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1.
Gynecol Oncol ; 154(2): 294-301, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31174889

RESUMO

OBJECTIVES: The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P). METHODS: Dose escalation started with a standard 3 + 3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUC = 5 mg/ml·min) and P (175 mg/m2). For enhanced bone safety the trial was revised to 6-patient cohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPA → C/P). RESULTS: 37 patients have been treated; 30 of whom were treated following protocol revision to q3w IPA(D1) → C/P(D3) (2 & 4 mg/kg). IPA-related TEAEs that occurred in ≥15% included: fatigue (40%); nausea (35%); diarrhea and decreased appetite (22%) each; dysgeusia (19%); and vomiting (16.2%). 22% reported ≥1 IPA related TEAE Grade ≥3 the most common of which was neutropenia at 16%. There were no DLTs; the MTD was not reached. The maximum administered dose based on bone safety was 6 mg/kg. The overall response rate (ORR) was 75.7%. Median PFS was 10.3 months (95% CI 8.5-14.2) and OS 33 months (95% CI 23.4-NR). CONCLUSIONS: IPA is well tolerated in combination with sequential C/P. ORR, PFS and OS are comparable to historical data but bone toxicity at efficacy doses of this particular Wnt inhibitor limit further development in EOC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Receptores Acoplados a Proteínas-G/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Antineoplásicos Fitogênicos , Osso e Ossos/efeitos dos fármacos , Carboplatina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Fragmentos Fc das Imunoglobulinas/farmacologia , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
2.
Int J Mol Sci ; 20(7)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934882

RESUMO

GLP-1 (glucagon-like peptide-1) has been reported to play a vital role in neuroprotection. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model widely used to study human multiple sclerosis, a chronic demyelination disease in the central nervous system (CNS). Recently, important studies have designated that the signaling axis of GLP-1 and its receptor controls the clinical manifestations and pathogenesis of EAE. However, it is elusive whether GLP-1 receptor signaling regulates the phenotype of autoreactive T cells in the CNS. We administered dulaglutide, a well-established GLP-1 receptor agonist (GLP-1 RA), to treat EAE mice prophylactically or semi-therapeutically and subsequently analyzed the mononuclear cells of the CNS. In this study, dulaglutide treatment significantly alleviates the clinical manifestations and histopathological outcomes of EAE. Dulaglutide decreases incidences of encephalitogenic Th1/Th17 cells and Th1 granulocyte-macrophage-colony-stimulating factor (GM-CSF) expression in the CNS. Administration of dulaglutide failed to control the chemotactic abilities of encephalitogenic Th1 and Th17 cells; however, prophylactic treatment considerably decreased the populations of dendritic cells and macrophages in the CNS parenchyma. These results obtained indicate that dulaglutide modulates the differentiation of encephalitogenic Th1/Th17 and the pathogenicity of Th1 cells by influencing antigen presenting cells quantities, providing mechanism insight on T cells regulation in ameliorating EAE by GLP-1.


Assuntos
Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Células Th1/imunologia , Células Th17/imunologia , Animais , Quimiotaxia/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Encefalomielite Autoimune Experimental/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Imunização , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/farmacologia , Subpopulações de Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos
3.
Biomed Pharmacother ; 112: 108677, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798123

RESUMO

Recombinant human interleukin-15 (IL-15) is a potent cancer immunotherapeutic candidate due to its excellent immune stimulating effects. Previous work demonstrated that IL-15 appeared with short half-life in circulation system, while the complex with its receptor can prolong the half-life as well as benefit its activities in vivo. Therefore, IL-15 complex was more favorably considered for clinical development. Herein we developed IL-15·sIL-15Rα/Fc, a complex comprising of IL-15 and the extracellular region of its receptor alpha subunit which fused to Immunoglobulin G (IgG1) Fc to further prolong the half-life in plasma. Through transient gene expression in HEK293 cells, we expressed the superagonist by co-transfection of plasmids encoding IL-15 and sIL-15Rα/Fc respectively, yielding 36 mg/L of product after purification. Pharmacokinetic study demonstrated that the combination profoundly prolonged the half-life of IL-15 to 13.1 h in mice, about 18 folds longer than that of IL-15 monomer which is around 0.7 h. The bioactivity of the superagonist was characterized by CTLL-2 cells proliferation assay in vitro, showing its capability of stimulating the expansion of memory CD8+ T cells (cluster of differentiation) in mouse spleen. Using a HT-29 xenograft NOD-SCID mouse model, we observed tumor growth inhibition in all groups that received the superagonist, indicating its anti-tumor efficacy via stimulating infused human immune cells. In addition, combo cancer treatment by IL-15·sIL-15Rα/Fc and programmed death-1 (PD-1) antibody have shown stronger inhibitory effects as compared with treatment with either single molecule. Therefore, we developed IL-15·sIL-15Rα/Fc to be a long half-life potential cancer immunotherapy candidate that can be applied alone or in synergy with PD-1/PD-L1 blockade.


Assuntos
Antineoplásicos Imunológicos/imunologia , Desenvolvimento de Medicamentos/métodos , Fragmentos Fc das Imunoglobulinas/imunologia , Subunidade alfa de Receptor de Interleucina-15/imunologia , Interleucina-15/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/metabolismo , Feminino , Células HEK293 , Células HT29 , Meia-Vida , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/metabolismo , Imunoglobulina G/administração & dosagem , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Interleucina-15/administração & dosagem , Interleucina-15/metabolismo , Subunidade alfa de Receptor de Interleucina-15/administração & dosagem , Subunidade alfa de Receptor de Interleucina-15/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
4.
Appl Microbiol Biotechnol ; 103(4): 1703-1712, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30607490

RESUMO

Staphylococcus aureus-induced bovine mastitis causes significant losses to the dairy industry and available vaccines do not confer adequate protection. As a more attractive alternative, we propose the use of antibody (Ab) therapy. In our previous study, we constructed a bovine single-chain variable fragment (scFv) Ab phage display and successfully obtained scFvs that bound to S. aureus antigens with high affinity. Here, we describe a novel Ab against S. aureus (scFv-Fc Ab). To construct the scFv-Fc Ab, the scFv Ab was genetically fused to the Fc fragment of a bovine IgG1 Ab. Western blot analysis showed that the bovine scFvs-Fc Abs were successfully expressed with horseradish peroxidase-conjugated goat-anti-bovine IgG (Fc) Ab in Escherichia coli cells. The purified bovine scFvs-Fc Abs had good binding activity to S. aureus and effectively inhibited the bacterial growth in culture medium and bovine scFvs-Fc Abs enhanced phagocytosis of S. aureus by neutrophils isolated from peripheral blood in a dose-dependent manner. In the experiment of bovine scFvs-Fc Abs for the treatment of S. aureus-induced bovine mastitis, the total effective percentage reached 82% (9/11). These novel bovine scFvs-Fc Abs may be useful as therapeutic candidates for the prevention and treatment of S. aureus-induced bovine mastitis.


Assuntos
Antibacterianos/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Mastite Bovina/tratamento farmacológico , Anticorpos de Cadeia Única/administração & dosagem , Infecções Estafilocócicas/veterinária , Animais , Bovinos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/isolamento & purificação , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/isolamento & purificação , Infecções Estafilocócicas/tratamento farmacológico , Resultado do Tratamento
5.
Yakugaku Zasshi ; 138(10): 1323-1327, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30270278

RESUMO

 Incretin-based therapy consists of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Whether switching from DPP-4 inhibitors to one of the GLP-1 receptor agonists, dulaglutide, has greater beneficial effects remains unknown. Therefore, this study aimed to investigate the effectiveness of switching from DPP-4 inhibitors to dulaglutide in four patients with type 2 diabetes. All four patients with hyperglycemia who switched from DPP-4 inhibitors to dulaglutide demonstrated noticeable decreased plasma glucose levels on the next day after switching. Two of the patients observed maintained a decreased plasma glucose level over 14 day after switching. Moreover, all patients demonstrated decreased glycosylated hemoglobin A1c levels during the observation period (1-6 months) after switching and lost weight from 6 to 27 day. Minor and manageable hypoglycemia, nausea, and diarrhea were observed as side effects in one case. The current findings suggest that dulaglutide is a suitable treatment alternative in patients with type 2 diabetes who are not currently achieving adequate glycemic control with DPP-4 inhibitors.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Substituição de Medicamentos , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hemoglobina A Glicada/análise , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Inibidores da Dipeptidil Peptidase IV/farmacologia , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Fragmentos Fc das Imunoglobulinas/farmacologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/farmacologia , Resultado do Tratamento
6.
Proc Natl Acad Sci U S A ; 115(15): 3912-3917, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29581255

RESUMO

Ipilimumab, a monoclonal antibody that recognizes cytotoxic T lymphocyte antigen (CTLA)-4, was the first approved "checkpoint"-blocking anticancer therapy. In mouse tumor models, the response to antibodies against CTLA-4 depends entirely on expression of the Fcγ receptor (FcγR), which may facilitate antibody-dependent cellular phagocytosis, but the contribution of simple CTLA-4 blockade remains unknown. To understand the role of CTLA-4 blockade in the complete absence of Fc-dependent functions, we developed H11, a high-affinity alpaca heavy chain-only antibody fragment (VHH) against CTLA-4. The VHH H11 lacks an Fc portion, binds monovalently to CTLA-4, and inhibits interactions between CTLA-4 and its ligand by occluding the ligand-binding motif on CTLA-4 as shown crystallographically. We used H11 to visualize CTLA-4 expression in vivo using whole-animal immuno-PET, finding that surface-accessible CTLA-4 is largely confined to the tumor microenvironment. Despite this, H11-mediated CTLA-4 blockade has minimal effects on antitumor responses. Installation of the murine IgG2a constant region on H11 dramatically enhances its antitumor response. Coadministration of the monovalent H11 VHH blocks the efficacy of a full-sized therapeutic antibody. We were thus able to demonstrate that CTLA-4-binding antibodies require an Fc domain for antitumor effect.


Assuntos
Antígeno CTLA-4/imunologia , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos de Imunoglobulinas/administração & dosagem , Neoplasias/terapia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Antígeno CTLA-4/química , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Fragmentos Fc das Imunoglobulinas/química , Fragmentos Fc das Imunoglobulinas/imunologia , Fragmentos de Imunoglobulinas/química , Fragmentos de Imunoglobulinas/imunologia , Imunoglobulina G/administração & dosagem , Imunoglobulina G/imunologia , Imunoterapia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Domínios Proteicos
7.
Diabetes Obes Metab ; 20(1): 42-49, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28573765

RESUMO

The aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/prevenção & controle , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Incretinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/uso terapêutico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/mortalidade , Cardiomiopatias Diabéticas/epidemiologia , Cardiomiopatias Diabéticas/mortalidade , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Feminino , Seguimentos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Incretinas/administração & dosagem , Incretinas/efeitos adversos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Mortalidade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Projetos de Pesquisa , Fatores de Risco
8.
Eur J Immunol ; 48(3): 482-491, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29244203

RESUMO

We characterized a novel population of tolerogenic myeloid dendritic cells (tmDCs) defined as CD11c+ CD11b+ CD14+ CD4+ and immunoglobulin-like transcript receptor (ILT)-4+ that are significantly more abundant in the circulation of infants and young children than in adults. TmDCs secrete the immunosuppressive lymphokine interleukin (IL)-10 when stimulated with the heavy constant region of immunoglobulins (Fc) and express high levels of the adenosine A2A receptor (A2A R), which, when activated by adenosine, inhibits the release of pro-inflammatory cytokines from most immune cells. Here we show that stimulation of the A2A R on tmDCs by regadenoson or N-ethylcarboxamidoadenosine (NECA) rapidly increases cyclic AMP accumulation and enhances IL-10 production under Fc stimulatory conditions. In co-culture experiments, tmDCs inhibit the differentiation of naïve T cells to a pro-inflammatory phenotype. In conclusion, although DCs are classically viewed as antigen presenting cells that activate T cells, we show an independent role of tmDCs in pediatric immune regulation that may be important for suppressing T cell responses to neoantigens in infants and young children.


Assuntos
Células Dendríticas/imunologia , Interleucina-10/biossíntese , Adenosina/farmacologia , Antígenos CD4/metabolismo , Diferenciação Celular , Criança , Pré-Escolar , Estudos de Coortes , AMP Cíclico/metabolismo , Células Dendríticas/classificação , Células Dendríticas/efeitos dos fármacos , Feminino , Humanos , Tolerância Imunológica , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Técnicas In Vitro , Lactente , Masculino , Glicoproteínas de Membrana/metabolismo , Síndrome de Linfonodos Mucocutâneos/imunologia , Receptor A2A de Adenosina/metabolismo , Receptores Imunológicos/metabolismo , Transdução de Sinais
9.
Value Health Reg Issues ; 14: 35-40, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29254540

RESUMO

BACKGROUND: Diabetes treatment includes very diverse drugs. It is essential to identify which drugs offer the best value for their costs. OBJECTIVES: To estimate comparative cost effectiveness for treating diabetes mellitus with dulaglutide, liraglutide, or glargine in Colombia. METHODS: A Markov model including diabetic microvascular and macrovascular complications was used to estimate cost-effectiveness. We used annual cycles, a 5-year time horizon, 5% discount rate, and third-party payer's perspective. Main outcomes were quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). Transition probabilities were obtained from primary studies and costs from local databases and studies. We used a threshold of 3 times the Colombian per capita gross domestic product (US $17,270 for 2015; US $1 = 2,743 Columbian pesos) to assess cost effectiveness. RESULTS: Total costs related to dulaglutide, liraglutide, and glargine were US $8,633, US $10,756, and US $5,783, yielding 3.311 QALYs, 3.229 QALYs, and 3.156 QALYs, respectively. Dulaglutide dominated liraglutide given lower total costs and higher QALYs. The estimated ICER for dulaglutide compared with glargine was US $18,385, greater than the accepted threshold. Sensibility analysis shows that decreased dulaglutide cost, increased consumption of glargine, nondaily injection, and number and cost of glucometry could result in ICERs lower than the threshold. Probabilistic sensitivity analysis showed consistent results. CONCLUSIONS: This estimation indicates that dulaglutide dominates liraglutide. Its ICER is, however, greater than the accepted threshold for Colombia in base case compared with glargine. By increasing population weight or glargine consumption, dulaglutide becomes cost effective compared with glargine, which could identify a niche where dulaglutide is the best option.


Assuntos
Análise Custo-Benefício , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Insulina Glargina/administração & dosagem , Liraglutida/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Colômbia , Diabetes Mellitus Tipo 2/economia , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hemoglobina A Glicada , Humanos , Hipoglicemiantes/economia , Anos de Vida Ajustados por Qualidade de Vida
10.
Clin Ther ; 39(11): 2284-2295, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29110972

RESUMO

PURPOSE: This 28-week, randomized, double-blind study compared a once-weekly injection of dulaglutide 1.5 mg to placebo, both added to titrated once-daily insulin glargine (with or without metformin), in patients with type 2 diabetes mellitus and inadequate glycemia control (control defined as hemoglobin A1c, ≥7% and ≤10.5%). Patient-reported outcomes were assessed as an exploratory objective to further understand patients' physical, psychological, and social aspects of well-being and injection-device experience. METHODS: Patients not naive to injectable therapy were randomly assigned (1:1) to receive dulaglutide/glargine or placebo/glargine; glargine was titrated to a fasting plasma glucose target of 71 to 99 mg/dL. The Impact of Weight on Self-Perceptions (IW-SP), the EQ-5D-5L (measure of health status), the 18-item Diabetes Health Profile (DHP-18), and the Medication Device Delivery Assessment (MDDAB) instruments for assessing the dulaglutide Single-Use Pen (SUP) and glargine-delivery device were administered at baseline and 28 weeks, and also at 6 or 12 weeks for some measures. A mixed model for repeated measures was used for analyzing changes from baseline scores. FINDINGS: At 28 weeks, improvements observed in the transformed total scores on the IW-SP and DHP-18 Disinhibited Eating domain were significantly greater with dulaglutide/glargine compared with placebo/glargine (least squares mean differences, +6.06 [P = 0.019] and -4.50 [P = 0.017], respectively). There were no significant overall between-treatment differences in quality of life as measured by the EQ-5D-5L or the Barriers to Activities and Psychological Distress domains of the DHP-18. Of all patients, 95% reported that overall, the dulaglutide SUP was "easy" or "very easy" to use at 28 weeks. Device-features scores showed that most patients liked the dulaglutide SUP features, with the 3 highest-rated items relating specifically to features of the needle (not having to touch the needle, not having to attach the needle, and automatic insertion). The majority of patients (~90%) "agreed" or "strongly agreed" that they were satisfied with the overall dulaglutide SUP injection experience at 28 weeks. IMPLICATIONS: Dulaglutide/glargine-treated patients had greater improvements in weight-related quality-of-life measures compared with placebo/glargine-treated patients, which may be clinically relevant when evaluating treatment options for insulin-requiring patients who often gain weight with insulin monotherapy. Results from the MDDAB indicated overall satisfaction with the dulaglutide SUP injection experience, which may be an important factor in some patients when initiating parenteral therapy. ClinicalTrials.gov identifier: NCT02152371.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Insulina Glargina/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Glicemia/efeitos dos fármacos , Peso Corporal , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Insulina Glargina/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida
11.
J Nutr Sci Vitaminol (Tokyo) ; 63(4): 244-248, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28978871

RESUMO

Myostatin, a member of the TGF-ß superfamily, is a negative regulator of skeletal muscle cell growth and differentiation, and binds with high affinity to the activin type IIB receptor (ActRIIB). The soluble ligand-binding domain of ActRIIB fused to the Fc domain of IgG (ActRIIB-Fc) potently binds and inhibits TGF-ß family members in muscle, leading to rapid and marked muscle growth. The present study was designed to assess the effectiveness of the co-delivery of myostatin-targeting siRNA (Mstn-siRNA) and ActRIIB-Fc into skeletal muscle as a potential treatment of atrophic myopathies. Eleven-week-old, male C57BL/6 mice were injected with atelocollagen (ATCOL)-mediated Mstn-siRNA with/without ActRIIB-Fc locally into the masseter muscle twice a week. Inhibition of myostatin function by the combination of Mstn-siRNA and ActRIIB-Fc increased muscle weight and myofibril size in murine masseter muscle. Real-time RT-PCR analysis revealed significant downregulation of myostatin mRNA expression in both the Mstn-siRNA-treated and the combination treatment group. Furthermore, myogenin mRNA expression was upregulated in the combination treatment group, while MuRF-1 and Atrogin-1 mRNA expression was downregulated compared to administration of each compound alone. These findings suggest that double inhibition of myostatin is a potentially useful treatment strategy to increase muscle mass and fiber size and could be a useful treatment of patients with various muscle atrophies, including muscular dystrophy.


Assuntos
Receptores de Activinas Tipo II/administração & dosagem , Músculo Masseter/crescimento & desenvolvimento , Fibras Musculares Esqueléticas/efeitos dos fármacos , Miostatina/genética , RNA Interferente Pequeno/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Receptores de Activinas Tipo II/genética , Animais , Expressão Gênica/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/genética , Imunoglobulina G/administração & dosagem , Imunoglobulina G/genética , Masculino , Músculo Masseter/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro Estocado/análise
12.
Clin Cancer Res ; 23(24): 7490-7497, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28954784

RESUMO

Purpose: Wnt signaling is implicated in tumor cell dedifferentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors.Experimental design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. The objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy.Results: 26 patients were treated in seven dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15, and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ∼4 days and had low incidence of antidrug antibody formation (7.69%) with no impact on drug exposure. Six patients had ß-C-terminal telopeptide (ß-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months.Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients. Clin Cancer Res; 23(24); 7490-7. ©2017 AACR.


Assuntos
Fragmentos Fc das Imunoglobulinas/administração & dosagem , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Via de Sinalização Wnt/efeitos dos fármacos , Adulto , Idoso , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Ligantes , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética
13.
Lancet Oncol ; 18(10): 1338-1347, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28870615

RESUMO

BACKGROUND: Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF ß) superfamily inhibitors of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes. METHODS: In this phase 2, multicentre, open-label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukaemia (white blood cell count <13 000/µL), and had anaemia with or without red blood cell transfusion support. Enrolled patients were classified as having low transfusion burden, defined as requiring less than 4 red blood cell units in the 8 weeks before treatment (and baseline haemoglobin <10 g/dL), or high transfusion burden, defined as requiring 4 or more red blood cell units in the 8 weeks before treatment. Patients received luspatercept subcutaneously once every 21 days at dose concentrations ranging from 0·125 mg/kg to 1·75 mg/kg bodyweight for five doses (over a maximum of 12 weeks). Patients in the expansion cohort were treated with 1·0 mg/kg luspatercept; dose titration up to 1·75 mg/kg was allowed, and patients could be treated with luspatercept for a maximum of 5 years. Patients in the base study were assessed for response and safety after 12 weeks in order to be considered for enrolment into the extension study. The primary endpoint was the proportion of patients achieving modified International Working Group-defined haematological improvement-erythroid (HI-E), defined as a haemoglobin concentration increase of 1·5 g/dL or higher from baseline for 14 days or longer in low transfusion burden patients, and a reduction in red blood cell transfusion of 4 or more red blood cell units or a 50% or higher reduction in red blood cell units over 8 weeks versus pre-treatment transfusion burden in high transfusion burden patients. Patient data were subcategorised by: luspatercept dose concentrations (0·125-0·5 mg/kg vs 0·75-1·75 mg/kg); pre-study transfusion burden (high transfusion burden vs low transfusion burden, defined as ≥4 vs <4 red blood cell units per 8 weeks); pre-study serum erythropoietin concentration (<200 IU/L, 200-500 IU/L, and >500 IU/L); presence of 15% or more ring sideroblasts; and presence of SF3B1 mutations. Efficacy analyses were carried out on the efficacy evaluable and intention-to-treat populations. This trial is currently ongoing. This study is registered with ClinicalTrials.gov, numbers NCT01749514 and NCT02268383. FINDINGS: Between Jan 21, 2013, and Feb 12, 2015, 58 patients with myelodysplastic syndromes were enrolled in the 12 week base study at nine treatment centres in Germany; 27 patients were enrolled in the dose-escalation cohorts (0·125-1·75 mg/kg) and 31 patients in the expansion cohort (1·0-1·75 mg/kg). 32 (63% [95% CI 48-76]) of 51 patients receiving higher dose luspatercept concentrations (0·75-1·75 mg/kg) achieved HI-E versus two (22% [95% CI 3-60]) of nine receiving lower dose concentrations (0·125-0·5 mg/kg). Three treatment-related grade 3 adverse events occurred in one patient each: myalgia (one [2%]), increased blast cell count (one [2%]), and general physical health deterioration (one [2%]). Two of these treatment-related grade 3 adverse events were reversible serious grade 3 adverse events: one patient (2%) had myalgia and one patient (2%) had general physical health deterioration. INTERPRETATION: Luspatercept was well tolerated and effective for the treatment of anaemia in lower-risk myelodysplastic syndromes and so could therefore provide a novel therapeutic approach for the treatment of anaemia associated with lower-risk myelodysplastic syndromes; further studies are ongoing. FUNDING: Acceleron Pharma.


Assuntos
Ativinas/administração & dosagem , Anemia/tratamento farmacológico , Anemia/etiologia , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Ativinas/efeitos adversos , Adulto , Idoso , Anemia/mortalidade , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Alemanha , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Proteínas Recombinantes de Fusão/efeitos adversos , Medição de Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
14.
BMJ Case Rep ; 20172017 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-28710307

RESUMO

We report two patients with chronic hyperglycaemia secondary to type 2 diabetes who developed severe vomiting on d. The first patient was diagnosed with a mixed picture of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS) and the second, with DKA. They were on insulin therapy which was discontinued on commencing d because of inefficacy and weight gain. The HHS patient developed dehydration secondary to vomiting and had lactic acidosis but no other precipitant could be found in either case. It appears that the abrupt insulin discontinuation coupled with vomiting and dehydration led to the metabolic derangements. Subsequent C-peptide levels were found to be low in both patients. In view of the predisposition of patients with chronic hyperglycaemia to glucagon-like peptide 1 receptor (GLP-1R) downregulation and the lag time to optimal efficacy of GLP-1R agonists, we propose that patients should have C-peptide levels measured to determine the risk of ketosis and whether insulin should be continued with dose adjustments when starting a GLP-1R agonist.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hiperglicemia/diagnóstico , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Insulina/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Diagnóstico Diferencial , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Hiperglicemia/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Insulina/administração & dosagem , Masculino , Proteínas Recombinantes de Fusão/administração & dosagem
15.
Drugs ; 77(11): 1235-1246, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28646426

RESUMO

Eftrenonacog alfa (Alprolix™) is a recombinant fusion protein comprising human factor IX (FIX) covalently linked to the constant region (Fc) domain of human IgG1 (i.e. rFIXFc). The presence of the Fc domain extends the terminal half-life (t½) of rFIXFc, permitting prolonged treatment intervals. rFIXFc is available for intravenous use for the prophylaxis and treatment of bleeding in patients with haemophilia B. In two multinational, phase III studies in previously treated children, adolescents and adults with severe haemophilia B, rFIXFc prophylaxis resulted in low median annualized bleeding rates (ABRs), and was associated with reductions in median weekly factor consumption and dosing frequency compared with pre-study FIX regimens. Preliminary data from an extension of both studies indicated sustained efficacy, as demonstrated by low median ABRs, with longer-term rFIXFc prophylaxis. rFIXFc was also effective in the treatment of bleeding episodes and when used in the perioperative setting in all age groups. rFIXFc was well tolerated in clinical studies in previously treated patients, with the majority of treatment-emergent adverse events considered to be unrelated to rFIXFc; there were no reports of inhibitor development. In conclusion, rFIXFc provides an effective alternative to plasma-derived and recombinant FIX products for the management of patients with haemophilia B, with its extended t½ permitting a less frequent administration schedule and potentially providing a prolonged protective haemostatic effect, which eases the treatment burden on the patient.


Assuntos
Fator IX/uso terapêutico , Hemofilia B/tratamento farmacológico , Hemorragia/tratamento farmacológico , Hemorragia/prevenção & controle , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Adolescente , Adulto , Criança , Ensaios Clínicos como Assunto , Fator IX/administração & dosagem , Fator IX/efeitos adversos , Fator IX/farmacocinética , Meia-Vida , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética
16.
Health Qual Life Outcomes ; 15(1): 123, 2017 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-28606095

