Treatment

Abstract

The present disclosure relates to use of an anti-IL-13Rα1 antibody or a binding fragment thereof and pharmaceutical formulations comprising the same to treat patients for airway hyper- responsiveness, including diseases or conditions associated with airway hyperresponsiveness, for example chronic pulmonary obstructive disease (COPD).

Description

[0001] TREATMENT

[0002] The present disclosure relates to use of an anti-IL-13Ral antibody or a binding fragment thereof and pharmaceutical formulations comprising the same to treat patients for airway hyperresponsiveness.

[0003] BACKGROUND

[0004] Airway hyperresponsiveness (AHR) is a condition whereby an individual’s airways narrow excessively in response to stimuli. It is a major clinical phenomenon in lung diseases (asthma, COPD and pulmonary fibrosis] which is a high-risk factor for perioperative airway spasm leading to hypoxaemia, haemodynamic instability and even "silent lung", but also a potential risk for increased mortality from underlying diseases (e.g. asthma, COPD).

[0005] For example, in asthma, more severe hyperresponsiveness is associated with more clinical symptoms and a steeper reduction in forced expiration volume in 1 second (FEVi), which is a standard clinical measure of lung function. In COPD, studies have shown that the severity of AHR was able to predict subsequent decline in COPD. Like asthma, patients with more severe COPD also had a more rapid decline in FEVi.

[0006] Airway remodelling is thought to play a major role in the loss of lung function observed in COPD and asthma. In both diseases, the airway wall and lung tissue are inflamed. This results in airflow obstruction due to the thickening of the bronchial walls and narrowing of the lumina. Studies have also demonstrated that in COPD, elastic fibers are reduced in the alveoli as well as small airway. This is thought to result in a loss of elastic recoil and increases in airway resistance because of the loss of elastic airway support. Emphysema, which is commonly found in COPD patients, is thought to further contribute to the airflow obstruction via the loss of the alveolar attachments to the small airways, which in turn results in loss of elastic recoil and increased narrowing of the airways.

[0007] Hence, inflammation is an important underlying mechanism which underpins airway remodelling and airway hyperresponsiveness. In this respect, IL-13 plays an important role as a central mediator of physiological changes induced by allergic inflammation in many tissues, such as the airway and alevoli. One way to inhibit the activity of IL- 13 is to interfere with the binding of IL- 13 to its receptor IL-13R, for example by using an antibody specific to IL-13R, such as an antibody specific to lL-13Ral. An effective antibody antagonist to IL- 13 Red may also interfere with the binding of IL-13 and prevent heterodimerization of IL-4Ra and IL-13Ral. Such an antibody could inhibit signaling of both IL-13 and IL-4 through the type II receptor while sparing IL-4 signalling through the type I receptor. Signalling through the type I receptor is essential in the induction phase of the immune response during which Th2 cells differentiate. T cells do notexpress IL-13Rcd so the type II receptor plays no role in Th2 differentiation. Hence, an IL-13Ral antibody should not affect the overall Thl / Th2 balance. Signalling through the type II IL-4 / IL-13 receptor is critical during the effector-A-stage of the immune response during established allergic inflammation. Thus, blockade of the type II receptor should have a beneficial effect on many of the symptoms of conditions mediated by lL-13R-mediated and therefore, be an effective disease modifying agent.

[0008] Antibodies against IL-13Ral (both monoclonal and polyclonal) have been described in the art; see, eg, WO 97 / 15663, WO 03 / 80675; WO 03 / 46009; WO 06 / 072564; Gauchat et al, 1998 Eur. J. Immunol. 28:4286-4298; Gauchat et a / , 2000 Eur. J. Immunol. 30:3157-3164; Clement et a / , 1997 Cytokine 9(11) :959 (Meeting Abstract); Ogata et al, 1998 J. Biol. Chem. 273:9864-9871; Graber et al, 1998 Eur. J. Immunol. 28:4286-4298; C. Vermot-Desroches et al, 2000 Tissue Antigens 5(Supp. l):52-53 (Meeting Abstract); Poudrier etal, 2000 Eur. J. Immunol. 30:3157-3164; Akaiwa etal, 2001 Cytokine 13:75-84; Cancino-Diaz et al, 2002 J. Invest. Dermatol. 119:1114-1120; and Krause et al, 2006 Mol. Immunol. 43:1799-1807.

[0009] One particularly promising anti-IL-13Ral antibody is described in W02008 / 060813 as antibody 10G5-6. 10G5-6 is an IgG4 with a hinge stabilising serine to proline mutation (S241P Kabat numbering). This antibody is now known as eblasakimab (previously called ASLAN004, both names used interchangeably herein). Eblasakimab has been shown to bind to human IL- 13 Rai with a high affinity (for example Kd may be 500pM). Eblasakimab was shown to effectively antagonise IL-13 function through inhibiting the binding of IL- 13 to its receptor IL-13Ral and to inhibit IL-13 and IL- 4 induced eotaxin release in NHDF cells, IL-13 and IL-4 induced STAT6 phosphorylation in NHDF cells and IL-13 stimulated release of TARC in blood or peripheral blood mononuclear cells.

[0010] The present inventors have generated data that anti-IL13R antibodies or antigen binding fragments thereof, such as eblasakimab have tissue specific effects in the lung and may be suitable for the treatment of airway hyperresponsiveness by way of their inhibition of IL-13 signalling.

[0011] What is more asthma and especially COPD are often poorly controlled, and these patients still have a serious unmet clinical need.

[0012] SUMMARY OF THE DISCLOSURE

[0013] The following paragraphs summarise the present disclosure:

[0014] 1. An antibody or antigen binding fragment thereof, which is an inhibitor of signalling through lL-13Ral, by binding the said receptor, for use in treating airway hyperresponsiveness (AHR) (also referred to as bronchial hyperresponsiveness) in a patient, for example a patient whose symptoms are not alleviated by a bronchodilator, such as a patient with chronic obstructive pulmonary disease (COPD), whereby the treatment improves respiratory airflow in the patient.

[0015] 1 An antibody or antigen binding fragment thereof, which is an inhibitor of signalling through IL-13Ral by binding the said receptor, for use in improving respiratory airflow in a patient in need thereof, for example a patient whose symptoms are not alleviated by a bronchodilator, such as a patient with chronic obstructive pulmonary disease (COPD).

[0016] 2. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the airway hyperresponsiveness is caused by airway remodelling, for example wherein the structure of the small airways is altered.

[0017] 3. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the airway hyperresponsiveness is caused by an airway obstruction, for example an airway constriction occurring in one or more parts of the respiratory tract

[0018] 4. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the airway constriction occurs in one or more of the following: the trachea, the bronchi, the bronchioles and / or the alveoli.

