Immunology of Asthma through Biologics Private Practice & St Michael’s Hospital Lecturer, Division of Clinical Immunology & Allergy Department of Medicine, University of Toronto Jason Lee, MD, FRCPC

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 Biologics and asthma is a fascinating topic with a lot of exciting new advances Barnes, JACI. 2012

Biologics are the future Current monoclonal antibodies are the fastest growing segment of the pharmaceutical industry 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

Why use Biologics? Easiest way to form a customized target medication Reduce the number of “collateral damage” thereby limiting side effects 12

What is happening?

Healthy airway Smooth muscle

Cells have no reaction to allergens Healthy airway

With asthma Constricted airway during a n asthma attack Mucus

Cells see allergens as pathogens = With asthma

Major Inflammatory Cells Mast CellEosinophil 12

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 In some asthma patients non-IgE mediated pathways that enhance Th2 cytokines = Even more IgE production

- IgE not acting in Isolation. - Expression of FcεRI receptor has been reported to be increased in fatal asthma Fatal asthm a (n=10) Non-pulmonary d eaths (n=9) Mild-intermittent a sthma † (n=16) *p<0.05 vs other groups; † biopsy Fregonese L, et al. Am J Respir Crit Care Med 2004 (abstract) 1,200 1, FceRI receptor expression in lamina propria (+ cells/mm 2 ) 1,085 *

Eosinophil Activation

Biologics used for asthma OmalizumabAnti-il-5 mAbs 12

Omalizumab

Omalizumab (n=209) Placebo (n=210) ∆ –50.0% p=0.002 Omalizumab (n=209) Placebo (n=210) ∆ –43.9% p=0.038 Severe exacerbation rateTotal emergency visit rate Humbert M, et al. Allergy 2005 Omalizumab significantly reduces severe exacerbation s and emergency visits

Omalizumab significantly reduces the need for systemic corticosteroid bursts Steroid bursts (mean) Omalizumab (n=2,511) Control (n=1,797)) 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;

OCS is reduced or stopped in 79% of patients following omalizumab therapy * Steroid bursts (mean) % ReducedStoppedNot reduced/stopped Patients (%) 54.5 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 , 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