Immunology of Asthma
through Biologics
Jason Lee, MD, FRCPC
Private Practice & St Michael’s Hospital
Lecturer, Division of Clinical Immunology & Allergy
Department of Medicine, University of Toronto
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 t
reatment approaches  learn the immunology
Why the need for Biologics?
Patients with severe asthma who are uncontrolled
with maximum doses of inhaled “conventional”
therapies
Although only 5% of all asthmatic patients are severe
and these patients represent ~50% of health care
spending Barnes, JACI. 2012
Biologics and asthma is a fascinating topic with
a lot of exciting new advances
Biologics are the future
Current monoclonal antibodies are the fastest
growing segment of the pharmaceutical industry
Albrecht H, Radosevich JA, Babich M. Fundamentals of antibody-related therapy
and diagnostics. Drugs Today (Barc) 2009
Produced based on understanding the underlying
immunology:
-Cytokines
-Monoclonal antibodies
-Fusion proteins
Why use Biologics?
1
Easiest way to
form a customized
target medication
2
Reduce the number
of “collateral damage”
thereby limiting
side effects
What is happening?
Healthy airway
Smooth muscle
Healthy airway
Cells have no reaction to allergens
With asthma
Constricted airway during a
n asthma attack
Mucus
With asthma
Cells see allergens as pathogens
=
Major Inflammatory Cells
1
2
Mast Cell
Eosinophil
Mast Cell Activation
Role of IgE in Asthma
Initially controversial
IgE cross-linking leads to :
- More IL4
- More CD40L on T cells
- Induction of Eosinophilic inflammation
= Even more IgE production
In some asthma patients non-IgE mediated
pathways that enhance Th2 cytokines
- IgE not acting in Isolation.
- Expression of FcεRI receptor has been reported to be
increased in fatal asthma
FceRI receptor expression2in
lamina propria (+ cells/mm )
1,085
*
1,200
1,000
800
600
400
328
302
Non-pulmonary d
eaths
(n=9)
Mild-intermittent
a
†
sthma
(n=16)
200
0
*p<0.05 vs other groups; †biopsy
Fatal asthm
a
(n=10)
Fregonese L, et al. Am J Respir Crit Care Med 2004 (abstract)
Eosinophil Activation
Biologics used for asthma
1
2
Omalizumab
Anti-il-5 mAbs
Omalizumab
Omalizumab significantly reduces severe exacerbation
s and emergency visits
0.6
Severe exacerbation rate
∆ –50.0%
p=0.002
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0
0.6
Total emergency visit rate
∆ –43.9%
p=0.038
0.1
Omalizumab
(n=209)
Placebo
(n=210)
0
Omalizumab
(n=209)
Placebo
(n=210)
Humbert M, et al. Allergy 2005
Omalizumab significantly reduces
the need for systemic corticosteroid bursts
Relative risk: –43.0%
p<0.001
Steroid bursts (mean)
0.8
0.6
0.6
0.4
0.4
0.2
0
Omalizumab
(n=2,511)
Control
(n=1,797))
Maykut R, et al. J Allergy Clin Immunol 2006 (abstract)
Busse W, et al. Curr Med Res Opin 2007;2379-2386
OCS is reduced or stopped in 79%
of patients following omalizumab therapy*
Steroid bursts (mean)
78.8%
Patients (%)
60
54.5
50
40
30
24.2
21.2
20
10
0
Reduced
Stopped
Not reduced/stopped
Niven R, et al. Thorax 2007 (abstract)
Anti-IL-5 mAbs
Mepolizumab
- Has been shown to reduce bronchial mucosa
eosinophilia
- In a subgroup: has clinical improvement or FEV1, B
HR, peak flows
- Reduces some extracellular matrix protein
remodeling
- 100% reduction in sputum eosinophils and airway
eosinophils by 55%
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
Thank you!
Q&A
MD, FRCPC