RESUMEN
Respiratory syncytial virus (RSV) infection is a major cause of severe lower respiratory tract infection and death in young infants and the elderly. With no effective prophylactic treatment available, current vaccine candidates aim to elicit neutralizing antibodies. However, binding and neutralization have poorly predicted protection in the past, and accumulating data across epidemiologic cohorts and animal models collectively point to a role for additional antibody Fc-effector functions. To begin to define the humoral correlates of immunity against RSV, here we profiled an adenovirus 26 RSV-preF vaccine-induced humoral immune response in a group of healthy adults that were ultimately challenged with RSV. Protection from infection was linked to opsonophagocytic functions, driven by IgA and differentially glycosylated RSV-specific IgG profiles, marking a functional humoral immune signature of protection against RSV. Furthermore, Fc-modified monoclonal antibodies able to selectively recruit effector functions demonstrated significant antiviral control in a murine model of RSV.
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Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Ratones , Animales , Infecciones por Virus Sincitial Respiratorio/prevención & control , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Inmunoglobulina G , Fragmentos Fc de Inmunoglobulinas , Proteínas Virales de FusiónRESUMEN
In this study we profiled vaccine-induced polyclonal antibodies as well as plasmablast-derived mAbs from individuals who received SARS-CoV-2 spike mRNA vaccine. Polyclonal antibody responses in vaccinees were robust and comparable to or exceeded those seen after natural infection. However, the ratio of binding to neutralizing antibodies after vaccination was greater than that after natural infection and, at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity. We also found a co-dominance of mAbs targeting the NTD and RBD of SARS-CoV-2 spike and an original antigenic-sin like backboost to spikes of seasonal human coronaviruses OC43 and HKU1. Neutralizing activity of NTD mAbs but not RBD mAbs against a clinical viral isolate carrying E484K as well as extensive changes in the NTD was abolished, suggesting that a proportion of vaccine-induced RBD binding antibodies may provide substantial protection against viral variants carrying single E484K RBD mutations.
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Anticuerpos Antivirales/inmunología , Vacunas contra la COVID-19/inmunología , ARN Mensajero/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunación , Sustitución de Aminoácidos , Enzima Convertidora de Angiotensina 2/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/aislamiento & purificación , Anticuerpos Neutralizantes/inmunología , Formación de Anticuerpos/inmunología , Unión Competitiva , Humanos , Inmunoglobulina G/metabolismo , Mutación/genética , Dominios Proteicos , Hipermutación Somática de Inmunoglobulina/genéticaRESUMEN
Proteinase 3 (PR3) is the main target antigen of antineutrophil cytoplasmic antibodies (ANCAs) in PR3-ANCA-associated vasculitis. A small fraction of PR3 is constitutively exposed on the surface of quiescent blood neutrophils in a proteolytically inactive form. When activated, neutrophils expose an induced form of membrane-bound PR3 (PR3mb) on their surface as well, which is enzymatically less active than unbound PR3 in solution due to its altered conformation. In this work, our objective was to understand the respective role of constitutive and induced PR3mb in the immune activation of neutrophils triggered by murine anti-PR3 mAbs and human PR3-ANCA. We quantified immune activation of neutrophils by the measurement of the production of superoxide anions and secreted protease activity in the cell supernatant before and after treatment of the cells by alpha-1 protease inhibitor that clears induced PR3mb from the cell surface. Incubation of TNFα-primed neutrophils with anti-PR3 antibodies resulted in a significant increase in superoxide anion production, membrane activation marker exposition, and secreted protease activity. When primed neutrophils were first treated with alpha-1 protease inhibitor, we observed a partial reduction in antibody-induced neutrophil activation, suggesting that constitutive PR3mb is sufficient to activate neutrophils. The pretreatment of primed neutrophils with purified antigen-binding fragments used as competitor significantly reduced cell activation by whole antibodies. This led us to the conclusion that PR3mb promoted immune activation of neutrophils. We propose that blocking and/or elimination of PR3mb offers a new therapeutic strategy to attenuate neutrophil activation in patients with PR3-ANCA-associated vasculitis.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Anticuerpos Anticitoplasma de Neutrófilos , Mieloblastina , Animales , Humanos , Ratones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/metabolismo , Mieloblastina/inmunología , Mieloblastina/metabolismo , Neutrófilos/metabolismo , Inhibidores de Proteasas/metabolismo , Superóxidos/metabolismoRESUMEN
Nipah virus (NiV) causes severe encephalitis in humans. Three NiV strains NiV-Malaysia (NiVM ), NiV Bangladesh (NiVB ), and NiV India (NiVI reported in 2019) have been circulating in South-Asian nations. Sporadic outbreak observed in South-East Asian countries but human to human transmission raises the concern about its pandemic potential. The presence of the viral genome in reservoir bats has further confirmed that NiV has spread to the African and Australian continents. NiV research activities have gained momentum to achieve specific preparedness goals to meet any future emergency-as a result, several potential vaccine candidates have been developed and tested in a variety of animal models. Some of these candidate vaccines have entered further clinical trials. Research activities related to the discovery of therapeutic monoclonal antibodies (mAbs) have resulted in the identification of a handful of candidates capable of neutralizing the virion. However, progress in discovering potential antiviral drugs has been limited. Thus, considering NiV's pandemic potential, it is crucial to fast-track ongoing projects related to vaccine clinical trials, anti-NiV therapeutics. Here, we discuss the current progress in NiV-vaccine research and therapeutic options, including mAbs and antiviral medications.