[0019] 5. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the airway constriction occurs in the bronchial tubes and / or alveoli. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the airway constriction is due to a loss of elasticity of tissue in the respiratory tract, for example a loss of elasticity of the bronchial tubes and / or the alveoli. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the airway constriction is due to a thickening of the airway walls, for example a thickening of the bronchial tube walls. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the airway obstruction is due to excessive mucus production. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the airway hyperresponsiveness is caused by allergic inflammation, for example allergic inflammation mediated by one or more pro-inflammatory cytokines. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the airway constriction is cytokine-induced, for example induced by one or more proinflammatory cytokines. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the one or more cytokines are selected from the group comprising IL- 13 and IL4, for example both IL-13 and IL4. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the airway constriction is induced by a bronchoconstrictor, such as methacholine. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the airway hyperresponsiveness is reversible with a bronchodilator, for example asthma. An antibody or antigen binding fragment thereof for use according to any one of paragraphs 1 to 12, wherein the airway hyperresponsiveness is not reversible with a bronchodilator. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has a disease or condition associated with airway hyperresponsiveness, for example asthma, bronchiectasis, chronic pulmonary obstructive disease (COPD) or cystic fibrosis. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has COPD. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has non-severe COPD. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has chronic bronchitis and / or emphysema. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has asthma. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has both asthma and COPD (asthma-COPD). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the airway hyperresponsiveness is in response to one or more stimuli. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the treatment results in a reduction in airway responsiveness to one or more stimuli, for example wherein the treatment results in a reduction of 10% or more, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in the amount of stimuli required to produce a 20% fall in forced expired volume in 1 second (FEVi). An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the treatment results in a greater reduction in airway responsiveness to one or more stimuli, for example wherein the treatment results in a reduction of 10% or more, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in the amount of stimuli required to produce a 20% fall in forced expired volume in 1 second (FEVi), compared to when dupilumab is administered. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the one or more stimuli is selected from the group comprising: acetylcholine, methacholine, histamine, propranolol, SOj, AMP, hyperventilation and fog. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the one or more stimuli is one or more cytokines, for example IL-13 and / or IL-4. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the respiratory airflow is improved by reducing or preventing airway constriction and / or by increasing airway dilation, for example in response to a bronchodilator. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the respiratory airflow is improved to a greater extent compared to when dupilumab is administered, for example by reducing or preventing airway constriction to a greater extent compared to dupilumab and / or by increasing airway dilation to a greater extent, for example in response to a bronchodilator. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the respiratory airflow is improved by an increase in and / or by preventing a loss of elasticity of tissue in the respiratory tract compared to baseline. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the respiratory airflow is improved by an increase in elasticity of the bronchial tubes and / or the alveoli. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the respiratory airflow is improved by an increase in elasticity of tissue in the respiratory tract compared to baseline, for example an increase of 10% or more, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in elasticity compared to baseline. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the respiratory airflow is improved by a greater increase in elasticity of tissue in the respiratory tract compared to when dupilumab is administered, for example an increase of 10% or more in responsiveness, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in responsiveness compared to when dupilumab is administered. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the respiratory airflow is improved by an increase in responsiveness to a bronchodilator, compared to baseline, for example an increase of 10% or more in responsiveness, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in responsiveness compared to baseline. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the respiratory airflow is improved by an increased responsiveness to a bronchodilator, compared to when dupilumab is administered, for example an increase of 10% or more in responsiveness, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in responsiveness compared to when dupilumab is administered. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the bronchodilator is selected from the group comprising: a beta 2- agonist, such as formoterol, salbutamol, levalbuterol or pirbuterol; an anticholinergic, such as aclidinium bromide, tiotropium bromide, glycopyrrolate, glycopyrronium bromide or umeclidinium bromide; and a xanthine derivative, such as theophylline. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the airway dilation agent is formoterol. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the patient has a reduced peak expiratory flow (PEF) compared to a control individual, for example a reduction of 10% or more in PEF, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% compared to a control individual. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the respiratory airflow is improved by an increase in peak expiratory flow (PEF) compared to baseline, for example an increase of at least 10% in PEF, such as a 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% increase in PEF. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the respiratory airflow is improved by a greater increase in peak expiratory flow (PEF) compared to when dupilumab is administered, for example an increase of at least 10% in PEF, such as a 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% increase in PEF. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the patient has a reduced forced expiratory volume in 1 second (FEVi) compared to a control, for example a reduction of 10% or more in FEVi, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% compared to a control individual. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the respiratory airflow is improved by an increase in FEVi compared to baseline, for example an increase of at least 10% in FEVi, such as a 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% increase in FEVi. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the respiratory airflow is improved by a higher increase in FEVi compared to when dupilumab is administered, for example an increase of at least 10% in FEVi, such as a 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% increase in FEVi. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the patient has a forced expiratory volume in 1 second / forced expiratory capacity (FEVi / FVC) ratio which is below 0.7. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the respiratory airflow is improved by an increased FEVi / FVC ratio in the patient compared to baseline, for example wherein the treatment results in the patient having an FEVi / FVC ratio of 0.7 or higher. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the respiratory airflow is improved by an increased FEVi / FVC ratio in the patient compared to when dupihimab is administered. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the respiratory airflow is improved by a more consistent peak expiratory flow (PEF) in the patient compared to before treatment. An antibody or antigen binding fragment thereof for use according to any preceding paragraph, wherein the respiratory airflow is improved by a more consistent peak expiratory flow (PEF) in the patient compared to when dupilumab is administered. An antibody or antigen binding fragment thereof according to any preceding paragraph, wherein the respiratory airflow is improved by a more consistent FEVi compared to before treatment An antibody or antigen binding fragment thereof according to any preceding paragraph, wherein the respiratory airflow is improved by a more consistent FEVi compared to when dupilumab is administered. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient is a highly allergic patient, for example where the baseline IgE levels have been established and are ata level of at least 10,000 KU / L + / - 2,000. An antibody or antigen binding fragment thereof for use according to paragraph23 wherein the baseline IgE levels are in the range 10,000 + / - 2,000 to 30,000 + / - 6,000 KU / L. An antibody or antigen binding fragment thereof for use according to any one of paragraphs 23 to 24, wherein the treatment reduces the IgE levels by at least 15% from baseline. An antibody or binding fragment thereof for use according to paragraph25, wherein the treatment reduces the IgE levels by at least 20% from the baseline. An antibody or binding fragment thereof for use according to paragraph25 or 26, wherein the treatment reduces the IgE levels by atleast 30% from baseline, for example reduces said levels 30 to 40%, such as 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40% from baseline. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has pruritus. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the pruritus is mediated by one or more of the following: histamine, 5- HT (serotonin), acetylcholine, substance P (SP), leukotrienes, bradykinin, proteases (such as typsin, tryptase, cathepsin S, or kallikrein-related peptidases such as KLK4 or KLK14), IL-31, lysophosphatidic acid, autotaxin and / or toll-like receptor 7 (TLR7). An antibody or antigen binding fragment thereof for use according to any one ofthe preceding paragraphs, wherein the pruritus is mediated by histamine. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the pruritus is mediated by IL- 13, IL-4 or a combination of both. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the pruritus is mediated by both IL-13 and IL-4. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has a skin condition, for example selected from the group comprising dermatitis; such as atopic dermatitis (AD), contact dermatitis, neurodermatitis or seborrheic dermatitis; eczema; hand-foot-and-mouth disease; hives (including urticaria associated with Lupus), psoriasis, an infection, such as a fungal or bacterial infection, for example impetigo or folliculitis; an allergic skin reaction; Ehlers- Danlos syndrome; asthma; and angioedema, such as hereditary angioedema (HAE). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has dermatitis, for example atopic dermatitis (AD), contact dermatitis, neurodermatitis or seborrheic dermatitis. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has atopic dermatitis (AD), for example moderate to severe atopic dermatitis. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has Ehlers-Danlos syndrome (EDS), asthma or angioedema (such as HAE). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has asthma. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has angioedema. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient does not have atopic dermatitis or psoriasis. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient does not have atopic dermatitis. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient does not have psoriasis. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient was previously administered dupilumab. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient had airway hyperresponsiveness that was poorly controlled by dupilumab. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the patient has COPD that was poorly controlled by dupilumab. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein an improvement in airflow is present after about two weeks from administration of the first dose (such as day 15). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein an improvement in airflow is present after about four weeks from administration of the first dose (such as day 29). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein an improvement in airflow is present after about six weeks from administration of the first dose (such as day 43). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein an improvement in airflow is present after about eight weeks from administration of the first dose (such as day 57). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the treatment is administered intravenously. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the treatment is administered subcutaneously. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein multiple doses are administered in a treatment cycle (for example wherein the treatment cycle is 4 to 8 weeks, such as 8 weeks). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein multiple treatment cycles are administered, for example 2, 3, 4 or more treatment cycles are administered. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein following the treatment cycle or cycles and disease modification, maintenance therapy is administered, for example the same dose administered less frequently (for example monthly), or a lower dose (such as 200mg) administered the same frequency or less frequently (such as about two weekly, about three weekly, or about four weekly. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein said antibody or binding fragment thereof is administered approximately weekly, (in particular a single treatment cycle, especially 8 weeks). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein said antibody or binding fragment thereof is administered once approximately every two weeks, (in particular a single treatment cycle, especially 8 weeks). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein said antibody or binding fragment thereof is administered once approximately every three weeks, (in particular a single treatment cycle, especially 8 weeks). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the antibody or binding fragment thereof is administered once approximately every four weeks (for example monthly), (in particular a single treatment cycle, especially 8 weeks). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein a loading dose in the range 400 to 900mg, for example 400, 500, 600, 700, 800 or 900mg is employed before administration of the treatment cycle. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein a loading dose of 600 mg is employed before administration of the therapeutic doses. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the loading dose is administered for 1 to 3 weeks, such as 1, 2 or 3 weeks prior to administration of the therapeutic doses. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the loading dose is administered only on week 0, for example 600 mg on week 0. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the loading dose is administered on weeks 0 and 1, for example 600 mg on week 0 and 600 mg on week 1. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the loading dose is administered on weeks 0, 1 and 2, for example 600 mg on week 0, 600 mg on week 1 and 600 mg on week 2 An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the treatment does not comprise a loading dose. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the dose, such as the therapeutic dose is in the range of 200 to 900 mg. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the dose is in the range of 300 to 600 mg. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the dose is 200mg. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the dose is 300 mg, for example administered weekly. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the dose is 400mg, for example administered bi-weekly or twice monthly. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the dose is 600mg, for example administered monthly. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the therapeutic dose of the anti-IL13R antibody or binding fragment thereof is 400 mg dosed every 2 weeks (400 mg Q2W). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the therapeutic dose of the anti-IL13R antibody or binding fragment thereof is 600 mg dosed every 2 weeks (600 mg Q2W). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the therapeutic dose of the anti-IL13R antibody or binding fragment thereof is 300 mg dosed every 2 weeks (300 mg Q2W). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein a loading dose of 600 mg is administered during weeks 0 and 1, followed by therapeutic dosing of 300 mg dosed every 2 weeks (300 mg Q2W], An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein a loading dose of 600 mg is administered during weeks 0 and 1, followed by therapeutic dosing of 400 mg dosed every 2 weeks (400 mg Q2W], An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein a loading dose of 600 mg is administered during weeks 0, 1 and 2 followed by therapeutic dosing of 600 mg dosed every 4 weeks (400 mg Q4W). An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the treatment cycles comprises, a first dose at 600mg, followed by three weekly doses of 400mg, for example wherein the treatment cycle is repeated twice i.e. two treatment cycles lasting 8 weeks, in particular day 1 600mg, approximately day 8 400mg, approximately day 15 400mg, approximately day 22 400mg, approximately day 29 600mg, approximately day 36400mg, approximately day 43400mg, and approximately day 50400mg are administered. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the disease modification occurs by day 8, wherein day 1 is the first administration of the antibody or binding fragment thereof. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the disease modification is a reduction in the SD score of POEM, for example wherein the reduction is a percentage from base line in the range -50 to -100%. An antibody or antigen binding fragment thereof for use according to paragraphSO, wherein the disease modification in the range -50 to -100% is achieved by about day 57 following first administration on day 1, for example maximum disease modification is achieved by about day 57. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the antibody or antigen binding fragment binds an epitope FFYQ (for example same epitope as the antibody with a VH shown in SEQ ID NO: 51 and a VL shown in SEQ ID NO: 53, or a sequence at least 95% identical to any one of the same. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the antibody or antigen binding fragment thereof is an anti-IL13Ral antibody or antigen binding fragment thereof. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the antibody or antigen binding fragment thereof comprises a VH CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a VH CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a VH CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the antibody or antigen binding fragment thereof comprises a VH domain comprising an amino acid sequence shown in SEQ ID NO: 51 or a sequence at least 95% identical thereto, in particular SEQ ID NO: 51. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the antibody or antigen binding fragment thereof comprises a VL CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 31, a VL CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 32, and a VL CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 45. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the antibody or antigen binding fragment thereof comprises a VL domain comprising an amino acid sequence shown in SEQ ID NO: 53 or a sequence at least 95% identical thereto, in particular SEQ ID NO: 53. An antibody or antigen binding fragment thereof for use according to any one of the preceding paragraphs, wherein the antibody comprises a VL domain comprising an amino acid sequence shown in SEQ ID NO: 53 or a sequence at least 95% identical thereto, in particular SEQ ID NO: 53, and a VH comprising an amino acid sequence shown in SEQ ID NO: 51 or a sequence at least 95% identical thereto, in particular SEQ ID NO: 51. A pharmaceutical formulation comprising the antibody or binding fragment thereof for use according to any one of the preceding paragraphs, said formulation comprising 150 to 210 mg / ml of an anti-IL-13R antibody or antigen binding fragment thereof, for example 150, 155,

[0020] 160. 165. 170. 175. 180. 185. 190. 195, 200, 205 or 210 mg / ml, in particular 150 mg / ml, 175 mg / ml or 200 mg / ml;

[0021] 170 to 250 mM of arginine (such as Arg-HCl or Arg-Glu), for example 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245 or 250 mM, in particular 150 mM, 175 mM or 250 mM;

[0022] 20 to 50 mM histidine buffer, for example 20, 25, 30, 35, 40, 45 or 50 mM, such as 20 mM or 50 mM histidine buffer;

[0023] 0.01-0.03% of a non-ionic surfactant, such as 0.02% w / w; and wherein the pH of the formulation is in the range 6.0 to 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 6.5. A pharmaceutical formulation comprising an antibody or binding fragment thereof for use according to any one of the preceding paragraphs, said formulation comprising 175 to 250 mg / ml of an anti-IL-13R antibody or antigen binding fragment thereof, for example 175, 180,

[0024] 185. 190. 195, 200, 205, 210, 215, 220 or 225 mg / ml, in particular 200 mg / ml, 225 mg / ml or 250 mg / ml;

[0025] 15 to 75 mM of tryptophan, such as 15 to 60 mM, in particular 25 to 50 mM tryptophan;

[0026] 190 to 270 mM of arginine (such as Arg-HCl or Arg-Glu), for example 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265 or 270 mM, in particular 200, 210, 225, 235, 250 or 260 mM;

[0027] 0.01-0.03% of a non-ionic surfactant, for example 0.01-0.03% w / w, such as 0.02% w / w; a buffer (such as histidine buffer); and wherein the pH of the formulation is in the range 6.0 to 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 6.4. A pharmaceutical formulation comprising an antibody or binding fragment thereof for use according to any one of the preceding paragraphs, said formulation comprising 175 to 250 mg / ml of an anti-IL-13R antibody or antigen binding fragment thereof, for example 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245 or 250 mg / ml, in particular 190, 200 mg / ml, 210 mg / ml, 225 mg / ml or 250 mg / ml, such as 200 mg / ml of an anti-IL-13R antibody or antigen binding fragment thereof;

[0028] 5 to 100 mM of tryptophan (including 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 M), for example 15 to 75 mM of tryptophan, such as 15 to 60 mM, in particular 25 to 50 mM tryptophan, such as 20 mM, 50 or 80 mM tryptophan;

[0029] 140 to 290 mM of arginine (including 150 or 151 to 290nM), for example 160 to 290 mM of arginine (such as Arg-HCl or Arg-Glu), for example 160, 165, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280 285 or 290 mM, in particular 150, 185, 215, 225, 250, 260 or 280 mM arginine;

[0030] 0.01-0.03% of a non-ionic surfactant (such as polysorbate), for example 0.01-0.03% w / w, such as 0.01%, 0.015%, 0.020%, 0.025% or 0.030% in particular 0.02% w / w of a non-ionic surfactant; a buffer (such as histidine buffer), for example 15 to 55 mM of a buffer (including 25 or 26 to 55), such as 15, 20, 25, 30, 35, 40, 45, 50 or 55 mM of a histidine buffer; in particular 20, 35 or 50 mM histidine buffer; and wherein the pH of the formulation is in the range 5.5 to 7.2 (including 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, for example 6.0 to 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 5.8, 6.3, 6.4, 6.5, 6.6, 6.7 or 6.8.

[0031] 117. A method of treating a patient having airway hyperresponsiveness (also referred to as bronchial hyperresponsiveness), for example a patient whose symptoms are not alleviated by a bronchodilator, such as a patient having chronic obstructive pulmonary disease (COPD), comprising administering a therapeutically effective amount of an antibody or antigen binding fragment thereof, which is an inhibitor of signalling through of the IL-13Ral by binding the said receptor, or a pharmaceutical formulation comprising the same, for example according to any one of the preceding paragraphs, whereby the treatment improves respiratory airflow in the patient

[0032] 118. Use of an antibody or antigen binding fragment thereof, which is an inhibitor of signalling through of the IL-13Ral by binding the said receptor, or a pharmaceutical formulation comprising the same, for example according to any one of the preceding paragraphs, in the manufacture of a medicament for treating a patient having airway hyperresponsiveness (also referred to as bronchial hyperresponsiveness), such as a patient whose symptoms are not alleviated by a bronchodilator for example a patient having chronic obstructive pulmonary disease (COPD), whereby the treatment improves respiratory airflow in the patient.

[0033] In one embodiment perioperative airway spasm is minimised, ameliorated or avoided in patients treated according to the present disclosure.

[0034] In one embodiment the AHR is treated in the context of cystic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, COPD and asthma, such as COPD and asthma, in particular COPD. In one embodiment the AHR is in the context of an acute and severe food allergy, such as a nut allergy. The rapid onset of action of the present treatment makes it suitable for administration in an emergency situation, for example in combination with the standard of care. Full occupancy of the receptors may be obtained within one hour of administration, which then complements the mechanisms of the standard of care.

[0035] The present inventors have established that the symptoms and severity of airway hyperresponsiveness (AHR) can be treated and / or ameliorated by administering an anti-IL13R antibody or antigen binding fragment, such as eblasakimab to subjects in need thereof.

[0036] In one embodiment there is provided a method of treating a patient having airway hyperresponsiveness (AHR), for example a highly allergic patient as defined herein with an antibody or binding fragment thereof or a pharmaceutical formulation as defined herein.

[0037] In one embodiment there is provided use of an antibody or binding fragment thereof or a pharmaceutical formulation, as defined herein for the manufacture of a medicament for the treatment of airway hyperresponsiveness (AHR) in a patient, for example in a highly allergic patient.

[0038] In one embodiment treatment with eblasakimab reduces the overall burden of disease, for example reduces the overall burden of AHR in a patient

[0039] In one embodiment patients have a reduced mortality rate.

[0040] In one embodiment treatment with eblasakimab improves quality of life in a patient having AHR, for example in a highly allergic patient

[0041] Surprisingly, the present inventors have established that disease modification following treatment with an anti-IL-13Ral antibody or antigen binding fragment thereof according to the present disclosure closely follows a reduction in airway obstruction, for example closely follows a reduction in an airway constriction occurring in one or more parts of the respiratory tract Thus, the treatment according to the present disclosure has tissue specific effects.

[0042] Furthermore, head-to-head experiments comparing eblasakimab with dupilumab (the current gold standard for treatment of atopic dermatitis), suggest that eblasakimab potentially outperforms dupilumab in reversing cytokine and methacholine-induced airway constriction, and enhancing airway dilation in response to formoterol. The presently disclosed treatment may thus provide potentially stronger relief to address bronchoconstriction and improve dilatory function in COPD, and possibly in other Th2-driven lung disorders.

[0043] In one embodiment, treatment with an anti-IL13Ral antibody or antigen binding fragment, such as eblasakimab results in a reduction in airway responsiveness to one or more stimuli, for example wherein the treatment results in a reduction of 10% or more, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in the amount of stimuli required to produce a 20% fall in forced expired volume in 1 second (FEVi).

[0044] In one embodiment treatment with an anti-IL13Ral antibody or antigen binding fragment, such as eblasakimab results in an improvement of 10% or more, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in respiratory airflow compared to baseline.

[0045] In one embodiment, the respiratory airflow is improved by a reduction in airway obstruction. In one embodiment, the respiratory airflow is improved by a reduction in airway constriction occurring in one or more parts of the respiratory tract, for example a reduction of 10% or more, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% compared to baseline. In one embodiment, the respiratory airflow is improved by an increase in elasticity of tissue in the respiratory tract compared to baseline, for example an increase of 10% or more, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in elasticity compared to baseline.

[0046] In one embodiment, the respiratory airflow is improved by an increase in responsiveness to an airway dilation agent, such a bronchodilator, compared to baseline, for example an increase of 10% or more in responsiveness, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in responsiveness compared to baseline.

[0047] In one embodiment, the respiratory airflow is improved by an increase in peak expiratory flow (PEF) compared to baseline, for example an increase of at least 10% in PEF, such as a 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% increase in PEF.

[0048] In one embodiment, the respiratory airflow is improved by an increase in FEVi compared to baseline, for example an increase of at least 10% in FEVi, such as a 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% increase in FEVi.

[0049] In one embodiment, the respiratory airflow is improved by an increased FEVi / FVC ratio in the patient compared to baseline, for example wherein the treatment results in the patient having an FEVi / FVC ratio of 0.7 or higher.

[0050] In one embodiment, the respiratory airflow is improved by a more consistent peak expiratory flow [PEF], i.e. a less variable PEF in the patient compared to before treatment

[0051] In one embodiment, the respiratory airflow is improved by a more consistent FEVi, i.e. a less variable FEVi compared to before treatment

[0052] In one embodiment, the patient has a disease or condition associated with airway hyperresponsiveness, for example selected from the group comprising COPD, asthma, cystic fibrosis and bronchiectasis. Thus, in one embodiment, the patienthas COPD. In one embodiment, the patient has non-severe COPD. In one embodiment, the patienthas asthma. In one embodiment, the patient has asthma and COPD [asthma-COPD], In one embodiment, the patient has bronchiectasis. In one embodiment, the patient has cystic fibrosis.

[0053] In one embodiment the patient has a chronic inflammatory condition. Examples of chronic inflammatory conditions include but are not limited to atopic dermatitis, asthma, rheumatoid arthritis, psoriatic arthritis, lupus, inflammatory bowel disease such as ulcerative colitis and Crohn’s disease, diabetes such as type 1 or type 2 diabetes, ankylosing spondylitis, gout, myositis, scleroderma, Sjogren's syndrome, endometriosis and vasculitis. Hence, in one embodiment, the patient has a chronic inflammatory condition selected from the group comprising atopic dermatitis, asthma, rheumatoid arthritis, psoriatic arthritis, lupus, inflammatory bowel disease such as ulcerative colitis and Crohn’s disease, diabetes such as type 1 or type 2 diabetes, ankylosing spondylitis, gout, myositis, scleroderma, Sjogren's syndrome, endometriosis and vasculitis.

[0054] In one embodiment the patient has a type 2-driven inflammatory skin disorder, for example a skin disorder exacerbated by pro-inflammatory cytokines present in the skin. Thus, in one embodiment eblasakimab is suitable for treating a patient having a type-2 driven inflammatory skin disorder. In one embodiment the type 2-driven inflammatory skin disorder is atopic dermatitis (AD).

[0055] In one embodiment, the patienthas pruritis. In one embodiment itch signalling in the patient is exacerbated by pro-inflammatory cytokines present in the skin of the patient, which may cause an immune response that disrupts the skin barrier and drives disease pathology. Thus, in one embodiment eblasakimab is able to reduce or inhibit itch signalling in a patient In one embodiment treatment with eblasakimab prevents or reduces the disruption of the skin barrier in a patient In one embodiment eblasakimab dampens or inhibits the immune response that drives disease pathology in a patient having pruritus.

[0056] In one embodiment the pro-inflammatory cytokines are IL-13, IL-4 or a combination of both IL-13 and IL4. In one embodimentIL-13, IL-4 or both act as neuronal enhancers for the amplification of itch pathways through the 13Ral subunit of the Type-2 receptor. Thus, in one embodiment eblasakimab inhibits or dampens neuronal enhancers for the amplification of itch pathways, such as IL-13 and / or IL-4.

[0057] In one embodiment treatment with eblasakimab results in a reduction of pruritic neuronal response, for example via eblaskimab’s dual blockade of both IL-4 and IL-13 through the Type 2 receptor.

[0058] In one embodiment a combination therapy is employed comprising the antibody, antigen binding fragment thereof or a formulation according to the present disclosure and a further medicament.

[0059] In one embodiment the patient has a skin condition, for example selected from the group comprising dermatitis; such as atopic dermatitis [AD], contact dermatitis, neurodermatitis or seborrheic dermatitis; eczema; hand- foot-and-mouth disease; hives (including urticaria associated with Lupus), psoriasis, an infection, such as a fungal or bacterial infection, for example impetigo or folliculitis; an allergic skin reaction; Ehlers-Danlos syndrome; and angioedema, such as hereditary angioedema (HAE).

[0060] In one embodiment the patient has dermatitis, for example atopic dermatitis (AD), contact dermatitis, neurodermatitis or seborrheic dermatitis.

[0061] In one embodiment the patient has atopic dermatitis (AD), for example moderate to severe atopic dermatitis.

[0062] In one embodiment the patient has eczema. In one embodiment, the sleep loss or sleep disturbance is due to the patient’s eczema.

[0063] In one embodiment the patient has hives.

[0064] In one embodiment the patient has Ehlers-Danlos syndrome (EDS), asthma or angioedema (such as HAE).

[0065] In one embodiment the patient has Ehlers-Danlos syndrome.

[0066] In one embodiment the patient has angioedema, such as HAE.

[0067] The present inventors have also established that the antibodies, antigen binding fragments and compositions of present invention can be employed to treated other diseases with an allergic component, for example allergic epithelial disease, such as allergic asthma, asthma-COPD and eosinophilic esophagitis.

[0068] Thus, in an independent aspect there is provided treatment of an allergic disease, for example with elevated IgE levels (elevated in comparison to normal levels), with an antibody, binding fragment or composition comprising the same, which is an inhibitor of signalling through IL-13Ral, by binding the said receptor, for example as described elsewhere herein (for atopic dermatitis).

[0069] In one embodiment the allergic disease is manifested in epithelial tissue. In one embodiment the allergic disease is allergic asthma, for example poorly controlled and / or moderate to severe asthma. In one embodiment the allergic disease is asthma-COPD, for example poorly controlled and / or moderate to severe asthma-COPD. In one embodimentthe allergic disease is eosinophilic esophagitis, for example poorly controlled and / or moderate to severe eosinophilic esophagitis.

[0070] In one embodimentthe patient is identified as allergic before treatment, for example where the baseline has been established and is ata level of at least 10,000 KU / L + / - 2,000.

[0071] Preferences described herein for atopic dermatitis, like dose and the like apply equally to allergic disease indications.

[0072] In one embodimentthe allergic disease is not atopic dermatitis.

[0073] In one embodimentthe allergic disease is not eosinophilic esophagitis.

[0074] In one embodiment the allergic disease is not psoriasis.

[0075] BRIEF DESCRIPTION OF THE FIGURES

[0076] Figure 1 - Graph demonstrating that eblasakimab inhibits cytokine-induced airway constriction (i.e. induced by IL-13+IL-4 challenge).

[0077] Figure 2 - Graph demonstrating that eblasakimab inhibits methacholine-induced airway constriction i.e. induced by IL-13+IL-4 challenge).

[0078] Figure 3 - Graph demonstrating that eblasakimab enhances acute airway dilation after IL-13+IL-4 challenge.

[0079] Figure 4 - Graph comparing the ability of eblasakimab vs dupilumab to reverse cytokine-induced basal airway constriction in a PCLS model derived from a healthy donor.

[0080] Figure 5 A - Graph comparing ability of eblasakimab vs dupilumab to enhance airway dilation in response to formoterol in a PCLS model derived from a healthy donor after 5 minutes of exposure to formoterol.

[0081] Figure 5B - Graph comparing ability of eblasakimab vs dupilumab to enhance airway dilation in response to formoterol in a PCLS model derived from a healthy donor after 15 minutes.

[0082] Figure 6 - Graph comparing the ability of eblasakimab vs dupilumab to reverse methacholine- induced airway constriction in a PCLS model derived from a healthy donor.

[0083] Figure 7 - Graph comparing the ability of eblasakimab vs dupilumab to reverse cytokine-induced basal airway constriction in a PCLS model derived from a COPD patient

[0084] Figure 8 - Graph comparing the ability of eblasakimab vs dupilumab to reverse methacholine- induced basal airway constriction in a PCLS model derived from a COPD patient.

[0085] Figure 9 - Graph comparing ability of eblasakimab vs dupilumab to enhance airway dilation in response to formoterol in a PCLS model derived from a COPD patient after 5 minutes.

[0086] Figure 10A - Serum concentration for eblasakimab.

[0087] Figure 10B - Serum concentration for dupilumab.

[0088] DETAILED DISCLOSURE

[0089] Airway as used herein refers to the continuous passageway by which air enters and exits the lungs through the nostrils. The airway can be further split into the upper airway, which begins from the nostrils and extends to the pharynx; and the lower airway, which extends all the way from the larynx to the alveoli.

[0090] Airway hyperresponsiveness (AHR) used interchangeably with bronchial hyperresponsiveness as employed herein refers to the predisposition of the airways in a patient to narrow excessively or too easily in response to one or more stimuli that would produce little or no effect in a normal healthy individual. AHR is a characteristic feature of various airway diseases, in particular cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). It may also be present in interstitial lung abnormalities, for example pulmonary fibrosis and idiopathic pulmonary fibrosis. Bronchial provocation tests are used to assess the presence of AHR This would generally involve exposing a patient to increasing doses of an inhaled stimulus, such as methacholine, until a particular level of bronchoconstriction is achieved, for example a 20% fall in forced expired volume in one second (FEVi).

[0091] Airway remodelling as used herein refers to structural alterations of both small and large airways due to subepithelial fibrosis, increased smooth muscle mass of airways, neovascularization, destruction of lung parenchyma, changes in interstitium and glandular hypertrophy. Remodelling in COPD generally includes small airways fibrosis and destruction of lung parenchyma but is not characterized by changes in the lung interstitium. Idiopathic pulmonary fibrosis is characterized by damage to the lung parenchyma and interstitium.

[0092] Airway constriction as used herein refers to a narrowing of the airway. This can be due to various factors, including but not limited to the thickening of the airway walls, a loss of elasticity of the airway, and a narrowing of the airway lumina.

[0093] Bronchodilator as used herein is an agent which is used to make breathing easier by relaxing the muscles in the lungs and / or by widening the airways. The use of bronchodilators in patients generally results in an improvement in respiratory airflow. Bronchodilators are available in 3 main categories: beta 2-agonists, anticholinergics and xanthine derivatives.

[0094] Thus, in one embodiment, the bronchodilator is a beta 2 -agonist, for example albuterol, levalbuterol, salbutamol, salmeterol, formoterol or vilanterol. In one embodiment, the bronchodilator is an anticholinergic, such as ipratropium bromide, or tiotropium bromide. In one embodiment, the bronchodilator is a xanthine derivative, such as theophylline.

[0095] Bronchoconstrictor as used herein is an agent that causes the bronchial tubes to constrict (bronchoconstriction) when administered. An example of a bronchoconstrictor is methacholine, which is a non-specific cholinergic agonist that acts through muscarinic receptors in the lungs to induce bronchoconstriction.

[0096] Respiratory airflow as used herein refers to amount of air which moves between through an airway in a given period of time. Thus, an improvement in respiratory airflow may refer to an increase in the amount of air moving through an airway in a given period of time, a reduction in the time required for an amount of air to move through an airway, or both. Respiratory airflow in patients is typically determined with a spirometer, which measures the volume of air inspired and expired by the lungs, and / or a peak flow meter, which measures the peak expiratory flow (PEF).

[0097] Peak expiratory flow (PEF) or peak expiratory flow rate (PEFR) as used herein refers to a simple measure of the maximal flow rate that can be achieved during forceful expiration following a full inspiration. It is typically measured in L / min. Forced expired volume in one second (FEVi) as used herein is a measure of the volume of air that a person can force out of their lungs in one second. FEVi readings can be used to stage diseases such as COPD and asthma by calculating the measured FEVI value as a percentage of the predicted FEVi value based on the age, race, height and gender of the individual tested. FEVi scores alone cannot however be used to diagnose COPD or asthma. Instead, they must be combined with another reading called the forced vital capacity (FVC).

[0098] Forced vital capacity (FVC) as used herein is a measure of the greatest volume of air that an individual can exhale after breathing in as deeply as possible.

[0099] Forced expiratory volume in 1 second / forced expiratory capacity (FEVi / FVC) ratio as used herein is a value that represents the percentage of an individual's lung capacity that can be expelled in one second. The higher the value, the better the individual’s overall lung function. A FEVi / FVC ratio of less than 70% or 0.7 is typically used to diagnose COPD, while a FEVi / FVC ratio of less than 80% or 0.8 is typically used to diagnose asthma.

[0100] Disease modification as employed herein relates to improvements in the disease status for example as measured by a clinically relevant score. A clinically relevant score is a score used in the clinic, for example used by a physician.

[0101] In one embodiment, the treatment disclosed herein results in disease modification after or during the treatment

[0102] In one embodiment, the disease modification is a reduction in the symptoms or severity of inflammation. In one embodiment, the disease modification is a reduction in the degree and / or extent of airway constriction. In one embodiment, the disease modification a reduction in airway responsiveness to one or more stimuli, for example wherein the treatment results in a reduction of 10% or more, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in the amount of stimuli required to produce a 20% fall in forced expired volume in 1 second (FEVi). In one embodiment, the disease modification is a reduction or prevention of airway constriction and / or by increasing airway dilation, for example in response to an airway dilation agent an increase in and / or by preventing a loss of elasticity of tissue in the respiratory tract compared to baseline. In one embodiment, the disease modification is an increase in elasticity of the bronchial tubes and / or the alveoli. In one embodiment, the disease modification is an increase in elasticity of tissue in the respiratory tract compared to baseline, for example an increase of 10% or more, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in elasticity compared to baseline. In one embodiment, the disease modification is an increase in responsiveness to a bronchodilator, compared to baseline, for example an increase of 10% or more in responsiveness, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in responsiveness compared to baseline. In one embodiment, the disease modification is an increase in peak expiratory flow (PEF) compared to baseline, for example an increase of at least 10% in PEF, such as a 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% increase in PEF. In one embodiment, the disease modification is an increase in FEVi compared to baseline, for example an increase of at least 10% in FEVi, such as a 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% increase in FEVi. In one embodiment, the disease modification is an increased FEVi / FVC ratio in the patient compared to baseline, for example wherein the treatment results in the patient having an FEVi / FVC ratio of 0.7 or higher. In one embodiment, the disease modification is a more consistent peak expiratory flow (PEF) in the patient compared to before treatment. In one embodiment, the disease modification is a more consistent FEVi compared to before treatment

[0103] Patient Oriented Eczema Measure (POEM) as used herein refers to a 7-item questionnaire for patients that assesses presence of disease symptoms (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) over the last week using a scoring system of 0 (no days) to 4 (every day). The total score ranges from 0 to 28 with higher scores indicating greater intensity of eczema.

[0104] Pruritus or pruritis as used herein refers to a condition where the skin becomes itchy. It results in a very uncomfortable and irritating sensation that compels the individual to scratch the skin. Pruritus can be caused by a range of different conditions, including skin conditions (such as atopic dermatitis and psoriasis), internal diseases (such as liver and kidney disease, lymphoma), nerve disorders (such as multiple sclerosis), psychiatric conditions (such as anxiety and obsessive compulsive disorder), and allergic reactions.

[0105] Pruritus numerical score / scale (P-NRS) as used herein is a patient assessed score of the intensity of his or her itch over the previous 24 hours based on a scale of 0 to 10, with a score of 0 referring to "no itch" and a top score of 10 referring to "worst imaginable itch”.

[0106] Average pruritus numerical score / scale (average P-NRS) as used herein refers a patient assessed score of the average intensity of his or her itch over the previous 2 hours based on a scale of 0 to 10, with a score of 0 referring to "no itch" and atop score of 10 referring to "worst imaginable itch".

[0107] Peak pruritus numerical score / scale (peak P-NRS) or worst pruritus numerical score / scale (worst P-NRS) as used herein refers a patient assessed score of the worst intensity of his or her itch over the previous 24 hours based on a scale of 0 to 10, with a score of 0 referring to "no itch" and a top score of 10 referring to "worst imaginable itch”.

[0108] In one embodiment the disease is modified by a percentage reduction in Eczema Area and Severity Index (EASI) score in the range -20 to -100% from the baseline, such as EASI 50, EASI 75 or EASI 90. EASI score and EASI are used interchangeably herein.

[0109] Eczema Area and Severity Index (EASI) score as used herein is a tool used to measure the area (which indicates the extent of disease) and severity of atopic eczema. The number after the term "EASI” indicates the % decrease in the score from baseline. Thus, EASI 50 for example refers to 50% decrease in the score and EASI 90 refers to a 90% decrease in the score.

[0110] In one embodiment disease modification is measured as a reduction in IGA.

[0111] In one embodiment there is a provided a reduction in the Investigator Global Assessment (IGA) with / after treatment according to the present disclosure, for example an assessment of 0, 1 or 2, (no inflammatory signs, almost clear and mild disease respectively). In particular there is provided an IGA score of 0 or 1.

[0112] Investigator’s global assessment (IGA) as used herein refers to a tool for the assessment of atopic dermatitis. It uses a 0-5 point scale depending on the severity of a patient’s symptoms:

[0113] In an independent aspect there is provided use of an antibody, antigen binding fragment or pharmaceutical formulation as disclosed herein for the treatment or amelioration of allergic food responses, in particular severe allergic food response, such as peanut allergy.

[0114] Poorly controlled as used herein refers to airway hyperresponsiveness or a disease / disorder associated therewith, such as COPD, which is inadequately managed by an existing treatments]. For example, the existing treatment may insufficiently control the disease’s symptoms, resulting in pain, discomfort, and / or poor quality of life for the patient. The existing treatment may also or alternatively fail to improve clinical measures to an adequate level, for example fail to increase peak expiratory flow [PEF] by at least 10% compared to baseline. In one embodiment, the existing treatment is dupilumab.

[0115] In one embodiment, the highly allergic patient’s baseline IgE levels have been established and are at a level of at least at least 10,000 KU / L + / - 2,000, such as 8000, 8500, 9000, 9500, 10000, 10500, 11000, 11500 or 12000 KU / L.

[0116] In one embodiment, the patient has been identified as a highly allergic patient before the treatment is administered, for example, wherein the patient’s baseline IgE levels have been established and are at a level of at least 10,000 KU / L + / - 2,000. Thus, in one embodiment the patient is identified as a highly allergic patient wherein the patient's baseline IgE levels have been established and are at a level of at least 10,000 KU / L + / - 2,000, prior to administration of the antibody or binding fragment thereof, pharmaceutical formulation or medicament as defined herein. Accordingly, in one embodimentthe target population to be treated is highly allergic patients whose baseline IgE levels have been established and are at a level of at least 10,000 KU / L + / - 2,000.

[0117] In one embodiment the patient is identified as highly allergic by clinical observation.

[0118] Chronic obstructive pulmonary disease [COPD] as used herein is a collection of chronic inflammatory lung diseases that obstruct airflow and result in breathing problems. Emphysema and chronic bronchitis are the two most common conditions that contribute to COPD. Empysema is a condition wherein the alveoli are damaged and chronic bronchitis is a condition whereby the bronchial tubes are inflamed. These two conditions usually occur together and can vary in severity among individuals with COPD.

[0119] COPD is typically graded using the GOLD (Global Initiative for Chronic Obstructive Lung Disease] system which bases the stage of COPD on various factors, such as symptoms, how many times the COPD has worsened, and by the results of spirometry tests, in particular FEVi readings:

[0120] • GOLD 1 - mild: FEVI >80% predicted

[0121] • GOLD 2 - moderate: 50% < FEVI <80% predicted

[0122] • GOLD 3 - severe: 30% < FEVI <50% predicted

[0123] • GOLD 4 - very severe: FEVI <30% predicted. Severe COPD as employed herein refers to COPD that has been graded as GOLD stages 3 or 4. Hence, non-severe COPD as employed herein refers to COPD that has been graded as GOLD stages 1 or 2.

[0124] Asthma as used herein is a respiratory disease characterized by inflammation and bronchospasm, wherein the muscles around the airways tighten and contract in an attempt to keep the airways open. This leaves patients with cough, wheezing, chesttightness and shortness of breath. When the breathing issues become severe, this is typically referred to as an asthma attack.

[0125] Allergic asthma (used interchangeably with allergy-induced asthma) as used herein refers to form of asthma whereby the lungs of a patient become inflamed, and the airways tighten in response to the inhalation of an allergen. Common allergens include pollen, dust, animal dander and mold. Patients with allergic asthma experience many of the same symptoms as patients with non- allergic asthma - cough, wheezing, chest tightness and shortness of breath. Hence, the major difference between the two conditions is that patients with allergic asthma normally experience symptoms after inhaling an allergen.

[0126] Asthma-COPD (used interchangeably with asthma-COPD overlap syndrome (ACOS)) as used herein refers to a condition whereby a patient has both asthma and COPD. Patients diagnosed with asthma-COPD have reduced lung function, have more severe asthma attacks and typically experience symptoms more frequently than patients with asthma or COPD alone. Hence, asthma- COPD is a more serious and dangerous condition than either disease alone.

[0127] Eosinophilic esophagitis (EOE) as used herein refers to a chronic immune system disease where eosinophils buildup in the esophagus (eosinophils are not normally found in the esophagus). This build-up occurs as a reaction to foods, allergens or acid reflux, and may inflame and cause injury to the esophageal tissue. This in turn may lead to narrowing of the eosphagus and difficulty swallowing. In serious cases it may even result in medical emergencies due to food getting stuck in the throat. The majority of patients with EOE are atopic. Thus, individuals with atopic dermatitis, food or other environmental allergies are at greater risk of developing EOE. Family history of EOE is also a risk factor for the condition. No medications are currently approved by the US FDA for treating EOE. However, proton pump inhibitors (PPIs) have been demonstrated to reduce esophageal inflammation in some EOE patients and are thus often used as a first treatment. Corticosteroids may also be administered to help control inflammation.

[0128] Atopic dermatitis (AD) as used herein refers to inflammation of the skin and includes: dry / itchy skin and red rashes. AD can be a very painful, demoralising and psychologically damaging disease. The most common side effect of AD is pruritus, and a diagnosis of active AD cannot be made without an accompanying history of itching. Indeed, AD patients often complain that the pruritus is the most annoying and hardest symptom they have to cope with.

[0129] Psoriasis as used herein refers to a skin disorder that causes skin cells to multiply much faster than normal. This results in red, itchy scaly patches, which are typically found on the scalp, knees, elbows, and trunk. There are different categories of psoriasis, including pustular psoriasis, guttate psoriasis, inverse psoriasis and erythrodermic psoriasis. Most types of psoriasis go through cycles, flaring for a few weeks or months, then subsiding for a time or even going into remission.

[0130] Angioedema as used herein refers to the rapid edema (swelling) of the area beneath the skin or mucosa caused by the build-up of fluid, typically in response to an allergic trigger. Angioedema can affect different parts of the body, but it typically manifests in the eyes, lips, genitalia, hands and feet Angioedema can arise with hives or alone. In more serious cases, angioedema can result in breathing difficulties, abdominal pain and dizziness.

[0131] Ehlers-Danlos syndrome [EDS] as used herein refers to a group of inherited disorders wherein the connective tissues, such as tendons, ligaments, bloodvessels, etc are affected. There are 13 types of EDS, including hypermobile EDS (the most common], classical EDS, vascular EDS and kyphoscoliotic EDS. The different types of EDS share some common symptoms such as increased range of joint mobility (hypermobility], and stretchy and fragile skin. There are no known cures for EDS and treatment is largely supportive in nature, for example physiotherapy.

[0132] Hives (urticaria] as used herein refers to a sudden outbreak of itchy pale red bumps or welts on the skin. There are several types of hives including acute urticaria which last less than 6 weeks and are commonly caused by foods, medication or infections; chronic urticaria which last more than 6 weeks; and physical urticaria which are caused by something that stimulates the skin, for example cold, heat, pressure, sweating etc.

[0133] Interleukin-13 receptor (IL-13R] as used herein is a type I cytokine receptor, which binds to Interleukin-13. It consists of two subunits, encoded by IL13Ral and IL4R, respectively. These two genes encode the proteins IL-13Ral and IL-4Ra. These form a dimer with IL-13 binding to the IL- 13Ral chain and lL-4Ra stabilises this interaction. Due to the presence of the 1L4R subunit, IL13R can also instigate IL-4 signalling. In both cases this occurs via activation of the Janus kinase (JAKJ / Signal Transducer and Activator of Transcription (STAT] pathway, resulting in phosphorylation of STAT6. Human IL-13Ral has the Uniprot number P3597.

[0134] IL-13Ra2, previously called IL-13R and IL-13Ra, is another receptor which is able to bind to IL-13. However, in contrast to IL-13Ral, this protein binds IL-13 with high affinity, but it does not bind IL-4. Human IL-13Ra2 has the Uniprot number Q14627.

[0135] In one embodiment the anti-lL-13R antibody or binding fragment thereof of the present disclosure binds to IL-13Ral. In one embodiment, the antibody or binding fragment thereof binds only to IL-13Ral and does not bind to IL-13Ra2.

[0136] In one embodiment CDRH1 is an amino acid sequence GYSFTSYYWIG (SEQ ID NO: 1].

[0137] In one embodiment CDRH2 is an amino acid sequence VIYPGDSYTR (SEQ ID NO: 2]

[0138] In one embodiment CDRH3 has the formula:

[0139] SEQ ID NO: 3 Xi Pro Asn Trp Gly X6X7Asp X9

[0140] Xi denotes Phe, Met, Gin, Leu or Vai

[0141] Xe denotes Ser or Ala

[0142] X? denotes Phe, Leu, Ala or Met

[0143] X9denotes Tyr, Gin, Lys, Arg, Trp, His, Ala, Thr, Ser, Asn or Gly

[0144] In one embodiment the IL13-Rlal antibody or binding fragment employed in the formulation of the present disclosure comprises a CDRH3 in dependently selected from SEQ ID NO: 4 to 30:

[0145] In one embodiment, the anti-IL13R antibody or binding fragment employed in the present disclosure comprises a VH CDR1 comprising an amino acid sequence as set forth in SEQ ID N 0: 1, a VH CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a VH CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: or 3.

[0146] In one embodiment, the anti-IL13R antibody or binding fragment employed in the present disclosure comprises a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as setforth in SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.

[0147] In one embodiment, the anti-IL13R antibody or binding fragment employed in the present disclosure comprises a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 10. In one embodiment CDRL1 is an amino acid sequence RASQSISSSYLA SEQ ID NO: 31.

[0148] In one embodiment CDRL2 is an amino acid sequence GASSRAT SEQ ID NO: 32

[0149] In one embodiment CDL3 has the formula:

[0150] SEQ ID NO: 33 Gin X2X3X4X5

[0151] X2denotes Gin, Arg, Met, Ser, Thr or Vai.

