Leosinofilo come nuovo target terapeutico Paola Parronchi XXX - - PowerPoint PPT Presentation

▶
l eosinofilo come nuovo target terapeutico
SMART_READER_LITE
LIVE PREVIEW

Leosinofilo come nuovo target terapeutico Paola Parronchi XXX - - PowerPoint PPT Presentation

Sep 19, 2022 114 likes •679 views

Leosinofilo 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

slide-1
SLIDE 1

XXX Congresso SIAAIC Sezione Toscana IX Congresso Sezione SIAAIC Toscana, Emilia Romagna, San Marino Firenze, 10-11 Ottobre 2014

L’eosinofilo come nuovo target terapeutico

Paola Parronchi

slide-2
SLIDE 2

Benign and sinister eosinophils Homeostatic role Variety of diseases

Defense against helminths Blood eosinophilia Tissue eosinophilia

Tissue fibrosis Tissue damage Hypercoagulability

slide-3
SLIDE 3

Nature Reviews Immunology 13, 9-22 (January 2013)

The complex interactions between eosinophils and immune cells

slide-4
SLIDE 4

Eosinophils as offenders or general bystanders ?

Resting state Growth factors ? No stimuli

slide-5
SLIDE 5

Eosinophils as offenders or general bystanders ?

Resting state Immuno regulation Growth factors ? No stimuli Ig Danger signals Cytokines Growth factors Cytokines

slide-6
SLIDE 6

Eosinophils as offenders or general bystanders ?

Resting state Immuno regulation Pro- inflammatory Growth factors ? No stimuli Ig Danger signals Cytokines Growth factors Cytokines Microbes Adhesion Immobilized Ig Granule proteins Inflammatory mediators

slide-7
SLIDE 7

Major causes of hypereosinophilia

Neoplastic

  • Chronic eosinophilic leukemia
  • Hematopoietic neoplasms

with abnormalities in PDGFRA

  • r B or FGFR1
  • CML and AML
  • MDS, MNP/MDS, JAK2

V617F MPN

  • Idiopathic HEUS

Reactive Non neoplastic

  • Helminth infections
  • Scabies and infestations
  • Allergic bronchopulmonary

aspergillosis

  • Drug reactions
  • Allergic reactions
  • Atopic diseases
  • Chronic GvHD
  • IBD
  • Autoimmune diseases
  • L-HES

Paraneoplastic

  • HDG
  • B or T cell lymphomas
  • Langerhans cell histiocytosis
  • Solid tumors/malignancies

Expert Rev Hematol. 2012 April ; 5(2): 157–176

slide-8
SLIDE 8

Interference with survival Interference with recruitment

Therapeutic options in Eosinophilia

slide-9
SLIDE 9

Corticosteroids: the ordinary way to defeat eosinophils

slide-10
SLIDE 10

Major stimulators of eosinophils GM-CSF IL-5 IL-3

Trafficking Survival, Degranulation Activation Adherence Cytokine production

Modified from Semin Hematol. 2012 April ; 49(2): 113–119

slide-11
SLIDE 11

IL-5 is essential for eosinophil physiology

IL-5

Differentiation Chemotaxis Proliferation

Modified from Semin Hematol. 2012 April ; 49(2): 113–119

slide-12
SLIDE 12

Anti-IL-5 strategies as powerful therapies in eosinophil-mediated diseases

IL-5

Differentiation Chemotaxis Proliferation

Mepolizumab (Bosatria) Reslizumab (Cinquil SCH55700)

slide-13
SLIDE 13

Anti-IL-5 strategies as powerful therapies in eosinophil-mediated diseases

IL-5

Differentiation Chemotaxis Proliferation

Mepolizumab (Bosatria) Reslizumab (Cinquil SCH55700) Benralizumab (Medi-563)

slide-14
SLIDE 14

Anti-IL-5 strategies as powerful therapies in eosinophil-mediated diseases

IL-5

Differentiation Differentiation Chemotaxis Chemotaxis Proliferation Proliferation

Mepolizumab (Bosatria) Reslizumab (Cinquil SCH55700) Benralizumab (Medi-563)

slide-15
SLIDE 15

Anti-IL-5 strategies. Mepolizumab: from failure to DREAMs

FEV1 Exacerbations Symptom score

AJRCCM Vol 176 2007

slide-16
SLIDE 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.

slide-17
SLIDE 17

Anti-IL-5 strategies. Mepolizumab: from failure to DREAMs

slide-18
SLIDE 18

Mepolizumab in severe eosinophilic asthma

p 0.02 p 0.03 p 0.001

MENSA group

High dose inhalant GCs

slide-19
SLIDE 19

Mepolizumab in severe eosinophilic asthma

Regular oral GCs

SIRIUS group

p 0.007 p 0.04

slide-20
SLIDE 20

Anti-IL-5 strategies. Reslizumab: a still open resource

slide-21
SLIDE 21

Anti-IL-5 strategies. Reslizumab: a still open resource

Eosinophilic esophagitis

slide-22
SLIDE 22

Anti-IL-5 strategies. Reslizumab: a still open resource Eosinophilic esophagitis

slide-23
SLIDE 23

Anti-IL-5 strategies. Benralizumab:a promise for future

Reduction of eosinophil infiltration Highly efficient ADCC

slide-24
SLIDE 24

Bone marrow Bronchial biopsy

slide-25
SLIDE 25

Bone marrow Bronchial biopsy

slide-26
SLIDE 26

Eosinophils and Th2 cytokines in asthma

Nature Medicine 2013; 19: 977–979

slide-27
SLIDE 27

Eosinophils and Th2 cytokines in asthma

Nature Medicine 2013; 19: 977–979

Anti-IL-4Rα Pitrakinra (Aerovant)  (Phase II) IL-4 variant AMG 317  (Phase II)

