Personalized medicine with biologics for severe type 2 asthma: current status and future prospects

Figures & data

Table 1. Asthma biomarkers used in clinical trials to predict the response to biologics directed at mediators of type 2 asthma.

Biomarker	Strengths	Weaknesses	Companion phenotyping for biologics
Induced sputum cell (eosinophils and neutrophils) analysis	• Correlates with:	• Difficult to obtain	• Good biomarker to adjust treatment with inhaled corticosteroids
	o Airway inflammation	• Expensive	• Has been used to predict the response to anti-IL-5 (e.g., mepolizumab) in specific centers
	o Decreased FEV1	• Technically demanding
	o Increased bronchial hyperresponsiveness	• Time consuming
	o Exacerbation risk	• Not widely available technique
	• Treatment responses (increased sputum eosinophil count significantly correlates with asthma severity)
Blood eosinophil count	• Correlates with airway inflammation• Inexpensive• Easy to obtain (in contrast to induced sputum eosinophil count)• Predictor of response to multiple type 2 targeting therapies	Reduced blood eosinophil countsin patients treated with oral corticosteroids (chronically or oral corticosteroids burst)	• Best predictive and responsive biomarker for anti-IL-5 (e.g., mepolizumab and reslizumab) and anti-IL-5Rα (e.g., benralizumab) • Readily available in clinical practice worldwide • Has been shown to predict the response to anti-IgE
Total serum IgE	• Correlates with airway inflammation • Inexpensive • Easy to obtain • Sensitive	Not specific for allergic asthma	Predictive biomarker for anti-IgE (e.g., omalizumab)
Exhaled nitric oxide	• Correlates with airway inflammation (higher levels of nitric oxide are released from epithelial cells of the bronchial wall) • Easy to obtain • Noninvasive measurement • Indicator of airway IL-13 activity: strongly correlated with the expression of NOS2 in asthmatic airway epithelial brushings (NOS2 is strongly induced in epithelial cells by IL-13)	• Expensive • Not widely available • Influenced by allergy, gender, smoking and inhaled corticosteroids	• Predictive biomarker for anti-IgE (e.g., omalizumab) • Predictive and responsive biomarker for anti-IL-13 (e.g., tralokinuzumab) and anti-IL-4Rα (e.g., dupilumab)
Serum periostin	• Correlates with airway inflammation (accelerates allergen-induced eosinophil recruitment in the lung and esophagus) • Accurate measurement in serum	• Expensive• Not readily available• Weak association with airway periostin level	Has been used as:• predictive biomarker for anti-IgE (e.g., omalizumab)• predictive and responsive biomarker for anti-IL-13 (e.g., tralokinuzumab) and anti-IL-4Rα (e.g., dupilumab)

FEV₁: forced expiratory volume in 1 second; IL: interleukin; IgE: immunoglobulin E; IL-4Rα: interleukin-4 receptor alpha; IL-5Rα: interleukin-5 receptor alpha; NOS2: nitric oxide synthase.

Table 2. Characteristics of type 2 and non-type 2 airway inflammations in asthma.

Asthma	Atopy	Airway inflammation	Sputum-based cellular analysis	Natural history	Clinical and physiological features	Pathobiology and biomarkers	Response to therapy	Comorbidities
Type 2	Atopic	Early-onset allergic eosinophilic asthma	≥3% sputum eosinophils and <76% sputum neutrophils	• Early age of onset • Most patients have mild-to-moderate asthma; rarely severe since childhood or deterioration in adulthood	• Allergic symptoms/recurrent exacerbations/sensitization/atopy • Increased blood eosinophil count, sputum eosinophils, IgE and high or normal FENO • Strong family history (related genetic factors)	• Specific IgE • TH2 cytokines • FENO • TH2-related genes (17q12) • Subbasement membrane thickness • Sputum and blood eosinophil counts (≥300 cells per μL)	Responsive to inhaled corticosteroids and to anti-IgE	• Allergic rhinitis • Allergic dermatitis
	Nonatopic	Late-onset nonallergic eosinophilic asthma		• Adult age of onset • Severe from onset	• Sinusitis • Less allergic • Recurrent exacerbations • High FENO and serum IgE • Reduced pulmonary function despite shorter disease duration	• Corticosteroid-refractory eosinophilia • IL-5 • FENO • Sputum and blood eosinophil counts (≥300 cells per μL)	• Relatively corticosteroid-refractory or requires higher doses/oral corticosteroids • Responsive to anti-IL-4/IL-13 and anti-IL-4Rα	• Chronic rhinosinusitis • Nasal polyps
Non-type 2	Nonatopic	Neutrophilic	<3% sputum eosinophils and ≥76% sputum neutrophils	Adult age of onset	• Low FEV1 • More air trapping • Bacterial infection • Increased sputum neutrophil count • Severe airway obstruction	• TH17 pathways • IL-8 • Sputum neutrophil count	• Corticosteroid insensitive (steroids can enhance airway neutrophilia by inhibiting neutrophil apoptosis and by promoting neutrophil activation) • Responsive to anti-LTB4 (adults and children) and macrolides (adults and children)	• Respiratory infections • Obesity • Smoking • Air pollution
	Nonatopic	Paucigranulocytic	<3% sputum eosinophils and <76% sputum neutrophils	Adult age of onset	?	?	?
	Nonatopic	Mixed granulocytic	≥3% sputum eosinophils and ≥76% sputum neutrophils	• Adult age of onset • Severe from onset	• High FENO • Granulomas • Increased sputum eosinophils and neutrophils	• FENO • Sputum neutrophil and eosinophil counts	?

Type 2 airway inflammation in asthma consists of both early- and later-onset diseases over a range of severities. It is likely that most of early-onset allergic asthma is mild, but that an increasing complexity of immune processes leads to greater severity. Additionally, later-onset nonallergic eosinophilic asthma without traditional allergic elements is more likely to be severe. Non-type 2 airway inflammation in asthma consists of later-onset diseases including neutrophilic, paucigranulocytic and mixed granulocytic asthma. Note that the sputum-based cellular analysis presented here was defined by Demarche et al., 2016.¹⁸ FE_NO: fractional exhaled nitric oxide; FEV₁: forced expiratory volume in 1 second; IL: interleukin; IgE: immunoglobulin E; LTB4: leukotriene B4; T_H2: T-helper type 2 cell; T_H17: T-helper type 17 cell.

Figure 1. Simplified schematic representation of four different types of airway inflammation in asthmatic patients. (A) Type 2 consists of allergic and nonallergic eosinophilic asthma. (a) In allergic eosinophilic asthma, T-helper type 2 (T_H2) cell lymphocytes and mast cells drive eosinophilic airway inflammation in an allergen-specific, immunoglobulin E (IgE)-dependent manner. (b) In nonallergic eosinophilic asthma, innate lymphocytes such as natural killer T cells (NKT cells) and innate lymphoid cells type 2 (ILC2) cells might contribute to airway eosinophilia via the production of interleukin (IL)-5, in response to pollutants or infectious agents. (B) Non-type 2 consists of neutrophilic and paucigranulocytic asthma. (c) The mechanisms underlying neutrophilic asthma need to be elucidated, but the IL-17 pathway and CXCL8 have been associated with the airway neutrophilia. More precisely, IL-17A and IL-17F play important roles in host responses to extracellular pathogens via the upregulation of antimicrobial proteins and induction of cytokines and chemokines involved in neutrophil expansion (e.g., GM-CSF) and recruitment (e.g., CXCR ligands). (d) Paucigranulocytic asthma has been poorly studied. It is thought to be not inflammatory and is characterized by the absence of increased numbers of inflammatory cells, suggesting the involvement of non-inflammatory mechanisms mediated by airway remodeling responses that lead to extensive airway narrowing. The biologics being evaluated in clinical trials or already approved as add-on treatment, on top of high-doses inhaled corticosteroid (ICS) and a short- or long-acting β₂-adrenergic agonist (LABA), for (C) allergic and (D) nonallergic eosinophilic asthma are depicted in light grey. CRTH₂: prostaglandin D2 receptor 2; CXCL8: C-X-C motif chemokine ligand 8; CXCR: C-X-C chemokine receptor; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; FcϵRI: Fc epsilon receptor I; GM-CSF: granulocyte-macrophage colony-stimulating factor; ICS: inhaled corticosteroid; IgE: immunoglobulin epsilon; ILC2: innate lymphoid cell type 2; IL: interleukin; IL-4Rα: interleukin-4 receptor alpha; IL-5Rα: interleukin-5 receptor alpha; IL-9R: interleukin-9 receptor; IL-25R: interleukin-25 receptor; IL-33R: interleukin-33 receptor; LABA: long-acting β₂-adrenergic; MHC: major histocompatibility complex; NKT: natural killer T; PGD₂: prostaglandin D2; TCR: T-cell receptor; T_H2: T-helper type 2 cell; T_H17: T-helper type 17 cell; TSLP: thymic stromal lymphoietin; TSLPR: thymic stromal lymphoietin receptor.

Table 3. Biologics evaluated for the treatment of moderate-to-severe type 2 asthma.