[0152] X3denotes Tyr or Vai.

[0153] X4 denotes Glu, Ala, Gly or Ser.

[0154] X5 denotes Thr, Ala or Ser.

[0155] In one embodiment the IL- 13 Rai antibody employed in the formulation of the present disclosure comprises a CDRL3 in dependently selected from SEQ ID NO: 34 to 47:

[0156] In one embodiment, the IL- 13 Rai antibody or binding fragment employed in the present disclosure comprises a VL CDR1 comprising an amino acid sequence as setforth in SEQ ID NO: 31, a VL CDR2 comprising an amino acid sequence as setforth in SEQID NO: 32, and a VL CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 45.

[0157] In one embodiment the lL-13Ral antibody employed comprises a CDRL3 independently selected from a sequence comprising SEQ ID NO: 34 to 47.

[0158] In one embodiment CDRL3 comprising an amino acid sequence as setforth in SEQ ID NO: 33.

[0159] In one embodiment the VH region is independently selected from a sequence from the group comprising: SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51 and a sequence at least 95% identical to any one of the same.

[0160] SEQ ID NO: 48:

[0161] Glu Vai Gin Leu Vai Gin Ser Gly Ala Glu Vai Lys Lys Pro Gly Glu Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr Trp He Gly Trp Vai Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly Vai lie Tyr Pro Gly Asp Ser Tyr Thr Arg Tyr Ser Pro Ser Phe Gin Gly Gin Vai Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala MetTyr Tyr Cys Ala Arg Phe Pro Asn Trp Gly Ser Phe Asp Tyr Trp Gly Gin Gly Thr Leu Vai Thr Vai Ser Ser

[0162] SEQ ID NO: 49:

[0163] Glu Vai Gin Leu Vai Gin Ser Gly Ala Glu Vai Lys Lys Pro Gly Glu Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr Trp He Gly Trp Vai Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly Vai He Tyr Pro Gly Asp Ser Tyr Thr Arg Tyr Ser Pro Ser Phe Gin Gly Gin Vai Thr He Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Met Pro Asn Trp Gly Ser Phe Asp Tyr Trp Gly Gin Gly Thr Leu Vai Thr Vai Ser Ser

[0164] SEQ ID NO: 50:

[0165] Glu Vai Gin Leu Vai Gin Ser Gly Ala Glu Vai Lys Lys Pro Gly Glu Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr Trp He Gly Trp Vai Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly Vai lie Tyr Pro Gly Asp Ser Tyr Thr Arg Tyr Ser Pro Ser Phe Gin Gly Gin Vai Thr He Ser Ala Asp Lys Ser He Ser Thr Ala Tyr Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Vai Arg Met Pro Asn Trp Gly Ser Leu Asp His Trp Gly Gin Gly Thr Leu Vai Thr Vai Ser Ser

[0166] SEQ ID NO: 51

[0167] Glu Vai Gin Leu Vai Gin Ser Gly Ala Glu Vai Lys Lys Pro Gly Glu Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr Trp He Gly Trp Vai Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly Vai He Tyr Pro Gly Asp Ser Tyr Thr Arg Tyr Ser Pro Ser Phe Gin Gly Gin Vai Thr He Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Met Pro Asn Trp Gly Ser Leu Asp His Trp Gly Gin Gly Thr Leu Vai Thr Vai Ser Ser

[0168] In one embodiment the VL is independently selected from a sequence from the group comprising:

[0169] SEQ ID NO: 52

[0170] EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTL TISRLEPEDFAVYYCQQYETFGQGTKVEI*

[0171] SEQ ID NO: 53

[0172] EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTL TISRLEPEDFAVYYCQQYASFGQGTKVEI*

[0173] SEQ ID NO: 54

[0174] EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTL TISRLEPEDFAVYYCQQYEAFGQGTKVEI* and a sequence at least 95% identical to any one of the same (* K deleted in a post translational modification).

[0175] In one embodiment the VH sequence is SEQ ID NO: 48 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 (or a sequence at least 95% identical to any one of the same).

[0176] In one embodiment the VH sequence is SEQ ID NO: 49 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 (or a sequence at least 95% identical to any one of the same).

[0177] In one embodiment the VH sequence is SEQ ID NO: 50 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 (or a sequence at least 95% identical to any one of the same). In one embodiment the VH sequence is SEQ ID NO: 51 (or a sequence at least 95% identical thereto] and the VL sequence is SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 (or a sequence at least 95% identical to any one of the same].

[0178] In one embodiment the VL sequence is SEQ ID NO: 52 (or a sequence atleast 95% identical thereto] and the VH sequence is SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50 or SEQ ID NO: 51. (or a sequence at least 95% identical to any one of the same].

[0179] In one embodiment the VL sequence is SEQ ID NO: 53 (or a sequence at]east 95% identical thereto] and the VH sequence is SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50 or SEQ ID NO: 51 (or a sequence at least 95% identical to any one of the same].

[0180] In one embodiment the VL sequence is SEQ ID NO: 54 (or a sequence at]east 95% identical thereto] and the VH sequence is SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50 or SEQ ID NO: 51 (or a sequence at least 95% identical to any one of the same].

[0181] In one embodiment the VH sequence is SEQ ID NO: 51 (or a sequence at least 95% identical thereto] and the VL sequence is SEQ ID NO: 53 ((or a sequence at least 95% identical thereto].

[0182] Variable region as employed herein refers to the region in an antibody chain comprising the CDRs and a suitable framework.

[0183] In one embodiment the heavy chain comprises a sequence independently selected from the group comprising:

[0184] SEQ ID NO: 55

[0185] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTIS ADKSISTAYLQWSSLKASDTAMYYCARMPNWGSFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVD KRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV MHEALHNHYTQKSLSLSLG*

[0186] SEQ ID NO: 56

[0187] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTIS ADKSISTAYLQWSSLKASDTAMYYCVRMPNWGSLDHWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVD KRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV MHEALHNHYTQKSLSLSLG*

[0188] SEQ ID NO: 57

[0189] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTIS ADKSISTAYLQWSSLKASDTAMYYCVRMPNWGSLDHWGQGTLVTVSSASIKGPSVFPLAPCSRSTSESTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNA KTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSD1AVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVM HEALHNHYTQKSLSLSLG* SEQ ID NO: 58

[0190] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTIS ADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVD KRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV MHEALHNHYTQKSLSLSLG*

[0191] SEQ ID NO: 59

[0192] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTIS ADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQGTLVTVSSASIKGPSVFPLAPCSRSTSESTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNA KTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSD1AVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVM HEALHNHYTQKSLSLSLG*

[0193] SEQ ID NO: 60

[0194] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTIS ADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVTSSNFGTQTYTCNVDHKPSNTKV DKTVERKC CVE CPP CPAPPVAGPSVFLFPPKPKDTLMI SRTPEVTCVWD VSQEDPE VQFN WYVD GVE VH NAKTKPREEQFNSTFRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCS

[0195] VMHEALHNHYTQKSLSLSPG* and a sequence at least 95% identical to any one of the same (*K deleted in a post translational modification).

[0196] In one embodiment the light chain is independently selected from a group comprising: SEQ ID NO: 61: SEQ ID NO: 62; SEQ ID NO: 63 and a sequence at least 95% identical to any one of the same.

[0197] SEQ ID NO: 61

[0198] Glu He Vai Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser He Ser Ser Ser Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu He Tyr Gly Ala Ser Ser Arg Ala Thr Gly He Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Arg Leu Glu Pro Glu Asp Phe Ala Vai Tyr Tyr Cys Gin Gin Tyr Ala Ser Phe Gly Gin Gly Thr Lys Vai Glu lie Lys Arg Thr Vai Ala Ala Pro Ser Vai Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Vai Vai Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Vai Gin Trp Lys Vai Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Vai Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Vai Tyr Ala Cys Glu Vai Thr His Gin Gly Leu Ser Ser Pro Vai Thr Lys Ser Phe Asn Arg Gly Glu Cys

[0199] SEQ ID NO: 62

[0200] Glu lie Vai Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser lie Ser Ser Ser Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu He Tyr Gly Ala Ser Ser Arg Ala Thr Gly lie Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Arg Leu Glu Pro Glu Asp Phe Ala Vai Tyr Tyr Cys Gin Gin Tyr Glu Ala Phe Gly Gin Gly Thr Lys Vai Glu lie Lys Arg Thr Vai Ala Ala Pro Ser Vai Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Vai Vai Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Vai Gin Trp Lys Vai Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Vai Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Vai Tyr Ala Cys Glu Vai Thr His Gin Gly Leu Ser Ser Pro Vai Thr Lys Ser Phe Asn Arg Gly Glu Cys

[0201] SEQ ID NO: 63

[0202] Glu lie Vai Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser He Ser Ser Ser Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu He Tyr Gly Ala Ser Ser Arg Ala Thr Gly lie Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Arg Leu Glu Pro Glu Asp Phe Ala Vai Tyr Tyr Cys Gin Gin Tyr Glu Thr Phe Gly Gin Gly Thr Lys Vai Glu He Lys Arg Thr Vai Ala Ala Pro Ser Vai Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Vai Vai Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Vai Gin Trp Lys Vai Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Vai Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Vai Tyr Ala Cys Glu Vai Thr His Gin Gly Leu Ser Ser Pro Vai Thr Lys Ser Phe Asn Arg Gly Glu Cys

[0203] In one embodiment the heavy chain is independently selected from SEQ ID NO: 55, 56, 57, 58, 59 and 60 (or a sequence at least 95% identical to any one of the same] and the light chain is independently selected from SEQ ID NO: 61 62 and 63 (or a sequence at least 95% identical to any one of the same].

[0204] In one embodiment the heavy chain is SEQ ID NO: 55 (or a sequence at least 95% identical thereto] and the light chain is independently selected from SEQ ID NO: 61 or 62 and 63 (or a sequence at least 95% identical to any one of the same].

[0205] In one embodiment the heavy chain is SEQ ID NO: 56 (or a sequence at least 95% identical thereto] and the light chain is independently selected from SEQ ID NO: 61 or 62 and 63 (or a sequence at least 95% identical to any one of the same].

[0206] In one embodiment the heavy chain is SEQ ID NO: 57 (or a sequence at least 95% identical thereto] and the light chain is independently selected from SEQ ID NO: 62 or 63 and 63 (or a sequence at least 95% identical to any one of the same].

[0207] In one embodiment the heavy chain is SEQ ID NO: 58 (or a sequence at least 95% identical thereto] and the light chain is independently selected from SEQ ID NO: 61 62 and 63 (or a sequence at least 95% identical to any one of the same].

[0208] In one embodiment the heavy chain is SEQ ID NO: 59 (or a sequence at least 95% identical thereto] and the light chain is independently selected from SEQ ID NO: 61 62 and 63 (or a sequence at least 95% identical to any one of the same].

[0209] In one embodiment the heavy chain is SEQ ID NO: 60 (or a sequence at least 95% identical thereto] and the light chain is independently selected from SEQ ID NO: 61 61 and 63 (or a sequence at least 95% identical to any one of the same].

