Immunology of Asthma through Biologics
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Immunology of Asthma through Biologics
Private Practice & St Michael’s Hospital
Lecturer, Division of Clinical Immunology & Al-lergy Department of Medicine, University of Toronto
Jason Lee, MD, FR-CPC
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Learning Objectives
To understand the pathophysiologic basis of biologics in asthma
To become familiar with various biologics that have been tried for asthma and the rationale behind these treatment approaches learn the immunology
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Why the need for Biologics?
Patients with severe asthma who are uncon-trolled with maximum doses of inhaled “conven-tional” therapies Although only 5% of all asthmatic patients are severe and these patients represent ~50% of health care spending
Biologics and asthma is a fascinating topic with a lot of exciting new advances
Barnes, JACI. 2012
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Biologics are the future
Current monoclonal antibodies are the fastest growing segment of the pharmaceutical in-dustry
Produced based on understanding the underlying immunology:
-Cytokines -Monoclonal antibodies -Fusion proteins
Albrecht H, Radosevich JA, Babich M. Fundamentals of antibody-related therapy and diagnostics. Drugs Today (Barc) 2009
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Why use Biolog-ics?
Easiest way to form a custom-
izedtarget medication
Reduce the num-ber
of “collateral damage” thereby
limitingside effects
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What is happen-ing?
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Healthy air-way
Smooth muscle
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Cells have no reaction to aller-gens
Healthy air-way
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With asthma
Constricted airway dur-ing an asthma attack
Mucus
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Cells see allergens as pathogens
=
With asthma
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Major Inflammatory Cells
Mast Cell Eosinophil
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Mast Cell Activa-tion
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Role of IgE in Asthma
Initially controversial
IgE cross-linking leads to : - More IL4 - More CD40L on T cells - Induction of Eosinophilic inflammation
In some asthma patients non-IgE mediated pathways that enhance Th2 cytokines
= Even more IgE production
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- IgE not acting in Isolation. - Expression of FcεRI receptor has been reported to be increased in fatal asthma
302328
Fatal asthma(n=10)
Non-pulmonary deaths(n=9)
Mild-intermit-tent asthma†
(n=16)
*p<0.05 vs other groups; †biopsy Fregonese L, et al. Am J Respir Crit Care Med 2004 (abstract)
1,2001,000
800600400200
0
FceRI receptor expression in lamina propria (+ cells/mm2)
1,085*
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Eosinophil Activa-tion
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Biologics used for asthma
Omalizumab Anti-il-5 mAbs
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Omal-izumab
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Omalizumab(n=209)
Placebo(n=210)
0.6
0.5
0.4
0.3
0.2
0.1
0
∆ –50.0%p=0.002
Omalizumab(n=209)
Placebo(n=210)
0.6
0.5
0.4
0.3
0.2
0.1
0
∆ –43.9%p=0.038
Severe exacerbation rate Total emergency visit rate
Humbert M, et al. Allergy 2005
Omalizumab significantly reduces severe ex-acerbations and emergency visits
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Omalizumab significantly reducesthe need for systemic corticosteroid bursts
0.4
0.6
Steroid bursts (mean)
Omalizumab(n=2,511)
Control(n=1,797))
0.8
0.6
0.4
0.2
0
Relative risk: –43.0%p<0.001
Maykut R, et al. J Allergy Clin Immunol 2006 (abstract)Busse W, et al. Curr Med Res Opin 2007;2379-2386
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OCS is reduced or stopped in 79% of patients following omalizumab therapy*
Steroid bursts (mean)
24.221.2
60
50
40
30
20
10
0
78.8%
Reduced Stopped Not reduced/stopped
Patients (%)
54.5
Niven R, et al. Thorax 2007 (abstract)
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Anti-IL-5 mAbs
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Mepolizumab
- Has been shown to reduce bronchial mucosa eosinophilia
- In a subgroup: has clinical improvement or FEV1, BHR, peak flows
- Reduces some extracellular matrix protein remodeling
- 100% reduction in sputum eosinophils and airway eosinophils by 55%
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Future Therapies
- TGF-B - Anti-IL-4 - Anti-IL-5 - Anti-IL-9 - Anti-IL-13 - Inhibition of Th2 cytokines - Inhaled anti-inflammatories targeting neutrophils - Novel classes of bronchodilators (Ro 25-1553, Rho kinase inhibitors - Targeting neutrophilic inflammatory mediators - Masitinib -> a tyrosine kinase inhibitor that blocks c-Kit - Cytokine receptor antagonists - TLR 4 and 9 agonists - Syk Kinase inhibitors - GATA3 antagonists
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Thank you! Q&A
Jason Lee MD, FRCPC