ABSTRACT
Eosinophilic asthma is the most common phenotype of severe asthma. It is characterized by abnormal production and release of type 2 cytokines from T helper type 2 (TH2) lymphocytes and type 2 innate lymphoid cells, such as IL-5. This leads to a persistent increase and activation of eosinophils in blood and the airways despite treatment with high-dose inhaled corticosteroids. Eosinophil differentiation, survival, and activation are preferentially regulated by IL-5, a cytokine that binds to the IL-5 receptor (IL-5R), which is located on the surface of eosinophils or basophils and plays a critical role in the pathogenesis and severity of asthma. Benralizumab is a monoclonal antibody that binds to IL-5R via its Fab domain, blocking the binding of IL-5 to its receptor and resulting in inhibition of eosinophil differentiation and maturation in bone marrow. In addition, this antibody is able to bind through its afucosylated Fc domain to the RIIIa region of the Fcy receptor on NK cells, macrophages, and neutrophils, thus strongly inducing antibody-dependent, cell-mediated cytotoxicity in both circulating and tissue-resident eosinophils. This double function of benralizumab induces almost complete fast and maintained depletion of eosinophils that is much greater than that induced by other monoclonal antibodies targeting the IL-5 pathway, such as mepolizumab and reslizumab. This review focuses on benralizumab as an alternative to other agents targeting the IL-5 pathway in the treatment of eosinophilic asthma.
Subject(s)
Anti-Asthmatic Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Asthma/drug therapy , Basophils/drug effects , Eosinophilia/drug therapy , Anti-Asthmatic Agents/administration & dosage , Anti-Asthmatic Agents/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Asthma/diagnosis , Asthma/immunology , Basophils/immunology , Basophils/metabolism , Clinical Trials as Topic , Drug Therapy, Combination , Eosinophilia/diagnosis , Eosinophilia/immunology , Humans , Phenotype , Research , Symptom Assessment , Treatment OutcomeABSTRACT
Eosinophilic asthma is the most common phenotype of severe asthma. It is characterized by abnormal production and release of type 2 cytokines from T helper type 2 (TH2) lymphocytes and type 2 innate lymphoid cells, such as IL-5. This leads to a persistent increase and activation of eosinophils in blood and the airways despite treatment with high-dose inhaled corticosteroids. Eosinophil differentiation, survival, and activation are preferentially regulated by IL-5, a cytokine that binds to the IL-5 receptor (IL-5R), which is located on the surface of eosinophils or basophils and plays a critical role in the pathogenesis and severity of asthma. Benralizumab is a monoclonal antibody that binds to IL-5R via its Fab domain, blocking the binding of IL-5 to its receptor and resulting in inhibition of eosinophil differentiation and maturation in bone marrow. In addition, this antibody is able to bind through its afucosylated Fc domain to the RIIIa region of the Fcgamma receptor on NK cells, macrophages, and neutrophils, thus strongly inducing antibody-dependent, cell-mediated cytotoxicity in both circulating and tissue-resident eosinophils. This double function of benralizumab induces almost complete fast and maintained depletion of eosinophils that is much greater than that induced by other monoclonal antibodies targeting the IL-5 pathway, such as mepolizumab and reslizumab. This review focuses on benralizumab as an alternative to other agents targeting the IL-5 pathway in the treatment of eosinophilic asthma
El asma eosinofílica es el fenotipo más común del asma grave. Se caracteriza por una producción y liberación anómala de citocinas de tipo 2, como la IL-5, por los linfocitos T colaboradores de tipo 2 (Th2) y las células linfoides innatas de tipo 2 (ILC-2). Con ello se activan los eosinófilos y se incrementa su número en sangre y vías respiratorias, a pesar del tratamiento con dosis altas de corticosteroides inhalados. La diferenciación, supervivencia y activación de los eosinófilos está regulada principalmente por la IL-5, una citocina que se une a su receptor (IL-5R), situado en la superficie de eosinófilos y basófilos, y que desempeña un papel fundamental en la patogénesis y gravedad del asma. El benralizumab es un anticuerpo monoclonal que se une al IL-5R a través de su dominio Fab, bloqueando la unión de la IL-5 a su receptor, lo que provoca una inhibición de la diferenciación y maduración de los eosinófilos en la médula ósea. Además, este anticuerpo es capaz de