Emerging monoclonal antibodies as targeted innovative therapeutic approaches to asthma

Abstract

Asthma is characterized by discordant responses among cells of the adaptive and innate immune systems. This interplay involves a complex pattern of cytokine-driven processes resulting in cell migration and recruitment, inflammation, and proliferative states. The significant majority of asthmatic patients respond well to conventional inhaled treatments. However, about 5% of asthmatics have severe refractory asthma and account for 50% of the health expenditure on asthma. Human(ized) monoclonal antibodies (hMabs) targeting inflammatory pathways are promising therapeutic agents in asthma management. The anti-IgE hMab omalizumab was the first biologic treatment approved for the treatment of allergic asthma. Potential future strategies and targets include interleukin (IL)-5, IL-4, and IL-13, anti-TSLP, IL-25, and IL-33. hMabs targeting IL-5 have shown great promise in severe refractory asthma with a persisting eosinophilia, and clinical trials with hMabs against IL-13 and IL4Rα have also shown clinical benefit. Studies of hMabs against other cytokines in severe asthma are under way.

Perfil de seguridad infecciosa para el uso de terapia biológica en asma con mepolizumab y omalizumab

“…Además, se ha informado que omalizumab tiene como efecto alternativo disminuir la densidad del receptor de alta afinidad para IgE (FcεRI) en los mastocitos y basófilos. Estos mediadores químicos desempeñan un papel en la eosinofilia, inflamación de los tejidos, hiperrespuesta y cambios estructurales de las vías respiratorias, a menudo observadas en pacientes con asma alérgica (1)(2)(3)(4).…”

“…Asimismo, por su papel en la eosinofilia se aprobó por la FDA para el uso en la urticaria crónica idiopá-tica en adultos y adolescentes >12 años con síntomas (4). Como indicaciones alternativas también se utiliza para el tratamiento de rinitis alérgica, poliposis nasal, aspergilosis broncopulmonar, alergia al látex, dermatitis atópica, anafilaxia, angioedema idiopático y mastocitosis (7,8).…”

“…Por esta razón, esta revisión se enfocará en estos dos medicamentos para conocer su perfil de seguridad infecciosa (3,4).…”

Human(ized) Monoclonal Antibodies in Asthma: Future Perspectives

“…Discriminating the complex systemic inflammatory and regulatory pathways underlying the immunopathogenesis of SPA has allowed the development of potent inhibitors at the cytokine/receptor level. This specific targeting minimizes the risks of side effects [2].…”

“…Approved HMA for the treatment of SPA in Phase II studies are as follows ; quilizumab (directed against an extracellular 52-aminoacid segment termed M1 prime of human membrane IgE through reduction of new IgE-producing plasma cells), ligelizumab (Binds C3 domain of IgE), dupilumab (Binds IL-4Ra inhibiting both IL-4 and IL-13 signaling), AMG 317 (AMG 317 is a fully human monoclonal IgG2 antibody to IL-4R), AMG 157(Human anti-TSLP monoclonal immunoglobulin G2k that specifically binds human TSLP), pitrakinra (Recombinant human IL-4 variant that is a potent inhibitor of both the IL-4 and IL-13 receptors), altrakincept (Soluble recombinant human IL-4 receptor: Phase III study completed), pascolizumab (Humanized mAb blocking IL-4), lebrikizumab (IgG4 humanized monoclonal antibody that binds IL-13 with high affinity), tralokinumab (IL-13-specific human monoclonal antibody that binds to and neutralizes IL-13: Phase III study ongoing), anrukinzumab (IMA-638 and IMA-026) (Fully humanized IgG [1], antibodies that bind to different epitopes and neutralize IL-13 bioactivity), mepolizumab (Anti IL-5 humanized IgG1 monoclonal antibody: Awaiting FDA and EBM approval), reslizumab (Humanized monoclonal anti-IL-5 antibody (IgG4/k): Phase III studies completed) , benralizumab (Humanized, afucosylated monoclonal antibody against IL-5Ra), brodalumab (Human IL-17RA-specific monoclonal antibody), secukinumab (Anti-IL-17 monoclonal antibody that selectively neutralizes IL-17A), eculizumab (mAb (a hybrid of IgG2 and IgG4 Fc portion) cleaves and deactivates C5) [2].…”