Anti-IL-4Rα mAb

Dupilumab (Phase II/III)

Anti-IL-4Rα mAb

Reduces allergen-induced late-phase asthmatic response Ineffective Reduces exacerbations, improves FEV1

slide-28
SLIDE 28

Eosinophils and Th2 cytokines in asthma

Nature Medicine 2013; 19: 977–979

Anti-IL-13 Lebrikizumab  (Phase II/III) anti-IL-13 mAb Tralokinumab (Phase I/II) Anti-IL-13 mAb Anrukinzumab (IMA-638) (Phase II) Anti-IL-13 mAb GSK679586 (Phase I/II) Anti-IL-13 mAb Improves asthma control in high- periostin group vs no FEV1 improvement Ineffective Reduces allergen-induced early and late asthmatic response Disappointing results

slide-29
SLIDE 29

Lebrikizumab as anti-IL-13 mAb in asthma

slide-30
SLIDE 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 FGF IL-10 IL-12 TGF-beta IFN-alfa IFN-gamma Siglec-8 GCs RANTES MCP-3 MCP-4 Eotaxin-1 Eotaxin-2 Eotaxin-3 SDF-1 PAF C3a C5a TLR1, 4, 7, 9, 10 VIP

slide-31
SLIDE 31

Eosinophil surface markers and products

slide-32
SLIDE 32

Eosinophil surface markers and products

slide-33
SLIDE 33

Eosinophil surface markers and products

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 have been actively studied as potential therapeutic targets have been actively studied as potential therapeutic targets for for eosinophilic diseases eosinophilic diseases 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 have been actively studied as potential therapeutic targets have been actively studied as potential therapeutic targets for for eosinophilic diseases eosinophilic diseases

slide-34
SLIDE 34

Eosinophil surface markers and products

Some of these regulatory cytokines and Some of these regulatory cytokines and eosinophil surface molecules are eosinophil surface molecules are unique unique to eosinophils and to eosinophils and have been actively studied as potential therapeutic targets have been actively studied as potential therapeutic targets for for eosinophilic diseases eosinophilic diseases Some of these regulatory cytokines and Some of these regulatory cytokines and eosinophil surface molecules are eosinophil surface molecules are unique unique to eosinophils and to eosinophils and have been actively studied as potential therapeutic targets have been actively studied as potential therapeutic targets for for eosinophilic diseases eosinophilic diseases

slide-35
SLIDE 35

TPI ASM8 Antisense ODN (inhaled) YM-355179 NCT01160224 GW766994 (per os) Splice- Switching ODN

No benefits Are inhibitors of Eos receptors novel potential drugs ?

slide-36
SLIDE 36

No clear benefits Are inhibitors of Eos receptors novel potential drugs ?

CAT-213

Bertilimumab

YM-355179

slide-37
SLIDE 37

Are inhibitors of Eos receptors novel potential drugs ?

2002

slide-38
SLIDE 38

Eosinophil surface markers and products

slide-39
SLIDE 39

The anti-CRTH2 antagonists

Infiltration Chemotaxis IgE

slide-40
SLIDE 40

The anti-CRTH2 antagonists

OC000459 AMG 853

slide-41
SLIDE 41

The anti-CRTH2 antagonist OC000459

  • R. Pettipher (Atopix Therapeutics Ltd) et al, Allergy 69 (2014) 1223–1232

Eos < 250/μl Eos > 250/μl

p 0.037

slide-42
SLIDE 42

The anti-CRTH2 antagonist AMG853

Busse WW et al. J Allergy Clin Immunol 2013 131(2):339–345

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

slide-43
SLIDE 43

Eosinophil surface markers and products

slide-44
SLIDE 44
slide-45
SLIDE 45
slide-46
SLIDE 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

slide-47
SLIDE 47

Tailoring biologic therapies on the patients’ phenotype

slide-48
SLIDE 48

New therapeutic strategies for treating Eosinophilia

slide-49
SLIDE 49
slide-50
SLIDE 50
slide-51
SLIDE 51

Università degli Studi di Firenze

Dipartimento di Medicina Sperimentale e Clinica Centro di Alta Specializzazione DENOTHE (dir. Prof. Enrico Maggi)

slide-52
SLIDE 52

The activity of omalizumab on eosinophils

slide-53
SLIDE 53

The activity of omalizumab on eosinophils

slide-54
SLIDE 54

The activity of omalizumab on eosinophils

slide-55
SLIDE 55

The activity of omalizumab on eosinophils