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1.
Lancet Oncol ; 22(4): 450-462, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33794205

RESUMEN

BACKGROUND: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued. FINDINGS: Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure). INTERPRETATION: The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Quimioradioterapia , Cisplatino/administración & dosificación , Método Doble Ciego , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Placebos/administración & dosificación , Supervivencia sin Progresión , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Nivel de Atención
2.
Int J Nanomedicine ; 16: 2477-2486, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33824586

RESUMEN

Purpose: Sensitive and selective point-of-care biosensor is an urgent pursuit of serological antibody detection to control parasite pathogen. For specific, quantitative and on-site screening of Trichinella spiralis infection in livestock, a quantum dot nanobead-monoclonal antibody (QB-mAb) probe-based immunochromatographic assay (ICA) was developed by introducing a competitive sandwich strategy (QB-CICA). Methods: In the QB-CICA, QB-mAb probes competed with serum antibody for a particular epitope, followed by immunocomplexes binding to capture antibody on the test line. With the accumulation of target antibody, captured probes served as signal elements for fluorescent readout in a "turn off" mode, along with the fluorescence gradually weakened. The sensitivity and standard calibration curve of the QB-CICA were quantified using swine sera as negative control (n = 200) and artificial infected swine sera (n = 80) compared with a commercial ELISA kit. Besides, Trichinella spiralis-antibody targeting test ability of the QB-CICA, instead of other parasites or viruses antibodies (n = 10), was evaluated. Results: The QB-CICA exhibited a good linear range, a low detection limit of 189.92 ng mL-1 and 100% selectivity that was higher than commercial ELISA kit (90%), as well as the same serological positive rate (100%) with commercial ELISA kit in different infection dose models. Conclusion: Taking advantage of its simplicity, short response time (25 min), sensitivity and specificity, the proposed QB-CICA has potential applications for parasite-related antibody monitoring in food safety and clinical diagnosis fields.


Asunto(s)
Anticuerpos Antihelmínticos/análisis , Anticuerpos Monoclonales/inmunología , Cromatografía de Afinidad/métodos , Nanopartículas/química , Puntos Cuánticos/química , Trichinella spiralis/inmunología , Triquinelosis/diagnóstico , Triquinelosis/inmunología , Animales , Anticuerpos Antihelmínticos/sangre , Anticuerpos Antihelmínticos/inmunología , Nanopartículas/ultraestructura , Puntos Cuánticos/ultraestructura , Porcinos , Triquinelosis/parasitología
3.
Brain Nerve ; 73(4): 327-337, 2021 Apr.
Artículo en Japonés | MEDLINE | ID: mdl-33824220

RESUMEN

Migraine is a common and debilitating neurological disorder characterized by recurrent headaches of moderate-to-severe intensity. Because of its high prevalence, migraine causes a considerable financial burden on society. There is ample evidence showing that migraine is a complex neurological disorder that involves not only the trigeminovascular and autonomic systems, but also the hypothalamus and cerebral cortex. Calcitonin gene-related peptide (CGRP) was originally discovered as a 37-amino acid neuropeptide derived from a calcitonin gene splicing variant, is enriched in trigeminal ganglion neurons. Much attention has been paid to CGRP since it was found to be released from trigeminal terminals in animal migraine models. Subsequent studies demonstrated that CGRP administration induced migraine-like headaches specifically in migraineurs, thus highlighting its pivotal role CGRP in the development of migraine attacks. Monoclonal antibodies targeting CGRP and its receptor exhibited consistent efficacy for migraine prophylaxis with excellent safety profiles in clinical trials. Furthermore, emerging data support the long-term safety and efficacy of these antibodies. On the other hand, there are several concerns that have newly surfaced in the real-world setting. In this review, the development and perspective of anti-migraine therapeutic strategies using CGRP-related antibodies are discussed.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina , Trastornos Migrañosos , Animales , Anticuerpos Monoclonales/uso terapéutico , Calcitonina , Trastornos Migrañosos/tratamiento farmacológico , Ganglio del Trigémino
4.
Brain Nerve ; 73(4): 347-355, 2021 Apr.
Artículo en Japonés | MEDLINE | ID: mdl-33824222

RESUMEN

Galcanezumab, a CGRP monoclonal antibody drug, has been approved by the U.S. Food and Drug Administration (FDA) for the prevention of recurrent cluster headaches. This was done after a randomized, double-blind, placebo-controlled trial found it to be effective and safe. Similarly sphenopalatine ganglion stimulation has been found to be effective and safe in a randomized, controlled trial as an acute treatment for chronic cluster headache. This article reviews the mechanisms of action of these therapies and their clinical trial results, clinical uses, and prospects in Japan.


Asunto(s)
Cefalalgia Histamínica , Anticuerpos Monoclonales , Cefalalgia Histamínica/diagnóstico , Cefalalgia Histamínica/tratamiento farmacológico , Método Doble Ciego , Cefalea , Humanos , Japón , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento
5.
Science ; 372(6537)2021 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-33795432

RESUMEN

Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here we unite form and function by the computational design of nanocages in which one structural component is an antibody or Fc-ligand fusion and the second is a designed antibody-binding homo-oligomer that drives nanocage assembly. Structures of eight nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage, respectively, closely match the corresponding computational models. Antibody nanocages targeting cell surface receptors enhance signaling compared with free antibodies or Fc-fusions in death receptor 5 (DR5)-mediated apoptosis, angiopoietin-1 receptor (Tie2)-mediated angiogenesis, CD40 activation, and T cell proliferation. Nanocage assembly also increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-angiotensin-converting enzyme 2 (ACE2) fusion proteins.


Asunto(s)
Anticuerpos/química , Anticuerpos/inmunología , Nanoestructuras , Ingeniería de Proteínas , Transducción de Señal , Angiopoyetinas/química , Angiopoyetinas/inmunología , Angiopoyetinas/metabolismo , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/química , Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , Antígenos CD40/química , Antígenos CD40/inmunología , Antígenos CD40/metabolismo , Línea Celular Tumoral , Proliferación Celular , Simulación por Computador , Genes Sintéticos , Humanos , Fragmentos Fc de Inmunoglobulinas/química , Activación de Linfocitos , Modelos Moleculares , Unión Proteica , Receptor TIE-2/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/inmunología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Linfocitos T/inmunología , Linfocitos T/fisiología
6.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802650

RESUMEN

As an essential modulator of IgG disposition, the neonatal Fc receptor (FcRn) governs the pharmacokinetics and functions many therapeutic modalities. In this review, we thoroughly reexamine the hitherto elucidated biological and thermodynamic properties of FcRn to provide context for our assessment of more recent advances, which covers antigen-binding fragment (Fab) determinants of FcRn affinity, transgenic preclinical models, and FcRn targeting as an immune-complex (IC)-clearing strategy. We further comment on therapeutic antibodies authorized for treating SARS-CoV-2 (bamlanivimab, casirivimab, and imdevimab) and evaluate their potential to saturate FcRn-mediated recycling. Finally, we discuss modeling and simulation studies that probe the quantitative relationship between in vivo IgG persistence and in vitro FcRn binding, emphasizing the importance of endosomal transit parameters.


Asunto(s)
Antígenos de Histocompatibilidad Clase I/química , Antígenos de Histocompatibilidad Clase I/metabolismo , Receptores Fc/química , Receptores Fc/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/farmacocinética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Receptores Fc/inmunología , Distribución Tisular/inmunología
9.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(3): 265-270, 2021 Mar.
Artículo en Chino | MEDLINE | ID: mdl-33766234

RESUMEN

Objective To prepare and identify mouse monoclonal antibodies against human vasorin (VASN) protein using electrofusion method. Methods The mice were immunized with human recombinant protein VASN-His, and then the cells were fused by electrofusion apparatus. Indirect ELISA was used to screen the positive hybridoma cells which could bind natural protein VASN. The titer and affinities of the antibodies were detected by ELISA, and Western blotting was used to determine whether the antibody could recognize VASN protein in HepG2 cells. Results The fusion rate reached 0.31% when the ratio of spleen cells and Sp2/0 myeloma cells was 2:1, the alternating electric field intensity was 50 V, 2 MHz for 20 seconds, and the direct current pulse intensity was 500 V for 0.5 second. Two mouse anti-human VASN monoclonal antibodies (4H1and 8B9) were obtained, with the highest titer of 1:256 000 and the highest affinity constant (Ka) of 4.9×106 L/mol. Western blotting showed that both monoclonal antibodies could specifically recognize VASN in HepG2 cells. Conclusion Two mouse anti-human VASN monoclonal antibodies have been successfully prepared by the cell electrofusion method.


