GX-188E administration site. These changes were fully or partially recovered over a 4-week period. Analysis of lymphocytes in spleen revealed that CD4+ T cells and total T cells decreased in rats treated with GX-188E in combination with a high dose of IL-7hyFc (1.25 mg/animal). However, these changes were not considered adverse because they were transient and may have been related to electroporation-mediated DNA delivery or the local migration of lymphocytes induced by IL-7. Therefore, the potential toxicity of the combination of GX-188E and IL-7hyFc treatment was comparable to that of GX-188E treatment alone, and the no observed adverse effect level for GX-188E with IL-7hyFc was considered as 320 µg/animal for GX-188E and 1.25 mg/animal for IL-7hyFc.
Sujet(s)
Fragments Fc des immunoglobulines/toxicité , Interleukine-7/toxicité , Vaccins contre les papillomavirus/toxicité , Vaccins à ADN/toxicité , Administration par voie vaginale , Animaux , Marqueurs biologiques/sang , Marqueurs biologiques/urine , Relation dose-effet des médicaments , Association de médicaments , Électroporation , Femelle , Fragments Fc des immunoglobulines/administration et posologie , Interleukine-7/administration et posologie , Granulocytes neutrophiles/effets des médicaments et des substances chimiques , Granulocytes neutrophiles/métabolisme , Dose sans effet nocif observé , Vaccins contre les papillomavirus/administration et posologie , Rat Sprague-Dawley , Protéines de fusion recombinantes/toxicité , Appréciation des risques , Lymphocytes T/effets des médicaments et des substances chimiques , Lymphocytes T/métabolisme , Facteurs temps , Vaccins à ADN/administration et posologieRÉSUMÉ
Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4+ T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM.