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Biological Therapy for Asthma

PCCSU Volume 25, Lesson 5

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

Hardware/software requirements: Web browsing device with working Web browser.

PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Sheharyar R. Durrani, MD; and William W. Busse, MD

Dr. Durrani is Fellow, Allergy and Clinical Immunology, and Dr. Busse is Professor of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Dr. Durrani and Dr. Busse have disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this chapter.

Objectives

  1. Describe, in detail, the two domains of asthma control.
  2. Detail why the heterogeneity of asthma is important in treatment selection.
  3. Summarize the clinical effects of omalizumab on asthma, as well as the current indications for its use in the treatment of asthma.
  4. Detail the importance of eosinophils in asthma and describe the phenotype of asthma that benefits most from interleukin-5 antagonism in early human clinical trials.
  5. Summarize the overall safety of biologics and discuss the importance of future safety studies.

Key words: antiasthmatic agents; antibodies; asthma; cytokines; drug therapy; immunologic factors; immunoglobulin E; immunology; interleukin-5; monoclonal; treatment outcome

Abbreviations: Ab = antibody; CRTH2 = chemoattractant receptor-homologous molecule expressed on TH2 cells; IL = interleukin; IL-4Rα = α-chain interleukin-4 receptor; PGD2 = prostaglandin D2; TH = helper T cell; TNF = tumor necrosis factor; Treg = regulatory T cell; VH = variable domain of an antibody heavy chain; VL = variable domain of an antibody light chain

Although asthma is characterized by variable airflow obstruction, airway inflammation, and bronchial hyperresponsiveness, it is becoming increasingly apparent that this disease is extremely heterogeneous.1 This heterogeneity manifests itself in multiple clinical presentations and variable responses to treatment. Treatment response variability has undoubtedly posed the greatest limitation to achieving optimal control of asthma for some patients. It has been difficult to achieve the recommended degree of control in more than 50% of patients under some circumstances, despite appropriate treatment.2 Thus, new treatments may offer a major step forward in improving asthma control in more patients.

In addition, the clinical end points used to assess the effectiveness of new treatments have expanded beyond pulmonary function improvements with the recognition that other outcomes—eg, exacerbations, symptoms, and quality of life—are also important to the patient and to controlling health-care costs. Moreover, correlations between lung function and other parameters of asthma often have not always been demonstrated.3

Based on these observations, the assessment of asthma control has shifted and expanded to two domains: impairment and future risk. The “impairment” domain includes symptoms, pulmonary function, and need for acute rescue treatment. The “future risk” domain includes exacerbations, loss of lung function, and medication side effects. As a result of this expanded focus, asthma is a disease whose morbidity now must be viewed as more than simply airflow obstruction, although the reversal of airflow obstruction remains important. Asthma’s heterogeneous nature needs to be considered in the selection of treatment options, and it can yield insights for new treatments that may be more effective in selected populations of asthma patients. This expanded consideration of asthma also marks a movement to more personalized treatment for some patients.

With increased insight into the basic mechanisms of asthma and the immunologic basis of much of the disease’s pathophysiology, researchers have developed biologics to modulate underlying immune processes. These biological therapies can influence asthma or a component of asthma, which may be integral to the clinical aspects of the disease and result in improved control. Building on this knowledge and rapidly expanding technology, treatments directed at mediator-releasing cells (mast cells and basophils), inflammatory cells (eosinophils, neutrophils, and basophils), products of inflammation (cytokines and chemokines), and transcription factors are now being developed and evaluated. Because many of these products have a limited effect on pulmonary function, their usefulness is reflected in other outcomes, such as symptoms, prevention or reduction of exacerbations, reduction of corticosteroid use (inhaled and/or oral), and quality of life. The following review will focus on biological modulators currently in use or in an advanced stage of development (Table 1), including inhibitors of IgE (omalizumab), cytokines (interleukin [IL]-4, IL-13, and IL-5), and chemoattractant receptor-homologous molecule expressed on helper T (TH2) cells (CRTH2).


Table 1Summary of Some of the Biologic Therapies Currently Used or Under Investigation for the Treatment of Asthma

Therapy Target/Mechanism of Action Clinical Benefits
Anti-IgE
Omalizumab Monoclonal Ab against IgE; decreases IgE levels; results in down-regulation of IgE receptor. Rodrigo et al5: Systematic review of eight trials (3,429 patients) showed decreases in exacerbations, dose of inhaled and oral corticosteroids, and hospitalizations, and improvement in quality of life when used as add-on therapy. No improvement in lung function.
Modulation of cytokines
Altrakincept Solubilized IL-4 receptor fragment, neutralizes IL-4 (altrakincept). Adcock et al11: Altrakincept reportedly failed to show efficacy in large phase 3 trial.
Pascolizumab Monoclonal Ab against IL- 4 (pascolizumab). Hart et al12 : Phase 2 study of pascolizumab discontinued because of inefficacy.
Pitrakinra IL-4 mutant protein. Binds to alpha subunit of IL-4 receptor (pitrakinra). Wenzel et al13: Inhaled form of pitrakinra improved pulmonary function and decreased exhaled nitric oxide in two phase 2a studies.
CAT-354/IMA- 638/QAX576 Monoclonal Abs against IL-13. Dimov et al29 : Preliminary reports suggest efficacy in phase 2 studies.
Mepolizumab Monoclonal Ab against IL-5. Haldar et al20 and Nair et al21: Demonstrated decrease in asthma exacerbations, increase in quality of life, decrease in need for prednisone in patients with severe, refractory, eosinophilic asthma.

 


 

Anti-Immunoglobulin E

IgE contributes to the pathophysiology of allergic asthma. Omalizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody (Ab) and binds to the Fc portion of free IgE to prevent its attachment to the Fcε receptor of mast cells, basophils, and dendritic cells (Fig 1). This action also decreases circulating IgE, which in turn leads to a downregulation of IgE receptor expression. Approved in 2003, omalizumab was the first biologic agent used in the treatment of asthma.4


L6Fig1

Figure 1. Mechanism of action of biologic therapies in reducing airway inflammation. At bottom of figure: Pathways of cytokine/IgE-induced airway inflammation in asthma. Agents currently in use or in development are illustrated. Red octagon indicates inhibition as mechanism of action. IFN-γ = interferon-gamma; IgE, immunoglobulin E; TGF-β = transforming growth factor-β; TH0 = TH0 cell; TH1 = TH1 cell; TH2 = TH2 cell. Adapted from Adcock et al.11


Numerous studies have established the efficacy and safety of omalizumab in adolescents and adults.5 Recently, a systematic review by Rodrigo and colleagues5 of eight placebo controlled trials (3,429 patients) using omalizumab as an add-on therapy confirmed that use of omalizumab decreased asthma exacerbations and the dose of corticosteroids (inhaled and oral) needed to control asthma. Additionally, hospitalizations for asthma exacerbations were reduced and patients reported a clinically significant overall improvement in quality of life. Lung function, however, did not improve.5

Two studies in children found omalizumab to be efficacious and safe; nonetheless, additional studies that focus exclusively on pediatric populations are needed to fully assess the use of anti-IgE in children.6,7 Furthermore, studies of mild to moderate asthma in all age groups are needed, as the majority of trials have been limited to patients with severe asthma.

Based on available information, the 2007 National Asthma Education and Prevention Program Expert Panel 3 positioned omalizumab as add-on therapy for adolescents (age ≥12 years) and adults with severe allergic asthma who have reached steps 5 and 6 of guideline care.8 Because there have been reports in the literature of anaphylaxis with omalizumab administration, the Expert Panel also recommended that clinicians should be prepared to treat anaphylaxis when administering omalizumab, even though this event is very rare.8,9

Modulation of Cytokines

Interleukin-4 and Interleukin-13
Many of the pathophysiologic processes associated with asthma have been attributed to cytokines produced by TH2 lymphocytes and as a result, these cytokines have become attractive therapeutic targets. IL-4 induces B-cell IgE isotype switching and promotes the differentiation of naive lymphocytes (TH0) to TH2 lymphocytes, which in turn leads to release of IL-4, IL-5, and IL-13 (Fig 1).10 A secreted form of α-chain IL-4 receptor (IL-4Rα) binds and neutralizes IL-4. In early studies of a soluble recombinant IL-4R, altrakincept, it was found to be well tolerated and prevented a decline in FEV1 during inhaled corticosteroid withdrawal10; however, subsequent clinical trials did not confirm this finding and the development of this product was stopped.11 Additionally, pascolizumab (humanized anti-IL-4 monoclonal Ab) did not demonstrate clinical efficacy in a large-scale, multidose, phase II trial.12

That approach to interrupting the actions of IL-4 was ineffective, but potentially exciting treatments directed towards IL-4’s receptor are in development. Both IL-4 and IL-13 bind to IL-4Rα, leading to downstream signaling and eventual biologic effects. The redundancy of the IL-4/IL-13/IL-4Rα complex has been thought to be a possible mechanism for the failure of IL-4 antagonists in trials. A recombinant human IL-4 mutant protein, pitrakinra, competitively inhibits the IL-4α complex to interfere with the actions of both IL-4 and IL-13.13 Two formulations of pitrakinra were found to decrease exhaled nitric oxide, decrease the late-phase response to an allergen challenge, and improve pulmonary function in two phase IIa studies.13 Further studies are currently underway.

Finally, humanized anti-IL-13-specific antibodies were found to be well tolerated and safe in phase I studies. Multiple antibodies against IL-13, including CAT-354, are undergoing clinical trials for asthma.14

Interleukin-5
IL-5 and its receptor are also therapeutic targets based on eosinophils’ role in many aspects of asthma and the biology of IL-5. For example, IL-5 prolongs survival, promotes terminal differentiation, and causes bone marrow release of eosinophils.15 Although the exact mechanisms are not fully defined, eosinophilic inflammation is thought to play a prominent role in the pathophysiology of asthma.16 It has also been estimated that 40% to 60% of asthmatic subjects have eosinophilic airway inflammation, and the concentration of sputum eosinophils predicts a risk for asthma exacerbations.17,18 The targeting of IL-5 to influence eosinophilic inflammation is also supported by studies demonstrating a correlation between increased IL-5 concentrations in bronchial samples of asthmatic patients15 and upregulation of IL-5 mRNA in bronchial mucosa after allergen challenge.15

Mepolizumab, a human recombinant anti-IL-5 monoclonal Ab, has been found to be safe and efficacious in patients with the hypereosinophilic syndrome.15 Subsequently, and surprisingly, several early clinical studies in asthma found that although mepolizumab significantly decreased peripheral blood and sputum eosinophils and, to a lesser extent, bronchial and bone-marrow eosinophils,19 no clinically significant changes in clinical end points (eg, exacerbations, quality of life, or FEV1) were observed.19

Recently, the results of two randomized, placebo-controlled, parallel-group studies of mepolizumab were reported in subpopulations of asthma patients who had severe, exacerbation-prone disease that was refractory to usual treatment and also had persistent airway eosinophilia.20,21 In these studies, mepolizumab significantly reduced exacerbation rates in patients with persistent eosinophilic asthma despite high doses of inhaled or systemic corticosteroids.15 It is likely that previous mepolizumab investigators had not selected asthma patients with ongoing airway eosinophilia to demonstrate the benefit of this immunomodulator.15 These studies also point out the importance of the presence of airway eosinophils in the risk for asthma exacerbation, even though the associated mechanism is not clear.

The IL-5 receptor is expressed on eosinophils, basophils, and possibly mast cells. MEDI-563 is a compound that binds to the alpha subunit of the IL-5 receptor, activating complement locally to lyse the eosinophil.16 A recent phase I trial of MEDI-563 showed an acceptable safety profile and a decrease in peripheral blood eosinophils.16 No data are available on its use in clinical asthma at this time.