Asunto(s)
Anticuerpos Monoclonales , Animales , Western Blotting , Humanos , Hibridomas , Ratones , Ratones Endogámicos BALB C , Proteínas Recombinantes
10.
Cochrane Database Syst Rev ; 3: CD013881, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33734435

RESUMEN

BACKGROUND: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance. OBJECTIVES: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events. MAIN RESULTS: We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes. AUTHORS' CONCLUSIONS: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Interleucina-6/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Sesgo , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto
12.
Medicine (Baltimore) ; 100(13): e25223, 2021 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-33787605

RESUMEN

ABSTRACT: This observational, longitudinal retrospective, noncomparative study was designed to assess the persistence and effectiveness of golimumab as a second anti-tumor necrosis factor (TNF) drug in patients with spondyloarthritis requiring discontinuation from a first anti-TNF drug.Data were collected retrospectively for all patients with axial spondyloarthritis or psoriatic arthritis from 20 rheumatology clinics in Spain who started golimumab as a second anti-TNF drug between January 2013 and December 2015. Golimumab persistence was assessed with Kaplan-Meier survival analysis, and associated factors were assessed with Cox regression analysis.210 patients started golimumab as a second anti-TNF drug: 131 with axial spondyloarthritis and 79 with psoriatic arthritis. In axial spondyloarthritis patients, the mean (standard deviation) Bath Ankylosing Spondylitis Disease Activity Index score at baseline was 5.5 (2.1), decreasing to 3.9 (2.0) at month 3 and 3.5 (2.0) at year 1, and remaining stable thereafter. In psoriatic arthritis patients, mean (standard deviation) baseline Disease Activity Score was 4.0 (1.3), reducing to 2.5 (1.2) at month 3 and to 2.2 (1.3) at year 1. Corresponding improvements were recorded from baseline in C-reactive protein levels and erythrocyte sedimentation rates. The probability of persistence of treatment with golimumab was 80% at year 1, 70% at year 2 and 65% at years 3 and year 4, and was similar in those who had stopped the first anti-TNF due to loss of efficacy or other reasons. Cox regression analysis showed that the probability of survival with golimumab was higher in patients with higher erythrocyte sedimentation rate, in patients with axial spondyloarthritis than with psoriatic arthritis, and in those who had discontinued adalimumab as first anti-TNF. Seventy-two patients (34.3%) discontinued golimumab during follow-up, 50 of them due to lack of efficacy.In patients with spondyloarthritis requiring discontinuation from a first anti-TNF drug, treatment with golimumab was effective and showed a high probability of persistence up to 4 years of treatment.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Productos Biológicos/uso terapéutico , Espondiloartritis/tratamiento farmacológico , Inhibidores del factor de Necrosis Tumorales/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento
13.
Cell Prolif ; 54(4): e13009, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33655556

RESUMEN

The sites of targeted therapy are limited and need to be expanded. The FGF-FGFR signalling plays pivotal roles in the oncogenic process, and FGF/FGFR inhibitors are a promising method to treat FGFR-altered tumours. The VEGF-VEGFR signalling is the most crucial pathway to induce angiogenesis, and inhibiting this cascade has already got success in treating tumours. While both their efficacy and antitumour spectrum are limited, combining FGF/FGFR inhibitors with VEGF/VEGFR inhibitors are an excellent way to optimize the curative effect and expand the antitumour range because their combination can target both tumour cells and the tumour microenvironment. In addition, biomarkers need to be developed to predict the efficacy, and combination with immune checkpoint inhibitors is a promising direction in the future. The article will discuss the FGF-FGFR signalling pathway, the VEGF-VEGFR signalling pathway, the rationale of combining these two signalling pathways and recent small-molecule FGFR/VEGFR inhibitors based on clinical trials.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias/tratamiento farmacológico , Transducción de Señal , Inhibidores de la Angiogénesis/farmacología , Anticuerpos Monoclonales/uso terapéutico , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Neoplasias/patología , Polimorfismo de Nucleótido Simple , Receptores de Factores de Crecimiento de Fibroblastos/genética , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo
14.
Int J Mol Sci ; 22(4)2021 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-33670003