Asunto(s)
Infecciones por Henipavirus , Virus Nipah , Vacunas Virales , Animales , Humanos , Virus Nipah/genética , Infecciones por Henipavirus/prevención & control , Australia , AntiviralesRESUMEN
CD137 is mainly a costimulatory receptor of CD8+ T cells. Two representative CD137 antibodies, utomilumab, and urelumab, show different costimulatory capacities in clinical trials. Balancing the antitumor effect and systemic toxicity of T cells activated by CD137 signaling is a challenge that requires clinical consideration. In this study, a panel of specific anti-human CD137 monoclonal antibodies (mAbs) were prepared and their affinities, isotypes, CD137-CRD (cysteine-rich domain) binding regions, cross-reactivity to mouse and rhesus CD137, inhibition of ligand-receptor binding and costimulatory activities were analyzed. The results showed that anti-human CD137 mAbs had high cross-reactivity with rhesus CD137. MAbs fell into three clusters according to their different binding regions of the CD137 extracellular domain. They bound to CRDI+CRDII, CRDIII or CRDIV+STP. CRDIII-binding mAbs had the strongest blocking activity. Highly costimulatory CD137 mAbs showed stronger abilities to promote CD8+ T-cell proliferation. However, the costimulatory capacity of mAbs on T cells was not closely related to their ability to block CD137L-CD137 binding and may be controlled by more elaborate CRD conformational structures. This study provides additional information for the development of next-generation CD137 mAbs to meet clinical needs.
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Comunicación Celular , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral , Ratones , Animales , Ligandos , Transducción de Señal , Anticuerpos Monoclonales , Linfocitos T CD8-positivosRESUMEN
Diabetes mellitus, a metabolic disorder that is characterized by elevated blood glucose levels, is common throughout the world and its prevalence is steadily increasing. Early diagnosis and treatment are important to prevent acute complications and life-threatening long-term organ damage. Glycation sites in human serum albumin (HSA) are considered to be promising biomarkers of systemic glycemic status. This work aimed to develop a sensitive and clinically applicable ELISA for the quantification of glycation site Lys414 in HSA (HSAK414 ). The monoclonal antibodies (mAbs) were generated by immunizing mice with a glycated peptide. The established indirect ELISA based on mAb 50D8 (IgG1 isotype) yielded a limit of detection of 0.39â nmol/g HSA for HSAK414 with a linear dynamic range from 0.50 to 6.25â nmol/g glycated HSA. The inter- and intra-day assays with coefficients of variation less than 20 % indicated good assay performance and precision. Assay evaluation was based on plasma samples from diabetic and non-diabetic subjects with known HSAK414 glycation levels previously determined by LC-MS. Both data sets correlated very well. In conclusion, the generated mAb 50D8 and the established ELISA could be a valuable tool for the rapid quantitation of glycation site HSAK414 in plasma samples to evaluate its clinical relevance.
