Immunotherapy in Asthma

胡雅姿藥師 CONTENT

 過敏炎症反應的調節機制  氣喘免疫治療藥物分類。 1.Subcutaneous immunotherapy 2.Sublingual immunotherapy 3.Anti-IgE therapy 4.TLR4 agonist conjugate 5.Recombinant allergens 6. Anti-IL-4 (13)、 Anti-IL-5 、Anti-TNF(Novel Anti- Inflammatory Treatments for Asthma)  未來發展: 1.TLR agonists and antagonists 2.DNA vaccines 3.Cytokine vaccines 4.Anti-IL-9, -17, -18 and -25

過敏炎症反應的調節機制

 Chronic inflammatory remodeling airflow obstruction within the lung

 Cytokines(細胞激素)(interleukin) Th 2 immune response Asthma Allergic response and potential sites for modulation. LTC4: Leukotriene C4; PGD: Phosphogluconate dehydrogenase; SCIT: Subcutaneous immunotherapy; TCR: T-cell receptor; TLR: Toll-like receptor; http://www.medscape.com/viewarticle/731067_8 Treg: Regulatory T cell. Chemokines and Cytokines

 The damaged lung epithelium increased levels of arginase reduces bronchodilatory and antiproliferative nitric oxide (NO) promotes the release of amino acids and polyamines regulating smooth muscle remodeling Classical Immunotherapy (Allergen Immunotherapy)  Subcutaneous Immunotherapy allergen administered grass pollen, dust mite

 Sublingual Immunotherapy allergen administered Langerhans-like dendritic cells in the oral mucosa grass pollen, dust mite

(hyposensitization) Modified Allergen Immunotherapy

 Recombinant  Allergoids  Adjuvants  Peptides  DNA Vaccines  Cytosine Phosphorothioate Guanosine & Toll-like Receptor Conjugates

Monoclonal Antibodies to Cytokines

 cell proliferation, survival and differentiation (i.e., IL-2, IL-4, IL-13、 IL- 9 and IL-12)  inflammatory response (i.e., IL-5, IL-17, IL-18, IL-25 and TNF-α).

Anti-IL-4/-13 based therapy in asthma Anti-CD25 & anti-IL-2

 Daclizumab is a monoclonal antibody that binds to the CD25 subunit of the high-affinity IL-2 receptor ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ FDA Approved: relapsing forms of multiple sclerosis (MS). Anti-IgE therapy

 Most asthmatic patients have elevated circulating immunoglobulin E (IgE) concentrations  Anti-CD23 Monoclonals to IgE: Omalizumab( Xolair ®)

 interleukin-4 (IL-4) interleukin-13 (IL-13) Omalizumab( Xolair *)  Monoclonals to IgE( high-affinity IgE receptor FcεR， Anti-CD23) 以測病患的 IgE 值藉以計算劑量 至少 需要 12 週的治療 每四週投與一次 每二週投與一次 健保:15856元

皮下注射 Lumiliximab

 Lumiliximab is a primatised monoclonal antibody against FcεRII(CD23， receptor for IgE) that has already been shown to block IgE synthesis in human B-cells and reduce serum IgE levels

http://err.ersjournals.com/content/24/138/594 IL-4 & IL-13

 Tralokinumab (IL-13)  Lebrikizumab (IL-13)  Dupilumab (IL-4 and IL-13) FDA: Atopic Dermatitis May 18, 2015 Regeneron and Sanofi Announce Positive Pivotal Phase 2b Dupilumab Data in Asthma  Pitakinra (IL-4 and IL-13) A Phase 2b Study Of Inhaled Pitrakinra 2011

Anti-IL-4/-13 based therapy in asthma(2015) Anti-IL5

A comparative study of Anti-IL5 trials in Asthma

 Mepolizumab (NUCALA®) FDA Approved 2015 Leckie 2000 Bȕttner 2003 Flood-page 2003 Nair 2009 Haldar 2009 Pavord 2012 Ortega 2014 Bel 2014

®  Reslizumab (CINQAIR ) FDA Approved 2016 Kips 2003 Castro 2011 Corren 2014 Bjermer 2014

 Benralizumab Busse 2010 Laviolette 2013 Castro 2014

World Allergy Organ J. 2014; 7(1): 32. Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma Mepolizumab (NUCALA®)

 100 mg administered subcutaneously once every 4 weeks

Adverse Effects Headache (19%) Systemic reactions, allergic and nonallergic (10%) Injection site reaction (8%) 台灣:有藥證、不給付 皮下注射 Reslizumab(CINQAIR®)

 indicated for add-on maintenance treatment of patients with severe asthma aged ≥18 years with an eosinophilic phenotype  3 mg/kg IV q4wk infused over 20-50 minutes

Adverse Effects: Elevated CPK (14%) Oropharyngeal pain (2.6%) 台灣:無藥證 Benralizumab

 AstraZeneca announces positive results from benralizumab phase III programme in severe asthma 2016/5/17 Anti-TNF  The discovery of increased TNF-α expression in BALF and bronchial biopsy tissue in severe asthmatics  A major source of TNF-α production in the airways is the mast cell Anti-TNF

 TNF-α :airway inflammation and late- phase airway responsiveness.  Infliximab: study  Etanercept: study  Adalimumab: none  TNF-α agents can cause reactivation of chronic infections, such as TB. 未來發展

 TLR agonists and antagonists  DNA vaccines  Cytokine vaccines  Anti-IL-9, -17, -18 and -25

TLR agonists and antagonists Anti-IL-9

 IL-9 is a cytokine produced by CD4+ T cells (mainly of the Th2 subtype)  In clinical studies, patients with allergic asthma have been shown to have increased levels of both the IL-9 protein and its receptor in BAL fluid Anti-IL-17 Anti-IL-18

 IL-18 induces airway hyperresponsiveness and pulmonary inflammation via CD4+ T cell and IL- 13.

IL-18 Induces Airway Hyperresponsiveness in Asthma 2013 Anti-IL-25

 IL-25 Promotes Th2 Immunity Responses in Asthma

IL-25 Promotes Th2 Immunity Responses in Asthmatic Mice via Nuocytes Activation 2016 THE END