RESUMEN

The C-terminal-fragments of alpha1-antitrypsin (AAT) have been identified and their diverse biological roles have been reported in vitro and in vivo. These findings prompted us to develop a monoclonal antibody that specifically recognizes C-36 peptide (corresponding to residues 359-394) resulting from the protease-associated cleavage of AAT. The C-36-targeting mouse monoclonal Immunoglobulin M (IgM) antibody (containing κ light chains, clone C42) was generated and enzyme-linked immunosorbent assay (ELISA)-tested by Davids Biotechnologie GmbH, Germany. Here, we addressed the effectiveness of the novel C42 antibody in different immunoassay formats, such as dot- and Western blotting, confocal laser microscopy, and flow cytometry. According to the dot-blot results, our novel C42 antibody detects the C-36 peptide at a range of 0.1-0.05 µg and shows no cross-reactivity with native, polymerized, or oxidized forms of full-length AAT, the AAT-elastase complex mixture, as well as with shorter C-terminal fragments of AAT. However, the C42 antibody does not detect denatured peptide in SDS-PAGE/Western blotting assays. On the other hand, our C42 antibody, unconjugated as well as conjugated to DyLight488 fluorophore, when applied for immunofluorescence microscopy and flow cytometry assays, specifically detected the C-36 peptide in human blood cells. Altogether, we demonstrate that our novel C42 antibody successfully recognizes the C-36 peptide of AAT in a number of immunoassays and has potential to become an important tool in AAT-related studies.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Péptidos/inmunología , alfa 1-Antitripsina/inmunología , Secuencia de Aminoácidos , Especificidad de Anticuerpos/inmunología , Trampas Extracelulares , Humanos , Lipopolisacáridos/farmacología , Neutrófilos/efectos de los fármacos , Neutrófilos/enzimología , Péptidos/sangre , Péptidos/química , Desnaturalización Proteica
15.
Cell ; 184(7): 1821-1835.e16, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33667349

RESUMEN

Human monoclonal antibodies are safe, preventive, and therapeutic tools that can be rapidly developed to help restore the massive health and economic disruption caused by the coronavirus disease 2019 (COVID-19) pandemic. By single-cell sorting 4,277 SARS-CoV-2 spike protein-specific memory B cells from 14 COVID-19 survivors, 453 neutralizing antibodies were identified. The most potent neutralizing antibodies recognized the spike protein receptor-binding domain, followed in potency by antibodies that recognize the S1 domain, the spike protein trimer, and the S2 subunit. Only 1.4% of them neutralized the authentic virus with a potency of 1-10 ng/mL. The most potent monoclonal antibody, engineered to reduce the risk of antibody-dependent enhancement and prolong half-life, neutralized the authentic wild-type virus and emerging variants containing D614G, E484K, and N501Y substitutions. Prophylactic and therapeutic efficacy in the hamster model was observed at 0.25 and 4 mg/kg respectively in absence of Fc functions.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Antivirales/administración & dosificación , Linfocitos B/inmunología , Convalecencia , Células 3T3 , Animales , Anticuerpos Monoclonales/aislamiento & purificación , Anticuerpos Neutralizantes/aislamiento & purificación , Anticuerpos Antivirales/aislamiento & purificación , Linfocitos B/citología , /prevención & control , Chlorocebus aethiops , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Fragmentos Fc de Inmunoglobulinas/inmunología , Masculino , Ratones , Glicoproteína de la Espiga del Coronavirus/inmunología , Células Vero
16.
Cell ; 184(7): 1804-1820.e16, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33691139

RESUMEN

SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes and CD8+ T cells for optimal clinical and virological benefit. Thus, potently neutralizing mAbs utilize Fc effector functions during therapy to mitigate lung infection and disease.