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Diabetes Mellitus , Albúmina Sérica , Humanos , Animales , Ratones , Albúmina Sérica/análisis , Lisina , Anticuerpos Monoclonales , Reacción de Maillard , Albúmina Sérica Humana/metabolismo , Ensayo de Inmunoadsorción EnzimáticaRESUMEN
Monoclonal antibodies (MAbs) are powerful therapeutic tools in modern medicine and represent a rapidly expanding multibillion USD market. While bioprocesses are generally well understood and optimized for MAbs, online quality control remains challenging. Notably, N-glycosylation is a critical quality attribute of MAbs as it affects binding to Fcγ receptors (FcγRs), impacting the efficacy and safety of MAbs. Traditional N-glycosylation characterization methods are ill-suited for online monitoring of a bioreactor; in contrast, surface plasmon resonance (SPR) represents a promising avenue, as SPR biosensors can record MAb-FcγR interactions in real-time and without labeling. In this study, we produced five lots of differentially glycosylated Trastuzumab (TZM) and finely characterized their glycosylation profile by HILIC-UPLC chromatography. We then compared the interaction kinetics of these MAb lots with four FcγRs including FcγRIIA and FcγRIIB at 5°C and 25°C. When interacting with FcγRIIA/B at low temperature, the differentially glycosylated MAb lots exhibited distinct kinetic behaviors, contrary to room-temperature experiments. Galactosylated TZM (1) and core fucosylated TZM (2) could be discriminated and even quantified using an analytical technique based on the area under the curve of the signal recorded during the dissociation phase of a SPR sensorgram describing the interaction with FcγRIIA (1) or FcγRII2B (2). Because of the rapidity of the proposed method (<5 min per measurement) and the small sample concentration it requires (as low as 30 nM, exact concentration not required), it could be a valuable process analytical technology for MAb glycosylation monitoring.
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Anticuerpos Monoclonales , Receptores de IgG , Anticuerpos Monoclonales/química , Receptores de IgG/metabolismo , Resonancia por Plasmón de Superficie , Glicosilación , Temperatura , TrastuzumabRESUMEN
PURPOSE: This study aims to establish a benchmark glycan profile for commercial therapeutic monoclonal antibodies (mAbs) approved by the US Food and Drug Administration (FDA). METHODS: We conducted a rigorous comparison of glycosylation data from the regulatory submissions for FDA-approved therapeutic antibodies up to May 2023. This analysis includes over 150 mAbs produced by various mammalian cell expression systems. RESULTS: The study identified nine prevalent glycan epitopes across all FDA-approved monoclonal antibodies produced by different expression systems. These epitopes include terminal N-acetylglucosamine, core fucose, terminal galactose, high mannose, α-galactose, terminal α2,3-linked N-acetylneuraminic acid, terminal α2,6-linked N-glycolylneuraminic acid, triantennary structure, and bisecting N-acetylglucosamine, thus establishing a benchmark glycan profile. CONCLUSIONS: The findings of this study have significant implications for therapeutic antibody development, quality control, and regulatory compliance. The benchmark glycan profile enables the assessment of glycosylation consistency and comparability across a diverse range of antibody products, ensuring improved product quality within the biopharmaceutical industry.
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Anticuerpos Monoclonales , Galactosa , Animales , Anticuerpos Monoclonales/química , Acetilglucosamina , Benchmarking , Polisacáridos/química , Epítopos , Mamíferos/metabolismoRESUMEN
OBJECTIVES: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are novel high-cost treatments for the prevention of migraine. This study presents data on utilization, expenditure, and treatment patterns with CGRP mAbs available under a managed access protocol in Ireland, to a cohort of treatment refractory patients (failed 3 or more previous treatments) with chronic migraine. METHODS: Data were extracted from the Primary Care Reimbursement Service High Tech claims database and special drug request online system and analyzed using Microsoft Excel and SAS. Treatment persistence was evaluated by refill patterns, and adherence was evaluated using the proportion of days covered method. Expenditure data were extracted directly from the database. RESULTS: Between September 1, 2021 and April 30, 2023, 1517 applications for reimbursement approval for a CGRP mAb were received; 1458 (96.1%) were approved for reimbursement. Total expenditure on CGRP mAbs in year 1 (September 1, 2021 to August 31, 2022) was 3.2 million. The majority of patients initiated treatment with fremanezumab (60.8%) or erenumab (37.1%). Almost 90% of patients were considered adherent, and treatment persistence was high, with more than 75% of patients receiving more than 12 months of treatment in our 18-month study time frame. CONCLUSIONS: This study demonstrates the importance of active health technology management, after reimbursement, in enabling cost-effective use of high-cost treatments while providing budget certainty for the healthcare payer. High levels of adherence and persistence suggest that treatment is successfully targeted in situations which unmet clinical need is greatest.