Tumor Necrosis Factor-α
Initial enthusiasm for anti-tumor necrosis factor (TNF)-α therapy in asthma has been tempered by a recent double-blind, placebo-controlled study by Wenzel and coworkers22 evaluating golimumab, an anti-TNF-α monoclonal antibody, in 309 people with asthma.22 The study was terminated early owing to severe adverse effects, including pneumonia, sepsis, increased rate of malignancy, and one death. Although studies have demonstrated efficacy in certain subgroups of asthma patients,23,24 the significant side-effect profile demonstrated by the Wenzel and colleagues study22 likely precludes future use of TNF-α inhibitors in asthma.

Prostaglandin D2
Prostaglandin D2 (PGD2) is a key mediator in various inflammatory diseases, including allergy and asthma. PGD2 stimulates chemotaxis of inflammatory cells, induces secretion of proinflammatory cytokines, causes sustained bronchoconstriction, and indirectly promotes IgE production.25 PGD2 mediates its biological functions via a distinct G protein-coupled receptor, CRTH2. CRTH2 receptors are currently being considered as highly promising therapeutic targets for combating allergic diseases and asthma.25 The only phase II study published (numerous other studies have been performed but not published) compared oral treatment with a CRTH2 antagonist vs placebo over a 28-day treatment period in patients with moderate-persistent asthma who were not using inhaled corticosteroids.25 These patients showed significant beneficial effects with respect to FEV1, peak flow, circulating IgE levels, nighttime asthma symptoms, and quality of life.25

Safety of Biologic Agents in Asthma

A recent review of the literature9 found that anaphylaxis and other treatment-related serious events occurred infrequently with the biological agents reviewed. Most cytokine therapies under investigation have been well tolerated, with the exception of anti-TNF-α therapy in asthma; with anti-TNF-α treatment, an increased risk of infections and malignancies was demonstrated.9,22

While the studies demonstrating the safety of biologics are reassuring, the clinical trials were performed in relatively small patient populations and were of relatively short duration. Long-term studies in large patient populations are needed to clarify the risk-benefit profile of these biologic agents in the treatment of asthma.9

The Future of Biologics

Nanobodies
Significant formatting and manufacturing issues remain with conventional Abs. In addition to the inherent problem of using mammalian expression systems, the large size (150 kDa) of most therapeutic Abs remains a fundamental problem for the majority of therapeutic Abs that are currently being developed.26 Large molecules have the inherent problems of poor penetration into certain tissues, difficulty in accessing the binding regions of some molecules, low stability in certain environments, and solubility.27 The next generation of antibody-based therapeutics—single-domain antibodies or nanobodies—may address many of these issues. Nanobodies are the smallest functional antigen-binding fragment (12 to 15 kDa) composed of either the variable domain of an antibody heavy chain (VH) or the variable domain of an antibody light chain (VL). Nanobodies were originally engineered from camelid heavy chain Abs, but phage display technology now allows generation of expansive libraries of very specific, high-affinity nanobodies that can be produced in a matter of weeks. In addition to small size and a short half-life, nanobodies can be imbued with unique biophysical and pharmacologic properties, most notably the creation of VH-VL pairings that bind two different antigens. This advantage is not possible with conventional monoclonal IgG therapeutic Abs.27

Tregitopes
Recently, two highly promiscuous major histocompatibility complex (MHC) class II T-cell epitopes in the Fc fragment of IgG that are capable of specifically activating natural regulatory T cells (Tregs) were identified. Co-incubation of these regulatory T-cell epitopes, or Tregitopes, and antigens with peripheral blood mononuclear cells led to suppression of effector cytokine secretion, reduced the proliferation of effector T cells, and caused an increase in cell surface markers associated with Tregs, such as FoxP3.28 In mice, administration of a homologue of the Fc region Tregitope resulted in what is believed to be tolerance rather than immunogenicity owing to activation of a subset of Treg cells. This study represents another exciting possible therapeutic modality that needs to be developed and studied in human clinical trials.28

Conclusion

Biological agents designed to modulate the immune response in asthma have been of considerable interest and have the potential to fill significant unmet needs, most notably in subpopulations, or phenotypes, of patients with asthma—primarily those with more severe disease. This approach has also provided additional insight into the mechanisms of asthma as these agents create a therapeutic “knockout” by antagonizing specific mediators. These interventions have also had effects on aspects of asthma outside of lung function or in addition to it. Most importantly, these new agents have the potential improve the care of asthma patients.