RESUMO

BACKGROUND: Standardized patient-reported outcome (PRO) questionnaires can be utilized to evaluate treatment satisfaction (subjective evaluation of treatment) in patients with type 2 diabetes (T2D). These outcomes are important because they may affect patient adherence and overall study results. METHODS: PROs were evaluated in two randomized 26-week clinical trials in Japanese patients with T2D taking dulaglutide 0.75 mg (dulaglutide) once weekly; comparators were once-daily liraglutide (0.9 mg/day) and once-weekly placebo in one study and once-daily insulin glargine (glargine) in the other study. The Perceptions About Medications-Diabetes 21 Questionnaire - Japanese version (PAM-D21-J) and the Injectable Diabetes Medication Questionnaire - Japanese version (IDMQ-J) were completed by patients in both studies. These measures were both considered exploratory endpoints. All scale scores range from 0 to 100, with higher scores reflecting better outcomes. RESULTS: Patients reported that dulaglutide was more convenient and flexible than liraglutide (PAM-D21-J Convenience/Flexibility subscale: dulaglutide least-square mean [LSM], 84.58; liraglutide LSM, 78.94; p = .026), and that they were more satisfied with dulaglutide than with liraglutide (IDMQ-J Satisfaction subscale: dulaglutide, 75.24; liraglutide, 69.53; p = .012). Patients also reported that dulaglutide was more convenient and flexible than glargine (PAM-D21-J Convenience/Flexibility subscale: dulaglutide, 87.89; glargine, 79.22; p < .001), and that they were more satisfied with dulaglutide than with glargine (IDMQ-J Satisfaction subscale: dulaglutide, 78.86; glargine, 69.66; p < .001), and felt dulaglutide was more effective than glargine, with fewer symptoms and adverse events (PAM-D21-J Perceived Effectiveness subscale: dulaglutide, 77.61; glargine, 67.22; p < .001; Emotional Effects subscale: dulaglutide, 93.02; glargine, 89.55; p = .017; IDMQ-J Blood Glucose Control subscale: dulaglutide, 76.33; glargine, 67.57; p < .001). In addition, patients responded that dulaglutide was superior to placebo in the PAM-D21-J Convenience/Flexibility, Perceived Effectiveness, and Emotional Effects subscales and all IDMQ-J subscales (Satisfaction, Ease of Use, Lifestyle Impact, Blood Glucose Control). CONCLUSIONS: Overall, after 26 weeks of once-weekly dulaglutide administration in Japanese patients with T2D, PROs were generally positive versus the three comparator treatments (liraglutide, glargine, and placebo), suggesting increased treatment satisfaction through better blood glucose control and convenience/flexibility and reduced negative emotional effects of diabetes. TRIAL REGISTRATION: ClinicalTrials.gov (monotherapy study: NCT01558271 , registered March 12, 2012; combination therapy study: NCT01584232 , registered April 23, 2012).


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Insulina Glargina/uso terapêutico , Liraglutida/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Esquema de Medicação , Quimioterapia Combinada , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Insulina Glargina/administração & dosagem , Liraglutida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Proteínas Recombinantes de Fusão/administração & dosagem
17.
Expert Opin Pharmacother ; 18(8): 781-788, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28443351

RESUMO

INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) are not perfect, since they have potential side effects. Iron therapy is also receiving growing attention in recent years. Areas covered: We performed a literature search on PubMed using the following key words: anemia, chronic kidney disease, HIF stabilisers, sotatercept, actin traps, iron, iron-containing phosphate binders, iron dialysate. We reviewed new drugs that are under clinical development to obtain better safety and activity and/or easier and cheaper manufacturing processes in comparison to available ESAs. We also considered new strategies to increase iron stores. Several phase 1 and 2 studies support the beneficial role of increasing Hypoxia Inducible factor (HIF) activity for stimulating endogenous erythropoiesis. Sotatercept and luspatercept, two activin traps, are undergoing clinical development mainly for indications other than CKD. They have the additional effect of improving osteoporosis. Iron-containing phosphate binders have become available recently. Expert opinion: Several medical needs are unmet with ESA. HIF stabilisers are the most appealing drugs undergoing clinical development. They expose patients to lower levels of EPO than ESA, possibly reducing unintended effects. Their long-term safety is still to be demonstrated. One new iron-containing phosphate binders has the potential of combining two indications: hyperphosphoremia and iron deficiency, possibly improving compliance.


Assuntos
Ativinas/uso terapêutico , Anemia/tratamento farmacológico , Hematínicos/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Ativinas/administração & dosagem , Ativinas/efeitos adversos , Anemia/complicações , Eritropoese/efeitos dos fármacos , Hematínicos/administração & dosagem , Hematínicos/efeitos adversos , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Ferro/metabolismo , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Insuficiência Renal Crônica/complicações , Resultado do Tratamento
18.
J Thromb Haemost ; 15(6): 1167-1179, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28397397