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Anticuerpos Monoclonales , Péptido Relacionado con Gen de Calcitonina , Trastornos Migrañosos , Humanos , Irlanda , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/economía , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/economía , Gastos en Salud , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/economía , Masculino , Persona de Mediana Edad , Adulto , Cumplimiento de la Medicación , Costos de los MedicamentosRESUMEN
Pyroptosis is a newly discovered type of pro-inflammatory programmed cell death that plays a vital role in various processes such as inflammations, immune responses, and pathogen infections. As one of the main executioners of pyroptosis, gasdermin D (GSDMD) is a membrane pore-forming protein that typically exists in a self-inhibitory state. Once activated, GSDMD will be cleaved into an N-terminal fragment with pore-forming activity, becoming the key indicator of pyroptosis activation, and a C-terminal fragment. Although commercial antibodies against human and murine GSDMD proteins are currently available, their reactivity with porcine GSDMD (pGSDMD) is poor, which limits research on the biological functions of pGSDMD and pyroptosis in pigs in vivo and in vitro. Here, five monoclonal antibodies (mAbs) were prepared by immunizing BALB/c mice with procaryotically expressed full-length pGSDMD, all of which did not cross react with human and murine GSDMD proteins. Epitope mapping demonstrated that 15H6 recognizes amino acids (aa) at positions 28-34 of pGSDMD (LQTSDRF), 19H3 recognizes 257-260aa (PPQF), 23H10 and 27A10 recognize 78-82aa (GPFYF), and 25E2 recognizes 429-435aa (PPTLLGS). The affinity constant and isotype of 15H6, 19H3, 23H10, 27A10, and 25E2 mAbs were determined to be 1.32 × 10-9, 3.66 × 10-9, 9.04 × 10-9, 1.83 × 10-9, and 8.00 × 10-8 mol/L and IgG1/κ, IgG2a/κ, IgG2a/κ, IgG1/κ, and IgG1/κ, respectively. Heavy- and light-chain variable regions sequencing showed that the heavy-chain complementarity-determining region (CDR) sequences of all five mAbs are completely different, while the light-chain CDR sequences of the four mAbs that recognize the N-terminus of pGSDMD are identical. Our prepared mAbs provide valuable materials for studying pGSDMD function and pyroptosis. KEY POINTS: ⢠A total of five mouse anti-pGSDMD mAbs were prepared, of which four recognize the N-terminus of pGSDMD and one recognize its C-terminus. ⢠The main performance parameters of the five mAbs, including epitope, antibody titer, affinity constant, isotype, and heavy- and light-chain CDR, were characterized. ⢠All five mAbs specifically recognize pGSDMD protein and do not cross react with human and murine GSDMD proteins.
Asunto(s)
Anticuerpos Monoclonales , Gasderminas , Humanos , Porcinos , Animales , Ratones , Inmunosupresores , Porinas , Inmunoglobulina G , Ratones Endogámicos BALB CRESUMEN
PURPOSE OF REVIEW: Calcitonin gene-related peptide (CGRP)-targeting agents are potential candidates for disease-modifying migraine drugs. However, most studies on CGRP-targeting agents have assessed efficacy outcomes rather than long-term effects after discontinuation. This review aimed to synthesize and scrutinize the latest clinical data on the outcomes after the discontinuation of CGRP-targeting therapy in patients with episodic and chronic migraine, with a particular focus on chronic migraine. RECENT FINDINGS: Real-world studies involving patients with migraine have reported consistent findings of worsened headache frequency and quality of life after the discontinuation of CGRP monoclonal antibodies (CGRP mAbs). Although many patients maintain improvements for up to 4 months after discontinuation compared to baseline (before starting CGRP mAbs), no studies have evaluated the effects of stopping treatment for > 5 months, which is the five-half-life of CGRP mAbs. Several studies have suggested that patients treated with CGRP receptor mAbs experience more rapid deterioration than those treated with CGRP ligand mAbs after discontinuing CGRP mAbs. The results of real-world studies suggest that for many patients with migraine, the benefits of CGRP mAbs diminish months after discontinuation. Therefore, anti-CGRP therapies may not be considered disease-modifying. However, the comprehensive assessment of the disease-modifying potential of these drugs requires studies with extended treatment and cessation durations.