Asunto(s)
Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Linfocitos T CD8-positivos , Fragmentos Fc de Inmunoglobulinas/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/uso terapéutico , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Células CHO , /terapia , Chlorocebus aethiops , Cricetulus , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Células Vero , Carga Viral
17.
Cancer Treat Rev ; 95: 102174, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33721596

RESUMEN

In 5% of metastatic colorectal cancer (mCRC) patients, tumours display a deficient mismatch repair (dMMR) system. Immunotherapy is beneficial in dMMR mCRC patients and has recently been approved by the Food and Drug Administration for patients with unresectable or metastatic dMMR CRC. Although dMMR and proficient MMR (pMMR) CRC tumours are biologically distinct, they are commonly treated with the same chemotherapy and monoclonal antibodies. This includes dMMR mCRC patients who did not respond to immunotherapy (20-30%). However, it is unclear if these treatments are equally beneficial in dMMR mCRC. Of note, dMMR mCRC patients have a worse prognosis compared to pMMR, which may in part be caused by a lower response to treatment. To avoid unnecessary exposure to ineffective treatments and their associated toxicity, it is important to identify which systemic treatments are most beneficial in dMMR mCRC patients, thus improving their outcome. Indeed, future treatment strategies are likely to involve combinations of immunotherapy, chemotherapy and monoclonal antibodies. In this evidence-based review, we summarize clinical trials reporting treatment efficacy of different types of chemotherapy and monoclonal antibodies in dMMR mCRC patients. We also review the biological rationale behind a potential differential benefit of chemotherapy with or without monoclonal antibodies in dMMR mCRC patients. A barrier in the interpretation of preclinical results is the choice of model systems. They largely comprise traditional models, including cell lines and xenografts, rather than more representative models, such as patient-derived organoids. We provide concrete recommendations for clinical investigators and fundamental researchers to accelerate research regarding which systemic therapy is most effective in dMMR mCRC patients.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Reparación de la Incompatibilidad de ADN/genética , Animales , Ensayos Clínicos como Asunto , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/secundario , Evaluación Preclínica de Medicamentos , Humanos , Inmunoterapia
18.
J Prim Care Community Health ; 12: 21501327211007020, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33771055

RESUMEN

Therapeutic interventions to manage symptoms of COVID-19 are continually evolving and being used in a variety of settings. In an attempt to reduce the potential for a high influx of hospital admissions for COVID-19 and mitigate the advancement of COVID-19 disease in infected patients, an outpatient therapy clinic for infusion therapy was established. The focus of the current paper is to outline the development of the outpatient treatment center, provide a detailed summary of workflow and discuss operational challenges and directions for the future.


Asunto(s)
Instituciones de Atención Ambulatoria , Atención Ambulatoria , Prestación de Atención de Salud , Terapia de Infusión a Domicilio , Pandemias , Población Rural , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Humanos , Servicios de Salud Rural
19.
Molecules ; 26(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670468

RESUMEN

Lateral flow assays (lateral flow immunoassays and nucleic acid lateral flow assays) have experienced a great boom in a wide variety of early diagnostic and screening applications. As opposed to conventional examinations (High Performance Liquid Chromatography, Polymerase Chain Reaction, Gas chromatography-Mass Spectrometry, etc.), they obtain the results of a sample's analysis within a short period. In resource-limited areas, these tests must be simple, reliable, and inexpensive. In this review, we outline the production process of antibodies against drugs of abuse (such as heroin, amphetamine, benzodiazepines, cannabis, etc.), used in lateral flow immunoassays as revelation or detection molecules, with a focus on the components, the principles, the formats, and the mechanisms of reaction of these assays. Further, we report the monoclonal antibody advantages over the polyclonal ones used against drugs of abuse. The perspective on aptamer use for lateral flow assay development was also discussed as a possible alternative to antibodies in view of improving the limit of detection, sensitivity, and specificity of lateral flow assays.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Inmunoensayo/métodos , Detección de Abuso de Sustancias , Animales , Técnicas de Visualización de Superficie Celular , Humanos , Valor Predictivo de las Pruebas , Proyectos de Investigación
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