[0210] In one embodiment the heavy chain is SEQ ID NO: 58 or 60 (or a sequence at least 95% identical to any one of the same] and a light chain with the sequence shown in SEQ ID NO: 61 (or a sequence at least 95% identical thereto]. In one embodiment the heavy chain is SEQ ID NO: 58 (or a sequence at least 95% identical to any one of the same] and a light chain with the sequence shown in SEQ ID NO: 61 (or a sequence at least 95% identical thereto).

[0211] In one embodiment the heavy chain is SEQ ID NO: 60 (or a sequence at least 95% identical to any one of the same) and a light chain with the sequence shown in SEQ ID NO: 61 (or a sequence at least 95% identical thereto).

[0212] In one embodiment, the anti-IL13R antibody of the present disclosure comprises a CDRH1 comprising an amino acid sequence as setforth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 10, a CDRL1 comprising an amino acid sequence SEQ ID NO: 31, a CDRL2 comprising an amino acid sequence SEQ ID NO: 32, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 45.

[0213] In one embodiment, the anti-IL13R antibody is eblasakimab (previously known as ASLAN004).

[0214] Derived from as employed herein refers to the factthatthe sequence employed or a sequence highly similar to the sequence employed was obtained from the original genetic material, such as the light or heavy chain of an antibody.

[0215] "At least 95% identical” as employed herein is intended to refer to an amino acid sequence which over its frill length is 95% identical or more to a reference sequence, such as 96, 97, 98 or 99% identical. Software programmes can be employed to calculate percentage identity.

[0216] Any discussion of a protein, antibody or amino acid sequence herein will be understood to include any variants of the protein, antibody or amino acid sequence produced during manufacturing and / or storage. For example, during manufacturing or storage an antibody can be deamidated (e.g., atan asparagine or a glutamine residue) and / or have altered glycosylation and / or have a glutamine residue converted to pyroglutamate and / or have a N-terminal or C-terminal residue removed or "clipped” (C-terminal lysine residues of encoded antibodies are often removed during the manufacturing process) and / or have part or all of a signal sequence incompletely processed and, as a consequence, remain at the terminus of the antibody. It is understood that an antibody comprising a particular amino acid sequence or binding fragment thereof may be a heterogeneous mixture of the stated or encoded sequence and / or variants of that stated or encoded sequence or binding fragment thereof.

[0217] In one embodiment the present disclosure extends to a sequence explicitly disclosed herein where the C-terminal lysine has been cleaved.

[0218] In one embodiment an antibody or binding fragment thereof, employed in a formulation of the present disclosure is humanised.

[0219] Humanised (which include CDR-grafted antibodies) as employed herein refers to molecules having one or more complementarity determining regions (CDRs) from a non-human species and a framework region from a human immunoglobulin molecule (see, for example US5,585,089; W091 / 09967). It will be appreciated that it may only be necessary to transfer the specificity determining residues of the CDRs rather than the entire CDR (see for example, Kashmiri et al 2005, Methods, 36, 25-34). Humanised antibodies may optionally further comprise one or more framework residues derived from the non-human species from which the CDRs were derived. For a review, see Vaughan et al, Nature Biotechnology, 16, 535-539, 1998.

[0220] When the CDRs or specificity determining residues are grafted, any appropriate acceptor variable region framework sequence may be used having regard to the class / type of the donor antibody from which the CDRs are derived, including mouse, primate and human framework regions. Examples of human frameworks which can be used in the present invention are KOL, NEWM, REI, EU, TUR, TEI, LAY and POM (Kabat et al). For example, KOL and NEWM can be used for the heavy chain, REI can be used for the light chain and EU, LAY and POM can be used for both the heavy chain and the light chain. Alternatively, human germline sequences may be used; these are available at: http: / / vbase.mrc-cpe.cam.ac.uk /

[0221] In a humanised antibody employed in the present invention, the acceptor heavy and light chains do not necessarily need to be derived from the same antibody and may, if desired, comprise composite chains having framework regions derived from different chains.

[0222] The framework regions need not have exactly the same sequence as those of the acceptor antibody. For instance, unusual residues may be changed to more frequently-occurring residues for that acceptor chain class or type. Alternatively, selected residues in the acceptor framework regions may be changed so that they correspond to the residue found at the same position in the donor antibody (see Reichmann et al., 1998, Nature, 332, 323-324). Such changes should be kept to the minimum necessary to recover the affinity of the donor antibody. A protocol for selecting residues in the acceptor framework regions which may need to be changed is set forth in W091 / 09967.

[0223] In one embodiment the anti-IL13R antibodies of the present disclosure are fully human, in particular one or more of the variable domains are fully human.

[0224] Fully human molecules are those in which the variable regions and the constant regions (where present) of both the heavy and the light chains are all of human origin, or substantially identical to sequences of human origin, not necessarily from the same antibody. Examples of fully human antibodies may include antibodies produced, for example by the phage display methods described above and antibodies produced by mice in which the murine immunoglobulin variable and optionally the constant region genes have been replaced by their human counterparts e.g. as described in general terms in EP0546073, US5,545,806, US5,569,825, US5,625,126, US5,633,425, US5, 661,016, US5,770,429, EP0438474 and EP0463151.

[0225] Thus, the presently disclosed anti-lL13R antibody may comprise one or more constant regions, such as a naturally occurring constant domain or a derivate of a naturally occurring domain. A derivative of a naturally occurring domain as employed herein is intended to refer to where one, two, three, four or five amino acids in a naturally occurring sequence have been replaced or deleted, for example to optimize the properties of the domain such as by eliminating undesirable properties but wherein the characterizing feature(s) of the domain is / are retained.

[0226] If desired an antibody for use in the present invention may be conjugated to one or more effector molecule(s). It will be appreciated that the effector molecule may comprise a single effector molecule or two or more such molecules so linked as to form a single moiety that can be attached to the antibodies of the present invention. Where it is desired to obtain an antibody fragment linked to an effector molecule, this may be prepared by standard chemical or recombinant DN A procedures in which tire antibody fragment is linked either directly or indirectly including via a coupling agent to the effector molecule. Techniques for conjugating such effector molecules to antibodies are well known in the art (see, Hellstrom et al, Controlled Drug Delivery, 2nd Ed., Robinson et al, eds., 1987, pp. 623-53; Thorpe etal, 1982, Immunol. Rev., 62:119-58 and Dubowchik etal, 1999, Pharmacology and Therapeutics, 83, 67-123). Particular chemical procedures include, for example, those described in W093 / 06231, WO92 / 22583, W089 / 00195, W089 / 01476 and W003 / 031581. Alternatively, where the effector molecule is a protein or polypeptide the linkage may be achieved using recombinant DNA procedures, for example as described in W086 / 01533 and EP0392745.

[0227] The term effector molecule as used herein includes, for example, biologically active proteins, for example enzymes, other antibody or antibody fragments, synthetic or naturally occurring polymers, nucleic acids and fragments thereof eg DNA, RNA and fragments thereof, radionuclides, particularly radioiodide, radioisotopes, chelated metals, nanoparticles and reporter groups such as fluorescent compounds or compounds which may be detected by NMR or ESR spectroscopy.

[0228] Other effector molecules may include detectable substances useful for example in diagnosis. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive nuclides, positron emitting metals (for use in positron emission tomography), and nonradioactive paramagnetic metal ions. See generally US4,741,900 for metal ions which can be conjugated to antibodies for use as diagnostics. Suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; suitable prosthetic groups include streptavidin, avidin and biotin; suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride and phycoerythrin; suitable luminescent materials include luminol; suitable bioluminescent materials include luciferase, luciferin, and aequorin; and suitable radioactive nuclides include 1251, 1311, lllln and 99Tc.

[0229] In another example the effector molecule may increase the half-life of the antibody in vivo, and / or reduce immunogenicity of the antibody and / or enhance the delivery of an antibody across an epithelial barrier to the immune system. Examples of suitable effector molecules of this type include polymers, albumin, albumin binding proteins or albumin binding compounds such as those described in W005 / 117984. Where the effector molecule is a polymer it may, in general, be a synthetic or a naturally occurring polymer, for example an optionally substituted straight or branched chain polyalkylene, polyalkenylene or polyoxyalkylene polymer or a branched or unbranched polysaccharide, e.g. a homo- or hetero- polysaccharide.

[0230] Specific optional substituents which may be present on the above-mentioned synthetic polymers include one or more hydroxy, methyl or methoxy groups.

[0231] Specific examples of synthetic polymers include optionally substituted straight or branched chain poly(ethyleneglycol), poly(propyleneglycol) poly(vinylalcohol) or derivatives thereof, especially optionally substituted poly(ethyleneglycol) such as methoxypoly(ethyleneglycol) or derivatives thereof.

[0232] Specific naturally occurring polymers include lactose, amylose, dextran, glycogen or derivatives thereof.

[0233] "Derivatives” as used herein is intended to include reactive derivatives, for example thiolselective reactive groups such as maleimides and the like. The reactive group may be linked directly or through a linker segment to the polymer. It will be appreciated that the residue of such a group will in some instances form part of the product as the linking group between the antibody fragment and the polymer.

[0234] Suitable polymers include a polyalkylene polymer, such as a poly(ethyleneglycol) or, especially, a methoxypoly(ethyleneglycol) or a derivative thereof, and especially with a molecular weight in the range from about 15000Da to about 40000Da.

[0235] In one example antibodies for use in the present invention are attached to poly(ethyleneglycol) [PEG] moieties. In one particular example the antibody is an antibody fragment and the PEG molecules may be attached through any available amino acid side-chain or terminal amino acid functional group located in the antibody fragment, for example any free amino, imino, thiol, hydroxyl or carboxyl group. Such amino acids may occur naturally in the antibody fragment or may be engineered into the fragment using recombinant DNA methods (see for example US5,219,996; US5,667,425; WO98 / 25971, W02008 / 038024]. In one example the antibody molecule of the present invention is a modified Fab fragment wherein the modification is the addition to the C-terminal end of its heavy chain one or more amino acids to allow the attachment of an effector molecule. Suitably, the additional amino acids form a modified hinge region containing one or more cysteine residues to which the effector molecule may be attached. Multiple sites can be used to attach two or more PEG molecules.

[0236] In patients with cancer, such as breast cancer, cancer related lymphedema (BCRL), the formulation of the present disclosure may prevent lymphedema associated effects, such as fibrosis, hyperkeratosis, the deposition of flbroadipose tissue, fluid accumulation, limb swelling, reduction of skin elasticity, and pain. By reducing the excess volume, said formulation may improve lymphatic and, for example limb functions.

[0237] The development of lymphedema after lymphatic injury is associated with tissue inflammation, the infiltration of CD4-positive ceils and their differentiation to the type 2 helper T- celJ (Th 2) phenotype. Th 2 cells produce 1 L-4 and IL-13 that play a key role in the development of lymphedema-associated symptoms as well as other Th2-mediated diseases.

[0238] In one embodiment the formulation herein is administered in combination with another therapy.