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Péptido Relacionado con Gen de Calcitonina , Trastornos Migrañosos , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Péptido Relacionado con Gen de Calcitonina/inmunología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Multiple mAbs are currently approved for the treatment of asthma. However, there is limited evidence on their comparative effectiveness. OBJECTIVE: Our aim was to compare the effectiveness of omalizumab, mepolizumab, and dupilumab in individuals with moderate-to-severe asthma. METHODS: We emulated a hypothetical randomized trial using electronic health records from a large US-based academic health care system. Participants aged 18 years or older with baseline IgE levels between 30 and 700 IU/mL and peripheral eosinophil counts of at least 150 cells/µL were eligible for study inclusion. The study period extended from March 2016 to August 2021. Outcomes included the incidence of asthma-related exacerbations and change in baseline FEV1 value over 12 months of follow-up. RESULTS: In all, 68 individuals receiving dupilumab, 68 receiving omalizumab, and 65 receiving mepolizumab met the inclusion criteria. Over 12 months of follow-up, 31 exacerbations occurred over 68 person years (0.46 exacerbations per person year) in the dupilumab group, 63 over 68 person years (0.93 per person year) in the omalizumab group, and 86 over 65 person years (1.32 per person year) in the mepolizumab group (adjusted incidence rate ratios: dupilumab vs mepolizumab, 0.28 [95% CI = 0.09-0.84]; dupilumab vs omalizumab, 0.36 [95% CI = 0.12-1.09]; and omalizumab vs mepolizumab, 0.78 [95% CI = 0.32-1.91]). The differences in the change in FEV1 comparing patients who received the different biologics were as follows: 0.11 L (95% CI = -0.003 to 0.222 L) for dupilumab versus mepolizumab, 0.082 L (95% CI -0.040 to 0.204 L) for dupilumab versus omalizumab, and 0.026 L (95% CI -0.083 to 0.140 L) for omalizumab versus mepolizumab. CONCLUSIONS: Among patients with asthma and eosinophil counts of at least 150 cells/µL and IgE levels of 30 to 700 kU/L, dupilumab was associated with greater improvements in exacerbation and FEV1 value than omalizumab and mepolizumab.
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Antiasmáticos , Asma , Humanos , Antiasmáticos/uso terapéutico , Asma/etiología , Inmunoglobulina E/uso terapéutico , Omalizumab/uso terapéutico , Investigación sobre la Eficacia ComparativaRESUMEN
BACKGROUND: Migraine is a highly prevalent neurological disease with a substantial societal burden due to lost productivity. From a societal perspective, we assessed the cost-effectiveness of eptinezumab for the preventive treatment of migraine. METHODS: An individual patient simulation of discrete competing events was developed to evaluate eptinezumab cost-effectiveness compared to best supportive care for adults in the United Kingdom with ≥ 4 migraine days per month and prior failure of ≥ 3 preventive migraine treatments. Individuals with sampled baseline characteristics were created to represent this population, which comprised dedicated episodic and chronic migraine subpopulations. Clinical efficacy, utility, and work productivity inputs were based on results from the DELIVER randomised controlled trial (NCT04418765). Timing of natural history events and treatment holidays-informed by the literature-were simulated to unmask any natural improvement of the disease unrelated to treatment. The primary outcomes were monthly migraine days, migraine-associated costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio, and net monetary benefit, each evaluated over a 5-year time horizon from 2020. Secondary analyses explored a lifetime horizon and an alternative treatment stopping rule. RESULTS: Treatment with eptinezumab resulted in an average of 0.231 QALYs gained at a saving of £4,894 over 5 years, making eptinezumab dominant over best supportive care (i.e., better health outcomes and less costly). This result was confirmed by the probabilistic analysis and all alternative assumption scenarios under the same societal perspective. Univariate testing of inputs showed net monetary benefit was most sensitive to the number of days of productivity loss, and monthly salary. CONCLUSIONS: This economic evaluation shows that from a societal perspective, eptinezumab is a cost-effective treatment in patients with ≥ 4 migraine days per month and for whom ≥ 3 other preventive migraine treatments have failed. TRIAL REGISTRATION: N/A.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Trastornos Migrañosos , Adulto , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Análisis Costo-Beneficio , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , Resultado del Tratamiento , Reino UnidoRESUMEN