RESUMO

Essentials Recombinant factor VIII (rFVIII) Fc fusion protein has a 1.5-fold longer half-life than rFVIII. Five orthogonal methods were used to characterize the structure of rFVIIIFc compared to rFVIII. The C-terminal Fc fusion does not perturb the structure of FVIII in rFVIIIFc. The FVIII and Fc components of rFVIIIFc are flexibly tethered and functionally independent. SUMMARY: Background Fusion of the human IgG1 Fc domain to the C-terminal C2 domain of B-domain-deleted (BDD) factor VIII (FVIII) results in the recombinant FVIII Fc (rFVIIIFc) fusion protein, which has a 1.5-fold longer half-life in humans. Objective To assess the structural properties of rFVIIIFc by comparing its constituent FVIII and Fc elements with their respective isolated components, and evaluating their structural independence within rFVIIIFc. Methods rFVIIIFc and its isolated FVIII and Fc components were compared by the use of hydrogen-deuterium exchange mass spectrometry (HDX-MS). The structure of rFVIIIFc was also evaluated by the use of X-ray crystallography, small-angle X-ray scattering (SAXS), and electron microscopy (EM). The degree of steric interference by the appended Fc domain was assessed by EM and surface plasmon resonance (SPR). Results HDX-MS analysis of rFVIIIFc revealed that fusion caused no structural perturbations in FVIII or Fc. The rFVIIIFc crystal structure showed that the FVIII component is indistinguishable from published BDD FVIII structures. The Fc domain was not observed, indicating high mobility. SAXS analysis was consistent with an ensemble of rigid-body models in which the Fc domain exists in a largely extended orientation relative to FVIII. Binding of Fab fragments of anti-C2 domain antibodies to BDD FVIII was visualized by EM, and the affinities of the corresponding intact antibodies for BDD FVIII and rFVIIIFc were comparable by SPR analysis. Conclusions The FVIII and Fc components of rFVIIIFc are structurally indistinguishable from their isolated constituents, and show a high degree of structural independence, consistent with the functional comparability of rFVIIIFc and unmodified FVIII.


Assuntos
Fator VIII/química , Hemofilia A/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/química , Proteínas Recombinantes de Fusão/química , Cristalografia por Raios X , Fator VIII/administração & dosagem , Células HEK293 , Meia-Vida , Hemofilia A/imunologia , Hemorragia , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Cinética , Espectrometria de Massas , Microscopia Eletrônica , Fragmentos de Peptídeos/química , Domínios Proteicos , Proteínas Recombinantes de Fusão/administração & dosagem , Espalhamento a Baixo Ângulo , Ressonância de Plasmônio de Superfície , Difração de Raios X
20.
Diabetes Obes Metab ; 19(7): 1024-1031, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28294499

RESUMO

AIM: To compare the addition of weekly dulaglutide vs the addition of placebo to titrated glargine in patients with type 2 diabetes (T2D) with sub-optimum glycated haemoglobin (HbA1c) concentration. MATERIALS AND METHODS: Patients (N = 300) from this phase III, double-blind, parallel-arm, placebo-controlled study were randomized to weekly subcutaneous injections of dulaglutide 1.5 mg or placebo with titrated daily glargine (mean ± standard deviation baseline dose: 39 ± 22 U), with or without metformin (≥1500 mg/d). The primary endpoint was superiority of dulaglutide/glargine to placebo/glargine with regard to change from baseline in HbA1c level at 28 weeks. RESULTS: Least squares (LS) mean ± standard error (s.e.) HbA1c changes from baseline were -1.44 ± 0.09% (-15.74 ± 0.98 mmol/mol) with dulaglutide/glargine and -0.67 ± 0.09% (-7.32 ± 0.98 mmol/mol) with placebo/glargine at 28 weeks (LS mean difference [95% confidence interval] -0.77% [-0.97, -0.56]; P < .001). Body weight decreased with dulaglutide/glargine and increased with placebo/glargine (LS mean difference: -2.41 ± 0.39 kg; P < .001). Increases from baseline in mean glargine dose were significantly smaller with dulaglutide/glargine vs placebo/glargine (13 ± 2 U [0.1 ± 0.02 U/kg] vs 26 ± 2 U [0.3 ± 0.02 U/kg], respectively; P < .001; LS mean ± s.e. final dose: dulaglutide/glargine, 51 ± 2 U; placebo/glargine, 65 ± 2 U). The hypoglycaemia rate (≤3.9 mmol/L threshold) was 7.69 ± 15.15 and 8.56 ± 16.13 events/patient/year, respectively (P = .488). One episode of severe hypoglycaemia occurred in the dulaglutide/glargine group. Common gastrointestinal adverse events with dulaglutide were nausea (12.0%), diarrhoea (11.3%) and vomiting (6.0%). CONCLUSIONS: Weekly dulaglutide 1.5 mg added to basal insulin is an efficacious and well tolerated treatment option for patients with T2D.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Incretinas/uso terapêutico , Insulina Glargina/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Esquema de Medicação , Monitoramento de Medicamentos , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hemoglobina A Glicada/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Incretinas/administração & dosagem , Incretinas/efeitos adversos , Injeções Subcutâneas , Insulina Glargina/administração & dosagem , Insulina Glargina/efeitos adversos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos
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