L’eosinofilo come nuovo target terapeutico Paola Parronchi XXX Congresso SIAAIC Sezione Toscana IX Congresso Sezione SIAAIC Toscana, Emilia Romagna, San Marino Firenze, 10-11 Ottobre 2014
Benign and sinister eosinophils Variety of diseases Homeostatic role Blood Tissue Defense against eosinophilia eosinophilia helminths Tissue damage Tissue fibrosis Hypercoagulability
The complex interactions between eosinophils and immune cells Nature Reviews Immunology 13, 9-22 (January 2013)
Eosinophils as offenders or general bystanders ? Growth factors ? Resting state No stimuli
Eosinophils as offenders or general bystanders ? Ig Growth factors Danger signals Cytokines Cytokines Immuno regulation Growth factors ? Resting state No stimuli
Eosinophils as offenders or general bystanders ? Ig Growth factors Danger signals Cytokines Cytokines Immuno regulation Granule proteins Inflammatory mediators Growth factors ? Resting Pro- state inflammatory Microbes No stimuli Adhesion Immobilized Ig
Major causes of hypereosinophilia Reactive Paraneoplastic Non neoplastic -HDG -B or T cell lymphomas -Helminth infections -Langerhans cell histiocytosis -Scabies and infestations -Solid tumors/malignancies -Allergic bronchopulmonary aspergillosis Neoplastic -Drug reactions -Allergic reactions -Chronic eosinophilic leukemia -Atopic diseases -Hematopoietic neoplasms -Chronic GvHD with abnormalities in PDGFRA -IBD or B or FGFR1 -Autoimmune diseases - CML and AML -L-HES -MDS, MNP/MDS, JAK2 V617F MPN -Idiopathic HEUS Expert Rev Hematol. 2012 April ; 5(2): 157–176
Therapeutic options in Eosinophilia Interference with recruitment Interference with survival
Corticosteroids: the ordinary way to defeat eosinophils
Major stimulators of eosinophils Trafficking GM-CSF Survival, Degranulation IL-5 Activation Adherence Cytokine IL-3 production Modified from Semin Hematol. 2012 April ; 49(2): 113–119
IL-5 is essential for eosinophil physiology Differentiation IL-5 Chemotaxis Proliferation Modified from Semin Hematol. 2012 April ; 49(2): 113–119
Anti-IL-5 strategies as powerful therapies in eosinophil-mediated diseases Mepolizumab (Bosatria) Differentiation IL-5 Chemotaxis Proliferation Reslizumab (Cinquil SCH55700)
Anti-IL-5 strategies as powerful therapies in eosinophil-mediated diseases Mepolizumab (Bosatria) Differentiation IL-5 Chemotaxis Proliferation Reslizumab (Cinquil SCH55700) Benralizumab (Medi-563)
Anti-IL-5 strategies as powerful therapies in eosinophil-mediated diseases Mepolizumab (Bosatria) Differentiation Differentiation IL-5 Chemotaxis Chemotaxis Proliferation Proliferation Reslizumab (Cinquil SCH55700) Benralizumab (Medi-563)
Anti-IL-5 strategies. Mepolizumab: from failure to DREAMs FEV1 Symptom score Exacerbations AJRCCM Vol 176 2007
Anti-IL-5 strategies. Mepolizumab: from failure to DREAMs These effects are very promising and give hope to many patients for whom no effective drugs are available without significant adverse effects.