unirse a través de su dominio Fc afucosilado a la región RIIIa del receptor Fcgamma situado en células NK, macrófagos y neutrófilos, induciendo así una intensa citotoxicidad mediada por células dependiente de anticuerpos (ADCC), tanto de los eosinófilos circulantes como de los residentes en tejidos. Esta doble función del benralizumab induce una disminución casi completa de los eosinófilos de una forma rápida y mantenida, mucho mayor a la inducida por otros anticuerpos monoclonales dirigidos contra la IL-5, como el mepolizumab o el reslizumab. Esta revisión se centra en describir el uso del benralizumab en el tratamiento del asma eosinofílica como una alternativa a otros agentes que actúan directamente sobre la IL-5
Subject(s)
Humans , Asthma/drug therapy , Eosinophilia/drug therapy , Interleukin-5/immunology , Lymphocytes/immunology , Cytokines/immunology , Basophil Degranulation Test/methods , Symptom Flare Up , Asthma/immunology , Eosinophilia/immunology , Biological Variation, Population/immunologyABSTRACT
BACKGROUND: Allergen immunotherapy is a treatment modality which can be applied using different vaccines. The aim of this study was to quantify and compare the allergen content of different house dust mites (HDM)' sublingual treatments and to review the evidence on their efficacy. METHODS: Five sublingual allergen immunotherapy (SLIT) products were ordered and purchased at an ordinary pharmacy and masked for blinding before the study was started. Detection of Dermatophagoides pteronyssinus and Dermatophagoides farinae allergens Der p 1, Der f 1, Der p 2 and Der f 2 was carried out by immunoblotting and fluorescent multiplex. A literature search for meta-analyses and systematic reviews that included SLIT-HDM products was performed. RESULTS: Der p 1 concentrations ranged from 0.6 to 14.5 µg/ml; similar figures were found for Der f 1 that ranged from 0.2 to 12.4 µg/ml. Der p 2+ Der f 2 ranged from 0.2 to 1.5 µg/ml. Data on efficacy are scarce for most of the five products. CONCLUSIONS: Substantial variations regarding allergen content were found among these five SLIT-HDM products. Therefore, it can be necessary to guarantee the quality of the SLIT-HDM products and to demonstrate their effectiveness before they are marketed. It seems necessary, for the moment, to take into account these characteristics of the products before prescribing.
Subject(s)
Allergens/immunology , Antigens, Dermatophagoides/immunology , Hypersensitivity/immunology , Hypersensitivity/therapy , Pyroglyphidae/immunology , Sublingual Immunotherapy , Allergens/administration & dosage , Allergens/metabolism , Animals , Antigens, Dermatophagoides/administration & dosage , Antigens, Dermatophagoides/metabolism , Humans , Sublingual Immunotherapy/methods , Treatment Outcome , Vaccines/administration & dosage , Vaccines/immunologyABSTRACT
BACKGROUND: Immunologically enhanced subcutaneous specific immunotherapy (SCIT) has been developed with a fast and simplified updosing phase containing equal parts of the house dust mites (HDM) Dermatophagoides pteronyssinus and Dermatophagoides farinae (Dermatophagoides mix) adsorbed on aluminum hydroxide. OBJECTIVE: To evaluate the tolerability and immunological impact of the updosing phase of this new allergen extract formulation. MATERIAL AND METHODS: We performed a multicenter, open-label, single-arm, phase II/III clinical trial. The inclusion criteria were a clinical history of rhinitis/conjunctivitis due to HDM (with/without asthma) and sensitization to HDM (positive specific IgE and skin prick test). Five updosing injections of Dermatophagoides mix (300, 600, 3000, 6000, and 15000 SQ+) were administered at weekly intervals with 1 maintenance injection (15000 SQ+) 2 weeks after the last updosing injection. Two days after each visit, patients were contacted by telephone to follow up on any adverse events. IgE-blocking factor, IgG4, and immediate skin reactivity were evaluated. RESULTS: The sample comprised 102 patients (mean [SD] age, 29.3 [7.7] years; male, 52.9%). There were 117 adverse drug reactions (ADR): 101 were local, regardless of reaction size, in 48 (47.1%) patients and 7 were systemic (all grade I) in 5 (4.9%) patients. All ADRs were mild, except for 1, which was moderate. Six weeks of treatment led to statistically significant increases in IgE-blocking factor and IgG4, as well as a significant reduction in immediate skin reactivity. CONCLUSION: This new updosing phase of Dermatophagoides mix-based immunotherapy had a good tolerability profile and induced a significant immunological effect.