BACKGROUND: Clinical characteristics and treatment practice of patients with migraine in Japan in real-world setting have not been fully investigated. We conducted a retrospective cohort study using claims database to understand the clinical practice of migraine in recent years and to characterize patients potentially not managed well by current treatment options. METHODS: Our study used data from the large claims database maintained by JMDC Inc. Patients with diagnosis of headache or migraine between January 1, 2018, and July 31, 2022, were defined as the headache cohort, and those with migraine diagnosis and prescription of migraine treatments among the headache cohort were included in the migraine cohort. In the headache cohort, characteristics of medical facilities and status of imaging tests to distinguish secondary headache were examined. Treatment patterns and characteristics of patients potentially not managed well by acute/preventive treatment were described in migraine cohort. RESULTS: In the headache cohort, 989,514 patients were included with 57.0% females and mean age of 40.3 years; 77.0% patients visited clinics (with ≤ 19 bed capacities) for their primary diagnosis, and 30.3% patients underwent imaging tests (computed tomography and/or magnetic resonance imaging). In the migraine cohort, 165,339 patients were included with 65.0% females and mean age of 38.8 years. In the migraine cohort, 95.6% received acute treatment while 20.8% received preventive treatment. Acetaminophen/non-steroidal anti-inflammatory drugs were most common (54.8%) as the initial prescription for migraine treatment followed by triptan (51.4%). First treatment prescription included preventive treatment in 15.6%, while the proportion increased to 82.2% in the fourth treatment prescription. Among patients with more than 12 months of follow-up, 3.7% had prescription patterns suggestive of risk of medication-overuse headache, and these patients were characterized by a higher percentage of females and a higher prevalence of comorbidities. CONCLUSIONS: This study revealed that approximately one-fifth of the patients with migraine visiting medical facilities use preventive drugs. The presence of potential patients at risk of medication-overuse headache and the role of clinics in migraine treatment were also described.
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Cefaleas Secundarias , Trastornos Migrañosos , Femenino , Humanos , Adulto , Masculino , Estudios Retrospectivos , Japón/epidemiología , Trastornos Migrañosos/diagnóstico por imagen , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/epidemiología , Cefalea/tratamiento farmacológico , Antiinflamatorios no Esteroideos/uso terapéutico , Cefaleas Secundarias/tratamiento farmacológicoRESUMEN
Objectives: Migraine is a neurological disease with a high frequency of incidence. The new monoclonal antibodies selective for the calcitonin gene-related peptide and its ligand (anti-CGRP mAbs) have been marketed both in the USA and EU based on the positive efficacy results in the prevention of migraine. This search has been carried out with the aim of collecting real-world evidence on the effectiveness of anti-CGRP mAbs, performing a cost-savings analysis, and comparing performances among anti-CGRP mAbs medicines marketed in the American and European market. Methods: The literature review has been performed in PubMed database on 31 December 2022; the cost of the unitary dose of anti-CGRP mAbs has been extracted consulting an American national database. Results: The results confirm efficacy and good tolerability of anti-CGRP mAbs, determining a difference in the purchase price. In fact, all extracted studies showed a protective risk factor exposure in monthly migraine days reduction for all the anti-CGRP mAbs, whereas the cost analysis showed that using eptinezumab, in a quarter there is a cost saving of at least $425 per patient, compared with the other anti-CGRP mAbs. Conclusions: With equal efficacy and equal safety, anti-CGRP mAbs should be prescribed also regard to the cost established at the negotiation, making sure to guarantee the best treatment to the patients, but at the same time impacting as little as possible to the healthcare services resources.
RESUMEN
Influenza virus neuraminidase (NA)-targeting antibodies are an independent correlate of protection against influenza. Antibodies against the NA act by blocking enzymatic activity, preventing virus release and transmission. As we advance the development of improved influenza virus vaccines that incorporate standard amounts of NA antigen, it is important to identify the antigenic targets of human monoclonal antibodies (mAbs). Here, we describe escape mutants generated by serial passage of A/Netherlands/602/2009 (H1N1)pdm09 in the presence of human anti-N1 mAbs. We observed escape mutations on the head domain of the N1 protein around the enzymatic site (S364N, N369T, and R430Q) and also detected escape mutations located on the sides and bottom of the NA (N88D, N270D, and Q313K/R). This work increases our understanding of how human antibody responses target the N1 protein. IMPORTANCE As improved influenza virus vaccines are being developed, the influenza virus neuraminidase (NA) is becoming an important new target for immune responses. By identifying novel epitopes of anti-NA antibodies, we can improve vaccine design. Additionally, characterizing escape mutations in these epitopes aids in identifying NA antigenic drift in circulating viruses.
Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza , Gripe Humana , Anticuerpos Monoclonales , Anticuerpos Antivirales/metabolismo , Epítopos/inmunología , Humanos , Subtipo H1N1 del Virus de la Influenza A/enzimología , Subtipo H1N1 del Virus de la Influenza A/genética , Vacunas contra la Influenza/genética , Vacunas contra la Influenza/inmunología , Gripe Humana/virología , Mutación , Neuraminidasa/química , Neuraminidasa/genética , Neuraminidasa/inmunologíaRESUMEN
BACKGROUND: Calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) are approved in Europe as preventive treatment of migraine in patients with at least four monthly migraine days. Migraine gives rise to direct healthcare expenditures, but most of the economic burden of migraine is socioeconomic. Evidence on the socioeconomic implications of CGRP-mAbs is, however, limited. There is an increasing interest in supplementing evidence from randomised controlled trials (RCTs) with real-world evidence (RWE) to aid clinical decision making and inform decision making for migraine management. The objective of this study was to generate RWE on the health economic and socioeconomic implications of administering CGRP-mAbs to patients with chronic migraine (CM) and episodic migraine (high-frequency episodic migraine (HFEM), and low-frequency episodic migraine (LFEM)). METHODS: Real-world data (RWD) on Danish patients with CM, HFEM, and LFEM were collected via two Danish patient organisations and two informal patient networks and used in a tailored economic model. Treatment effects of CGRP-mAbs on health economic and socioeconomic outcomes were estimated using a sub-sample of patients with CM who receive CGRP-mAb treatment. RESULTS: A total of 362 patients (CM: 199 [55.0%], HFEM: 80 [22.1%], LFEM: 83 [22.9%]) were included in the health economic model (mean age 44.1 ± 11.5, 97.5% female, 16.3% received treatment with CGRP-mAbs), and 303 patients were included in the socioeconomic model (15.2% received treatment with CGRP-mAbs). Health economic savings from initiating CGRP-mAb treatment totalled 1,179 per patient with CM per year on average (HFEM: 264, LFEM: 175). Socioeconomic gains from initiating CGRP-mAb treatment totalled an average gross domestic product (GDP) gain of 13,329 per patient with CM per year (HFEM: 10,449, LFEM: 9,947). CONCLUSION: Our results indicate that CGRP-mAbs have the potential to reduce both health economic expenditures and the socioeconomic burden of migraine. Health economic savings are used as a basis for health technology assessments (HTAs) of the cost-effectiveness of new treatments, which implies that important socioeconomic gains may not be given enough importance in decision making for migraine management.
Asunto(s)
Anticuerpos Monoclonales , Péptido Relacionado con Gen de Calcitonina , Trastornos Migrañosos , Femenino , Humanos , Masculino , Anticuerpos Monoclonales/uso terapéutico , Europa (Continente) , Renta , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , Adulto , Persona de Mediana EdadRESUMEN
BACKGROUND: The complexity of clinical practice extends far beyond the controlled settings of trials, and there is a need for real-world studies aimed at identifying which patients will respond to anti-CGRP monoclonal antibodies in different countries. This study aimed to investigate the efficacy and safety of galcanezumab in treating migraine in a real-life setting in Turkey, as well as identify predictors of treatment response. METHODS: A total of 476 patients who diagnosed with migraine according to ICHD-3 criteria and treated with galcanezumab by headache specialists were voluntarily participated in this cross-sectional study. Galcanezumab is indicated for the prevention of migraine in adults who have at least 4 monthly migraine days in Turkey. All patients filled out a survey on Google Form that comprised 54 questions, addressing various aspects such as demographics, migraine characteristics, previous use of acute symptomatic medication, failures with preventive drug classes, comorbidities, most bothersome symptoms, as well as the interictal burden of migraine. RESULTS: Among the participants, 89.3% reported that galcanezumab treatment was beneficial for them. A decrease in the frequency (80.0%), severity (85.7%), and acute medication usage for migraine attacks (71.4%) was reported with galcanezumab treatment. An adverse effect related to galcanezumab was reported in 16.3% of cases, but no serious adverse reactions were observed. Remarkably, 14.3% of participants reported no longer experiencing any headaches, and 18.9% did not require any acute treatment while receiving galcanezumab treatment. A logistic regression model showed that male gender, lack of ictal nausea, and previous failure of more than 2 prophylactic agents may predict the non-responders. CONCLUSIONS: The first large series from Turkey showed that galcanezumab treatment is safe and effective in most of the patients diagnosed with migraine by headache experts in the real-life setting. Patients reported a significant decrease in both ictal and interictal burden of migraine and expressed satisfaction with this treatment.