Anti-IL-5 strategies. Mepolizumab: from failure to DREAMs
Mepolizumab in severe eosinophilic asthma MENSA group High dose inhalant GCs p 0.02 p 0.03 p 0.001
Mepolizumab in severe eosinophilic asthma SIRIUS group Regular oral GCs p 0.04 p 0.007
Anti-IL-5 strategies. Reslizumab: a still open resource
Anti-IL-5 strategies. Reslizumab: a still open resource Eosinophilic esophagitis
Anti-IL-5 strategies. Reslizumab: a still open resource Eosinophilic esophagitis
Anti-IL-5 strategies. Benralizumab:a promise for future Reduction of eosinophil infiltration Highly efficient ADCC
Bronchial biopsy Bone marrow
Bronchial biopsy Bone marrow
Eosinophils and Th2 cytokines in asthma Nature Medicine 2013; 19: 977–979
Eosinophils and Th2 cytokines in asthma Anti-IL-4Rα Reduces allergen-induced late-phase Pitrakinra (Aerovant) asthmatic response (Phase II) IL-4 variant Ineffective AMG 317 (Phase II) Anti-IL-4Rα mAb Dupilumab Reduces exacerbations, improves (Phase II/III) FEV1 Anti-IL-4Rα mAb Nature Medicine 2013; 19: 977–979
Eosinophils and Th2 cytokines in asthma Anti-IL-13 Lebrikizumab Improves asthma control in high- (Phase II/III) anti-IL-13 mAb periostin group vs no FEV1 improvement Tralokinumab (Phase I/II) Anti-IL-13 mAb Ineffective Anrukinzumab Reduces allergen-induced early (IMA-638) and late asthmatic response (Phase II) Anti-IL-13 mAb GSK679586 Disappointing results (Phase I/II) Anti-IL-13 mAb Nature Medicine 2013; 19: 977–979
Lebrikizumab as anti-IL-13 mAb in asthma
The complex network of signals acting on eosinophil IL-1 RANTES IL-10 IL-2 MCP-3 IL-12 IL-4 MCP-4 TGF-beta IL-13 Eotaxin-1 IFN-alfa IL-16 Eotaxin-2 IFN-gamma IL-25 Eotaxin-3 Siglec-8 IL-27 SDF-1 GCs IL-33 PAF TSLP C3a VEGF C5a Angiopoietin TLR1, 4, 7, 9, 10 PDGF VIP FGF
Eosinophil surface markers and products
Eosinophil surface markers and products
Eosinophil surface markers and products Some of these regulatory cytokines and Some of these regulatory cytokines and Some of these regulatory cytokines and Some of these regulatory cytokines and eosinophil surface molecules are unique to eosinophils and eosinophil surface molecules are unique to eosinophils and eosinophil surface molecules are unique to eosinophils and eosinophil surface molecules are unique to eosinophils and have been actively studied as potential therapeutic targets have been actively studied as potential therapeutic targets have been actively studied as potential therapeutic targets have been actively studied as potential therapeutic targets for for for for eosinophilic diseases eosinophilic diseases eosinophilic diseases eosinophilic diseases
Eosinophil surface markers and products Some of these regulatory cytokines and Some of these regulatory cytokines and Some of these regulatory cytokines and Some of these regulatory cytokines and eosinophil surface molecules are unique unique to eosinophils and to eosinophils and eosinophil surface molecules are eosinophil surface molecules are unique unique to eosinophils and to eosinophils and eosinophil surface molecules are have been actively studied as potential therapeutic targets have been actively studied as potential therapeutic targets have been actively studied as potential therapeutic targets have been actively studied as potential therapeutic targets for for for for eosinophilic diseases eosinophilic diseases eosinophilic diseases eosinophilic diseases
Are inhibitors of Eos receptors novel potential drugs ? TPI ASM8 GW766994 Antisense ODN (per os) (inhaled) Splice- YM-355179 Switching ODN NCT01160224 No benefits
Are inhibitors of Eos receptors novel potential drugs ? YM-355179 CAT-213 Bertilimumab No clear benefits
Are inhibitors of Eos receptors novel potential drugs ? 2002
Eosinophil surface markers and products
The anti-CRTH2 antagonists Infiltration Chemotaxis IgE
The anti-CRTH2 antagonists AMG 853 OC000459
The anti-CRTH2 antagonist OC000459 Eos > 250/μl p 0.037 Eos < 250/μl R. Pettipher (Atopix Therapeutics Ltd) et al, Allergy 69 (2014) 1223–1232
The anti-CRTH2 antagonist AMG853 AMG 853 as an add-on to inhaled corticosteroid therapy demonstrated no associated risks but was not effective at improving asthma symptoms or lung function in patients with inadequately controlled moderate-to-severe asthma Busse WW et al. J Allergy Clin Immunol 2013 131(2):339–345
Eosinophil surface markers and products
Conclusions -Diseases characterized by eosinophilia are heterogeneous and eosinophils may accumulate in the peripheral blood, tissues or both - several targets are currently being investigated with variable promises -why a specific targeyted therapy works in some but not in all patients with eosinophilia remains unclear - biomarkers, if any, that accurately predict responsiveness to therapy need to be identified
Tailoring biologic therapies on the patients’ phenotype
New therapeutic strategies for treating Eosinophilia
Università degli Studi di Firenze Dipartimento di Medicina Sperimentale e Clinica Centro di Alta Specializzazione DENOTHE (dir. Prof. Enrico Maggi)
The activity of omalizumab on eosinophils
The activity of omalizumab on eosinophils
The activity of omalizumab on eosinophils
The activity of omalizumab on eosinophils
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