Subject(s)
Allergens/immunology , Asthma/therapy , Conjunctivitis, Allergic/therapy , Dermatophagoides farinae/immunology , Dermatophagoides pteronyssinus/immunology , Desensitization, Immunologic/methods , Rhinitis, Allergic/therapy , Adult , Animals , Desensitization, Immunologic/adverse effects , Female , Humans , Immunoglobulin E/immunology , Immunoglobulin G/immunology , Male , Young AdultABSTRACT
Background: Immunologically enhanced subcutaneous specific immunotherapy (SCIT) has been developed with a fast and simplified updosing phase containing equal parts of the house dust mites (HDM) Dermatophagoides pteronyssinus and Dermatophagoides farina ( Dermatophagoides mix) adsorbed on aluminum hydroxide. Objective: To evaluate the tolerability and immunological impact of the updosing phase of this new allergen extract formulation. Material and Methods: We performed a multicenter, open-label, single-arm, phase II/III clinical trial. The inclusion criteria were a clinical history of rhinitis/conjunctivitis due to HDM (with/without asthma) and sensitization to HDM (positive specific IgE and skin prick test). Five updosing injections of Dermatophagoides mix (300, 600, 3000, 6000, and 15 000 SQ+) were administered at weekly intervals with 1 maintenance injection (15 000 SQ+) 2 weeks after the last updosing injection. Two days after each visit, patients were contacted by telephone to follow up on any adverse events. IgE-blocking factor, IgG4, and immediate skin reactivity were evaluated. Results: The sample comprised 102 patients (mean [SD] age, 29.3 [7.7] years; male, 52.9%). There were 117 adverse drug reactions (ADR): 101 were local, regardless of reaction size, in 48 (47.1%) patients and 7 were systemic (all grade I) in 5 (4.9%) patients. All ADRs were mild, except for 1, which was moderate. Six weeks of treatment led to statistically significant increases in IgE-blocking factor and IgG4, as well as a significant reduction in immediate skin reactivity. Conclusion: This new updosing phase of Dermatophagoides mixbased immunotherapy had a good tolerability profile and induced a significant immunological effect (AU)
Antecedentes: Se ha desarrollado una mejorada vacuna de inmunoterapia específica (SCIT) adsorbida en hidróxido de aluminio y administración subcutánea con una fase de incremento de dosis más rápida y simplificada que contiene D. pteronyssinus y D. farinae (HDM; Dermatophagoides mezcla) a partes iguales. Objectivo: Evaluar la tolerabilidad de la fase de incremento de dosis de esta nueva formulación de extracto alergénico en SCIT y su impacto inmunológico. Material y Métodos: Ensayo clínico multicéntrico, abierto, de un brazo, fase II/III. Los sujetos que se podían incluir eran pacientes con una historia clínica de rinitis/conjuntivitis a ácaros de polvo doméstico (con/sin asma) y que presentaran sensibilización a HDM (IgE específica y prueba cutánea positiva). Se administraron cinco dosis semanales de Dermatophagoides mezcla en la fase de inicio (300, 600, 3000, 6000 y 15.000 SQ+) y una inyección de mantenimiento (15.000 SQ+) dos semanas tras la última inyección de la fase de incremento de dosis. Dos días tras cada visita se contactó con los pacientes por teléfono para seguir cualquier acontecimiento adverso (AE). Además, se evaluaron la IgG4, factor bloqueante de IgE y la respuesta cutánea inmediata. Resultados: Se incluyeron 102 sujetos en el ensayo (52,9% varones) con una edad media de 29,3±7,7 años. Se notificaron 117 reacciones adversas (RA) relacionadas con el medicamento en investigación: 101 locales, con independencia del tamaño de la reacción, en 48 (47,1%) pacientes y 7 sistémicas, todas grado I, en 5 (4,9%) pacientes. Todas las RA fueron de intensidad leve, excepto una, de intensidad moderada. Tras seis semanas de tratamiento, se obtuvieron incrementos estadísticamente significativos en el factor bloqueante de IgE y en IgG4, así como en la reducción de la respuesta cutánea inmediata. Conclusión: Esta nueva fase de incremento de dosis con inmunoterapia con Dermatophagoides mezcla presenta un buen perfil de tolerabilidad e induce una respuesta inmunológica significativa (AU)
Subject(s)
Humans , Male , Female , Vaccination/instrumentation , Vaccination/methods , Desensitization, Immunologic/classification , Desensitization, Immunologic/methods , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations , Rhinitis/diagnosis , Conjunctivitis, Allergic/metabolism , Vaccination/psychology , Vaccination , Desensitization, Immunologic , Pharmaceutical Preparations/analysis , Pharmaceutical Preparations/supply & distribution , Rhinitis/complications , Conjunctivitis, Allergic/diagnosis , Evaluation Studies as TopicABSTRACT
Precision in the calculation of the size of the wheal caused by the cutaneous response is faced with the problem derived from the variability of such response. The possibility of creating dose-response curves and posterior regression line, allow a comparison of these lines by means of an analysis of covariance. With this method we have analysed different factors which may influence this response. With a sample of 138 healthy subjects we have shown that factors such as: age, sex and time the skin test is carried out, have a significant influence on the size of the wheal. In the same way and with a group of 22 patients with allergy to house dust mites, we have shown that factors such as: age, sex, disease (rhinitis-asthma) or time the skin test is carried out, have no influence on the size of the cutaneous response. We have also shown that the average size of the wheal is smaller in healthy subjects than in allergic patients, presenting regression lines with different slope which allow no further comparison.