References

  1. Lemanske RF Jr, Busse WW. Asthma: clinical expression and molecular mechanisms. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S95-S102.
  2. Bateman ED, Boushey HA, Bousquet J, et al; GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med. 2004;170(8):836-844.
  3. Reddel HK, Taylor DR, Bateman ED, et al; American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59-99.
  4. Ballow M. Biologic immune modifiers: trials and tribulations—are we there yet? J Allergy Clin Immunol. 2006;118(6):1209-1215; quiz 1216-1217.
  5. Rodrigo GJ, Neffen H, Castro-Rodriguez JA. Efficacy and safety of subcutaneous omalizumab vs placebo as add-on therapy to corticosteroids for children and adults with asthma: a systematic review. Chest. 2010;139(1):28-35.
  6. Lanier B, Bridges T, Kulus M, Taylor AF, Berhane I, Vidaurre CF. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J Allergy Clin Immunol. 2009;124(6):1210-1216.
  7. Milgrom H, Berger W, Nayak A, et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics. 2001;108(2):E36.
  8. National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. http://www.nhlbi.nih.gov/guidelines/asthma. Published August 2007. Updated August 2008. Accessed February 7, 2011.
  9. Cox LS. How safe are the biologicals in treating asthma and rhinitis? Allergy Asthma Clin Immunol. 2009;5(1):4.
  10. Borish LC, Nelson HS, Corren J, et al; IL-4R Asthma Study Group. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol. 2001;107(6):963-970.
  11. Adcock IM, Caramori G, Chung KF. New targets for drug development in asthma. Lancet. 2008;372(9643):1073-1087.
  12. Hart TK, Blackburn MN, Brigham-Burke M, et al. Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma. Clin Exp Immunol. 2002;130(1):93-100.
  13. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 2007;370(9596):1422-1431.
  14. Desai D, Brightling C. Cytokine and anti-cytokine therapy in asthma: ready for the clinic? Clin Exp Immunol. 2009;158(1):10-19.
  15. Busse WW, Ring J, Huss-Marp J, Kahn JE. A review of treatment with mepolizumab, an anti-IL-5 mAb, in hypereosinophilic syndromes and asthma. J Allergy Clin Immunol. 2010;125(4):803-813.
  16. Busse WW, Katial R, Gossage D, et al. Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma. J Allergy Clin Immunol. 2010;125(6):1237-1244.e2.
  17. Zhang JY, Wenzel SE. Tissue and BAL based biomarkers in asthma. Immunol Allergy Clin North Am. 2007;27(4):623-632; vi.
  18. Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med. 1990;323(15):1033-1039.
  19. Flood-Page P, Swenson C, Faiferman I, et al; International Mepolizumab Study Group. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176(11):1062-1071.
  20. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360(10):973-984.
  21. Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360(10):985-993.
  22. Wenzel SE, Barnes PJ, Bleecker ER, et al; T03 Asthma Investigators. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med. 2009;179(7):549-558.
  23. Berry MA, Hargadon B, Shelley M, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. The N Engl J Med. 2006;354(7):697-708.
  24. Howarth PH, Babu KS, Arshad HS, et al. Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax. 2005;60(12):1012-1018.
  25. Schuligoi R, Sturm E, Luschnig P, et al. CRTH2 and D-type prostanoid receptor antagonists as novel therapeutic agents for inflammatory diseases. Pharmacology. 2010;85(6):372-382.
  26. Holt LJ, Herring C, Jespers LS, Woolven BP, Tomlinson IM. Domain antibodies: proteins for therapy. Trends Biotechnol. 2003;21(11):484-490.
  27. Dimitrov DS. Engineered CH2 domains (nanoantibodies). MAbs. 2009;1(1):26-28
  28. De Groot AS, Moise L, McMurry JA, et al. Activation of natural regulatory T cells by IgG Fc-derived peptide “Tregitopes.” Blood. 2008;112(8):3303-3311.
  29. Dimov VV, Stokes JR, Casale TB. Immunomodulators in asthma therapy. Curr Allergy Asthma Rep. 2009;9(6):475-483.