L eosinofilo come nuovo target terapeutico. Paola Parronchi
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1 L eosinofilo come nuovo target terapeutico Paola Parronchi XXX Congresso SIAAIC Sezione Toscana IX Congresso Sezione SIAAIC Toscana, Emilia Romagna, San Marino Firenze, Ottobre 2014
2 Benign and sinister eosinophils Variety of diseases Blood eosinophilia Tissue eosinophilia Homeostatic role Defense against helminths Tissue damage Tissue fibrosis Hypercoagulability
3 The complex interactions between eosinophils and immune cells Nature Reviews Immunology 13, 9-22 (January 2013)
4 Eosinophils as offenders or general bystanders? Growth factors? No stimuli Resting state
5 Eosinophils as offenders or general bystanders? Ig Danger signals Cytokines Growth factors? No stimuli Immuno regulation Resting state Growth factors Cytokines
6 Eosinophils as offenders or general bystanders? Ig Danger signals Cytokines Growth factors? No stimuli Immuno regulation Growth factors Cytokines Granule proteins Inflammatory mediators Resting state Proinflammatory Microbes Adhesion Immobilized Ig
7 Major causes of hypereosinophilia Reactive Non neoplastic -Helminth infections -Scabies and infestations -Allergic bronchopulmonary aspergillosis -Drug reactions -Allergic reactions -Atopic diseases -Chronic GvHD -IBD -Autoimmune diseases -L-HES Expert Rev Hematol April ; 5(2): Paraneoplastic -HDG -B or T cell lymphomas -Langerhans cell histiocytosis -Solid tumors/malignancies Neoplastic -Chronic eosinophilic leukemia -Hematopoietic neoplasms with abnormalities in PDGFRA or B or FGFR1 - CML and AML -MDS, MNP/MDS, JAK2 V617F MPN -Idiopathic HEUS
8 Therapeutic options in Eosinophilia Interference with recruitment Interference with survival
9 Corticosteroids: the ordinary way to defeat eosinophils
10 Major stimulators of eosinophils GM-CSF IL-5 IL-3 Modified from Semin Hematol April ; 49(2): Trafficking Survival, Degranulation Activation Adherence Cytokine production
11 IL-5 is essential for eosinophil physiology IL-5 Modified from Semin Hematol April ; 49(2): Differentiation Chemotaxis Proliferation
12 Anti-IL-5 strategies as powerful therapies in eosinophil-mediated diseases Mepolizumab (Bosatria) IL-5 Reslizumab (Cinquil SCH55700) Differentiation Chemotaxis Proliferation
13 Anti-IL-5 strategies as powerful therapies in eosinophil-mediated diseases Mepolizumab (Bosatria) IL-5 Reslizumab (Cinquil SCH55700) Differentiation Chemotaxis Proliferation Benralizumab (Medi-563)
14 Anti-IL-5 strategies as powerful therapies in eosinophil-mediated diseases Mepolizumab (Bosatria) IL-5 Reslizumab (Cinquil SCH55700) Differentiation Chemotaxis Proliferation Benralizumab (Medi-563)
15 Anti-IL-5 strategies. Mepolizumab: from failure to DREAMs FEV1 Symptom score Exacerbations AJRCCM Vol
16 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.
17 Anti-IL-5 strategies. Mepolizumab: from failure to DREAMs
18 Mepolizumab in severe eosinophilic asthma High dose inhalant GCs MENSA group p 0.02 p 0.03 p 0.001
19 Mepolizumab in severe eosinophilic asthma Regular oral GCs SIRIUS group p 0.04 p 0.007
20 Anti-IL-5 strategies. Reslizumab: a still open resource
21 Anti-IL-5 strategies. Reslizumab: a still open resource Eosinophilic esophagitis
22 Anti-IL-5 strategies. Reslizumab: a still open resource Eosinophilic esophagitis
23 Anti-IL-5 strategies. Benralizumab:a promise for future Reduction of eosinophil infiltration Highly efficient ADCC
24 Bronchial biopsy Bone marrow
25 Bronchial biopsy Bone marrow
26 Eosinophils and Th2 cytokines in asthma Nature Medicine 2013; 19:
27 Eosinophils and Th2 cytokines in asthma Anti-IL-4Rα Pitrakinra (Aerovant) Reduces allergen-induced late-phase asthmatic response (Phase II) IL-4 variant AMG 317 (Phase II) Ineffective Dupilumab (Phase II/III) Reduces exacerbations, improves FEV1 Anti-IL-4Rα mab Anti-IL-4Rα mab Nature Medicine 2013; 19:
28 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 (IMA-638) (Phase II) Anti-IL-13 mab Reduces allergen-induced early and late asthmatic response GSK (Phase I/II) Anti-IL-13 mab Disappointing results Nature Medicine 2013; 19:
29 Lebrikizumab as anti-il-13 mab in asthma
30 The complex network of signals acting on eosinophil IL-1 IL-2 IL-4 IL-13 IL-16 IL-25 IL-27 IL-33 TSLP VEGF Angiopoietin PDGF RANTES MCP-3 MCP-4 Eotaxin-1 Eotaxin-2 Eotaxin-3 SDF-1 PAF C3a C5a TLR1, 4, 7, 9, 10 VIP IL-10 IL-12 TGF-beta IFN-alfa IFN-gamma Siglec-8 GCs
31 Eosinophil surface markers and products
32 Eosinophil surface markers and products
33 Eosinophil surface markers and products Some Some of of these these regulatory regulatory cytokines cytokines and and eosinophil eosinophil surface surface molecules molecules are are unique unique to to eosinophils eosinophils and and have have been been actively actively studied studied as as potential potential therapeutic therapeutic targets targets for for eosinophilic eosinophilic diseases diseases
34 Eosinophil surface markers and products Some Some of of these these regulatory regulatory cytokines cytokines and and eosinophil eosinophil surface surface molecules molecules are are unique unique to to eosinophils eosinophils and and have have been been actively actively studied studied as as potential potential therapeutic therapeutic targets targets for for eosinophilic eosinophilic diseases diseases
35 Are inhibitors of Eos receptors novel potential drugs? TPI ASM8 Antisense ODN (inhaled) GW (per os) SpliceSwitching ODN YM NCT No benefits
36 Are inhibitors of Eos receptors novel potential drugs? CAT-213 YM Bertilimumab No clear benefits
37 Are inhibitors of Eos receptors novel potential drugs? 2002
38 Eosinophil surface markers and products
39 The anti-crth2 antagonists Infiltration Chemotaxis IgE
40 The anti-crth2 antagonists AMG 853 OC000459
41 The anti-crth2 antagonist OC Eos > 250/μl p Eos < 250/μl R. Pettipher (Atopix Therapeutics Ltd) et al, Allergy 69 (2014)
42 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 (2):
43 Eosinophil surface markers and products
44
45
46 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
47 Tailoring biologic therapies on the patients phenotype
48 New therapeutic strategies for treating Eosinophilia
49
50
51 Università degli Studi di Firenze Dipartimento di Medicina Sperimentale e Clinica Centro di Alta Specializzazione DENOTHE (dir. Prof. Enrico Maggi)
52 The activity of omalizumab on eosinophils
53 The activity of omalizumab on eosinophils
54 The activity of omalizumab on eosinophils
55 The activity of omalizumab on eosinophils
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