Target	Cell(s) targeted	International non-proprietary, proprietary and common name	Format, species and development technology	Company	Mechanism	Developmental and regulatory approval status
IgE	• Mast cells	• Omalizumab	• IgG1κ	• Genentech	Targets the Cϵ3 domain of IgE	Phase 4:
	• Basophils	• XOLAIR®• rhuMab-E25	• Humanized• Hybridoma technology	• Novartis		• FDA (June 20, 2003) and EMA (25 October 2005) approvals as add-on therapy to treat moderate-to-severe persistent allergic asthma, having a positive skin test or in vitro reactivity to an airborne allergen and symptoms that are inadequately controlled with inhaled corticosteroids, in patients 12 years and older.
						• EMA (January 23, 2014) and FDA (July 07, 2016) approvals in children six to 11 years of age.
IL-13	• Structural cells	• Lebrikizumab• MILR1444A/RG3637	• IgG4κ• Humanized	• Chugai Pharmaceutical	Targets specifically IL-13	Phase 3, discontinued
	• Macrophages			• Genentech
	• B cells			• Roche
				• Tanox
		• Tralokinumab	• IgG4λ	• Astrazeneca	Targets specifically IL-13	Phase 3
		• CAT-354	• Homo sapiens	• LEO Pharma
			• Cambridge Antibody Technology	• MedImmune
IL-4Rα/ IL-4	• Structural cells	• Dupilumab• DUPIXENT®	• IgG4κ• Homo sapiens	• Regeneron Pharmaceuticals	Targets specifically IL-4Rα, inhibiting IL-4 and IL-13 signaling pathways	Phase 3
	• T cells			• Sanofi
	• Macrophages• B cells	• REGN668/SAR23 1893	• VelocImmune®
		• Pitrakinra	15-kDa recombinant human IL-4 variant	• Aerovance	Inhibits binding IL-4 and/or IL-13 to IL-4Rα	Phase 3, discontinued
		• AEROVANT®		• Bayer
		• AER 001
		• Altrakincept	54-kDa soluble recombinant extracellular portion of the human IL-4Rα	• Amgen	Targets specifically and inactivates IL-4 without mediating cellular activation	Phase 2, discontinued
		• NUVANCE®
		• AMG 317	• IgG2κ	• Amgen	Targets specifically IL-4Rα, inhibiting IL-4 and IL-13 signaling pathways	Phase 2, discontinued
			• Homo sapiens
IL-5	Eosinophils	• Mepolizumab	• IgG1κ	• GlaxoSmithKline	Targets specifically IL-5	Phase 4: FDA (November 04, 2015) and EMA (02 December 2015) approvals as an add-on maintenance treatment of patients with severe asthma aged 12 years and older, with an eosinophilic phenotype
		• NUCALA®	• Humanized
		• SB-240563
		• Reslizumab	• IgG4κ	• UCB Celltech	Targets specifically IL-5	Phase 4: FDA (CINQAIR®, 23 March 2016) and EMA (CINQARO®, 23 June 2016) approvals for use with other asthma medicines for the maintenance treatment of severe eosinophilic asthma in patients aged 18 years and older
		• CINQAIR® (US)/ CINQAERO® (EU)	• Humanized	• Schering-Plough
		• JES1-39D10		• Teva Pharmaceuticals
IL-5Rα	• Eosinophils	• Benralizumab	• Afucosylated IgG1κ	• Astrazeneca	Binds and induces depletion of IL-5Rα-expressing target cells by antibody-mediated cellular toxicity	Phase 3
	• Basophils	• KHK4563, MEDI-563	• Humanized	• MedImmune
			• POTELLIGENT®	• Kyowa Hakko Kirin

The hybridoma technology corresponds to the process of fusion between different somatic cells to produce hybrid cells in which there is often one fused nucleus. The core focus of the Cambridge Antibody Technology was partly on phage and ribosome display technologies, allowing the discovery of tralokinumab. VelocImmune® is the technology developed by Regeneron Pharmaceuticals, for producing fully human monoclonal antibodies from immunized humanized mice. BioWa, Inc., a member of the Kyowa Hakko Kirin Group, is the exclusive licensor of the POTELLIGENT® technology, which enables monoclonal antibodies to be manufactured in 100% fucose-free form, resulting in significant enhancement of antibody-dependent cellular cytotoxicity and tumor cell-killing activity. EMA: European medicines agency; FDA: food drug administration; IgE: immunoglobulin epsilon; IgG: immunoglobulin gamma; IL: interleukin; IL-4Rα: interleukin-4 receptor alpha; IL-5Rα: interleukin-5 receptor alpha.

Figure 2. Simplified schematic representation of targeted T_H2 and T_H17 cytokines therapies that can lead to amplification of activity of the opposing pathway in a murine house dust mite model of asthma.⁷³ (A) With suppression of T_H2 activity by targeted therapy or corticosteroids, a T_H17-permissive environment exists. A direct relationship between T_H17 and T_H2 disease exists, whereby, through mutual cross regulation, T_H17 asthma may represent a transition or switch away from T_H2-mediated disease. Thus, by treating T_H2 patients with corticosteroids, T_H17 asthma may have been promoted. (B) Combination therapy targeting T_H2 cytokine, such as interleukin-13, and T_H17 cytokine, such as interleukin-17, in patients expressing either a T_H2 or T_H17 signature may provide additional efficacy over single T_H2 or T_H17 inhibition. T_H2: T-helper type 2 cell; T_H17: T-helper type 17 cell.

Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, Jia G, Ohri CM, Doran E, Vannella KM, et al. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci Transl Med. 2015;7:301ra129. doi:10.1126/scitranslmed.aab3142. PMID:26290411.

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