Asunto(s)
Trastornos Migrañosos , Adulto , Humanos , Masculino , Resultado del Tratamiento , Turquía/epidemiología , Estudios Transversales , Método Doble Ciego , Trastornos Migrañosos/diagnóstico , Cefalea/tratamiento farmacológico , Cefalea/epidemiologíaRESUMEN
BACKGROUND: Blocking the major cat allergen, Fel d 1, with mAbs was effective in preventing an acute cat allergic response. OBJECTIVES: This study sought to extend the allergen-specific antibody approach and demonstrate that a combination of mAbs targeting Bet v 1, the immunodominant and most abundant allergenic protein in birch pollen, can prevent the birch allergic response. METHODS: Bet v 1-specific mAbs, REGN5713, REGN5714, and REGN5715, were isolated using the VelocImmune platform. Surface plasmon resonance, x-ray crystallography, and cryo-electron microscopy determined binding kinetics and structural data. Inhibition of IgE-binding, basophil activation, and mast cell degranulation were assessed via blocking ELISA, flow cytometry, and the passive cutaneous anaphylaxis mouse model. RESULTS: REGN5713, REGN5714, and REGN5715 bind with high affinity and noncompetitively to Bet v 1. A cocktail of all 3 antibodies, REGN5713/14/15, blocks IgE binding to Bet v 1 and inhibits Bet v 1- and birch pollen extract-induced basophil activation ex vivo and mast cell degranulation in vivo. Crystal structures of the complex of Bet v 1 with immunoglobulin antigen-binding fragments of REGN5713 or REGN5715 show distinct interaction sites on Bet v 1. Cryo-electron microscopy reveals a planar and roughly symmetrical complex formed by REGN5713/14/15 bound to Bet v 1. CONCLUSIONS: These data confirm the immunodominance of Bet v 1 in birch allergy and demonstrate blockade of the birch allergic response with REGN5713/14/15. Structural analyses show simultaneous binding of REGN5713, REGN5714, and REGN5715 with substantial areas of Bet v 1 exposed, suggesting that targeting specific epitopes is sufficient to block the allergic response.
Asunto(s)
Alérgenos/inmunología , Anticuerpos Monoclonales/farmacología , Antígenos de Plantas/inmunología , Epítopos Inmunodominantes/inmunología , Inmunoglobulina G/farmacología , Anafilaxis Cutánea Pasiva/inmunología , Animales , Basófilos/efectos de los fármacos , Basófilos/inmunología , Humanos , Inmunoglobulina E/inmunología , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Ratones Endogámicos BALB C , Rinitis Alérgica Estacional/sangre , Rinitis Alérgica Estacional/inmunologíaRESUMEN
Immunotherapies based on immune checkpoint blockade have shown remarkable clinical outcomes and durable responses in patients with many tumor types. Nevertheless, these therapies lack efficacy in most cancer patients, even causing severe adverse events in a small subset of patients, such as inflammatory disorders and hyper-progressive disease. To diminish the risk of developing serious toxicities, intratumor delivery of monoclonal antibodies could be a solution. Encouraging results have been shown in both preclinical and clinical studies. Thus, intratumor immunotherapy as a new strategy may retain efficacy while increasing safety. This approach is still an exploratory frontier in cancer research and opens up new possibilities for next-generation personalized medicine. Local intratumor delivery can be achieved through many means, but an attractive approach is the use of gene therapy vectors expressing mAbs inside the tumor mass. Here, we summarize basic, translational, and clinical results of intratumor mAb delivery, together with descriptions of non-viral and viral strategies for mAb delivery in preclinical and clinical development. Currently, this is an expanding research subject that will surely play a key role in the future of oncology.