[0239] "In combination” as employed herein is intended to encompass where the anti-IL13Rantibody is administered before, concurrently with another therapy or after another therapy, as the same or different formulations. Thus, combination is where the pharmacological effect of a first therapy exists at the same as the existence of a pharmacological effect of second therapy in the body and / or the two therapies are part of treatment plan designed to be employed together.

[0240] Therapeutic dose as employed herein refers to the amount of the anti-IL13R antibody, such as ASLAN004 that is suitable for achieving the intended therapeutic effect when employed in a suitable treatment regimen, for example ameliorates symptoms or conditions of a disease, in particular without eliciting dose limiting side effects. Suitable therapeutic doses are generally a balance between therapeutic effect and tolerable toxicity, for example where the side-effect and toxicity are tolerable given the benefit achieved by the therapy.

[0241] In one embodiment a formulation according to the present disclosure (including a formulation comprising same) is administered monthly, for example in a treatment cycle or as maintenance therapy. In one embodiment the antibody or antigen binding fragment thereof is administered topically to the airways by inhalation for example as a liquid formulation (delivered directly to the airways or a nebulised), aresol formulation or as a dry powder formulation, for example the antibody or fragment may be adsorbed onto carrier particles for inhalation or admixed with the same (such as where the antibody or fragment is lyophilised). Thus in one embodiment there is provided a formulation for inhalation of the antibody or antigen binding fragment for use in the treatment of AHR, in particular for delivery to the airways (including nasal passages) and / or lungs. Advantageously this allows the antibody / fragment to act immediately in the target tissue and may also allow smaller doses to be delivered and / or result in reduced side effects.

[0242] Suitable inhalable preparations include inhalable powders, metering aerosols containing propellant gases or inhalable solutions free from propellant gases. Inhalable powders according to the disclosure containing the active substance may consist solely of the abovementioned active substances or of a mixture of the abovementioned active substances with physiologically acceptable excipient

[0243] These inhalable powders may include monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextranes), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these with one another. Mono- or disaccharides are suitably used, the use of lactose or glucose, particularly but not exclusively in the form of their hydrates.

[0244] Particles for deposition in the lung require a particle size less than 10 microns, such as 1-9 microns for example from 0.1 to 5 pm, in particular from 1 to 5 pm. The particle size of the active ingredient (such as the binding protein or fragment) is of primary importance.

[0245] The propellent gases which can be used to prepare the inhalable aerosols are known in the art Suitable propellent gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as chlorinated and / or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned propellent gases may be used on their own or in mixtures thereof.

[0246] Particularly suitable propellent gases are halogenated alkane derivatives selected from among TG 11, TG 12, TG 134a and TG227. Of the abovementioned halogenated hydrocarbons, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof are particularly suitable.

[0247] The propellent-gas-containing inhalable aerosols may also contain other ingredients such as cosolvents, stabilisers, surface-active agents (surfactants), antioxidants, lubricants and means for adjusting the pH. All these ingredients are known in the art.

[0248] The propellant-gas-containing inhalable aerosols according to the invention may contain up to 5 % by weight of active substance. Aerosols according to the invention contain, for example, 0.002 to 5 % by weight, 0.01 to 3 % by weight, 0.015 to 2 % by weight, 0.1 to 2 % by weight, 0.5 to 2 % by weight or 0.5 to 1 % by weight of active ingredient.

[0249] Alternatively topical administrations to the lung may also be by administration of a liquid solution or suspension formulation, for example employing a device such as a nebulizer, for example, a nebulizer connected to a compressor (e.g., the Pari LC-Jet Plus(R) nebulizer connected to a Pari Master(R) compressor manufactured by Pari Respiratory Equipment, Inc., Richmond, Va.). The molecule of the invention can be delivered dispersed in a solvent, e.g., in the form of a solution or a suspension. It can be suspended in an appropriate physiological solution, e.g., saline or other pharmacologically acceptable solvent or a buffered solution. Buffered solutions known in the art may contain 0.05 mg to 0.15 mg disodium edetate, 8.0 mg to 9.0 mg NaCl, 0.15 mg to 0.25 mg polysorbate, 0.25 mg to 0.30 mg anhydrous citric acid, and 0.45 mg to 0.55 mg sodium citrate per 1 ml of water so as to achieve a pH of about 4.0 to 5.0. A suspension or solution can be reconstituted, for example, lyophilised molecules.

[0250] The therapeutic suspensions or solution formulations can also contain one or more excipients. Excipients are well known in the art and include buffers (e.g., citrate buffer, phosphate buffer, acetate buffer and bicarbonate buffer], amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins (e.g., serum albumin], EDTA, sodium chloride, liposomes, mannitol, sorbitol, and glycerol. Solutions or suspensions can be encapsulated in liposomes or biodegradable microspheres. The formulation will generally be provided in a substantially sterile form employing sterile manufacture processes.

[0251] This may include production and sterilization by filtration of the buffered solvent / solution used for the formulation, aseptic suspension of the molecule in the sterile buffered solvent solution, and dispensing of the formulation into sterile receptacles by methods familiar to those of ordinary skill in the art

[0252] Nebulizable formulation according to the present disclosure may be provided, for example, as single dose units (e.g., sealed plastic containers or vials] for example packed in foil envelopes. Each vial contains a unit dose in a volume, e.g., 2 mL, of solvent / solution buffer.

[0253] Unit dose as used herein generally refers to a product comprising the amount of anti-IL13R antibody or binding fragment thereof of the present disclosure that is administered in a single dose including any overage.

[0254] A unit dose of the presently claimed anti-IL1 R antibody or antigen binding fragment thereof may refer to the marketed form of the product, such as a formulation of the anti-IL13R antibody or binding fragment thereof, wherein the product is apportioned into the amount of anti-IL13R antibody that is required for a single dose. Thus, the manufacturer is able to determine and control the exact amount of anti-13R antibody or binding fragment thereof to be included in each unit dose.

[0255] The product may be in various forms, familiar to the skilled addressee, such as vials, ampoules, infusion bags or a device (including an auto-injection device].

[0256] The exact amount as employed herein refers to the amount to be administer as a dose to the patient and any overage.

[0257] In one embodiment, the unit dose or unit doses are for use according to a method of the present disclosure.

[0258] In the context of this specification "comprising" is to be interpreted as "including". Embodiments of the invention comprising certain features / elements are also intended to extend to alternative embodiments "consisting" or "consisting essentially" of the relevant elements / features. Where technically appropriate, embodiments of the invention may be combined.

[0259] Technical references such as patents and applications are incorporated herein by reference.

[0260] Any embodiments specifically and explicitly recited herein may form the basis of a disclaimer either alone or in combination with one or more further embodiments. The background section of this specification contains relevant technical information and may be used as basis for amendment

[0261] Subject headings herein are employed to divide the document into sections and are not intended to be used to construe the meaning of the disclosure provided herein.

[0262] The present invention is further described by way of illustration only in the following examples.

[0263] BRIEF DESCRIPTION OF FIGURES

[0264] Figure 1 shows a graph which demonstrates that eblasakimab inhibits cytokine-induced airway constriction. n=number of airways assessed over at least 6 lung slices. ** = p<0.01

[0265] Figure 2 shows a graph which demonstrates that eblasakimab inhibits metacholine (Meh) induced airway constriction. n=number of airways assessed over at least 6 lung slices. * = p<0.05

[0266] Figure 3 shows a graph which demonstrates that eblasakimab enhances acute airway dilation. n=number of airways assessed over at least 6 lung slices. * = p<0.05

[0267] Figure 4 shows a graph which compares the ability of eblasakimab vs dupilumab to reverse cytokine-induced basal airway constriction in a PCLS model derived from a healthy donor. * = p<0.05, ** = p<0.01

[0268] Figure 5A shows a graph which compares the ability of eblasakimab vs dupilumab to enhance airway dilation in response to formoterol in a PCLS model derived from a healthy donor after 5 minutes of exposure to formoterol. * = p<0.05

[0269] Figure 5B shows a graph which compares the ability of eblasakimab vs dupilumab to enhance airway dilation in response to formoterol in a PCLS model derived from a healthy donor after 15 minutes of exposure to formoterol. * = p<0.05

[0270] Figure 6 shows a graph which compares the ability of eblasakimab vs dupilumab to reverse methacholine-induced airway constriction in a PCLS model derived from a healthy donor. * = p<0.05, ** = p<0.01, *** = p<0.001

[0271] Figure 7 shows a graph which compares the ability of eblasakimab vs dupilumab to reverse cytokine-induced airway constriction in a PCLS model derived from a COPD patient. * = p<0.05, ns = not significant

[0272] Figure 8 shows a graph which compares the ability of eblasakimab vs dupilumab to reverse methacholine-induced basal airway constriction in a PCLS model derived from a COPD patient ** = p<0.01, *** = p<0.001, ns = not significant.

[0273] Figure 9 shows a graph which compares the ability of eblasakimab vs dupilumab to enhance airway dilation in response to formoterol in a PCLS model derived from a COPD patient after 5 minutes exposure to formoterol. * = p<0.05, ns = not significant

[0274] Figure 10A shows graph of serum concentrations for eblasakimab over a range of subcutaneous doses.

[0275] Figure 10B shows graph of serum concentration for dupilumab over a range of subcutaneous doses. Source: Figure 1C, Li Z etal, Clinical Pharmacology in Drug Development, Aug; 9(6)742-755 EXAMPLES

[0276] Example 1 - Experiment to establish IL-13 and IL-4 induced airway hyper-responsiveness (AHR) in a precision cut lung slices (PCLS) model of airway hyperresponsiveness.

[0277] Airway obstruction and airway hyperresponsiveness (AHR) are hallmark features of lung disorders such as asthma and chronic obstructive pulmonary disease (COPD). Thus, to assess eblasakimab’s ability to provide relief in AHR, Type 2 cytokine stimulation (IL-13 and IL-4) in a human precision cut lung slices (PCLS) ex vivo model was used.

[0278] Materials and Methods

[0279] PCLS were treated for 48h in presence of IL-13 and IL-4 at 100 ng / ml each, or in the presence of IL- 13 and IL-4 at 100 ng / ml each and also eblasakimab at 500 pg / ml. The use of PCLS to measure lung stiffness is described in more detail in Kim et al, Sci Adv. 2023 May: 9(20): eadf2535.

[0280] 3 different tests were then carried out:

[0281] 1. Eblasakimab's ability to inhibit cytokine-induced airway constriction

[0282] The % of contraction of the PCLS was compared between control (vehicle), IL-13 and IL-4 only, or IL-13, IL-4 and eblasakimab.

[0283] 2. Eblasakimab's ability to inhibit methacholine (MCh)-induced airway constriction Methacholine was administered at a lOuM dose (~EC90) and % of contraction of the PCLS after 30 minutes was compared between control (vehicle), IL-13 and IL-4 only, or IL-13, IL- 4 and eblasakimab

[0284] 3. Eblasakimab's ability to enhance acute airway dilation

[0285] Formoterol was administered acutely at a lOnM dose (-IC80) and the % relaxation of the PCLS after 5 and 15 minutes was compared between control (vehicle), IL-13 and IL-4 only, or IL- 13, IL-4 and eblasakimab.

[0286] Results

[0287] The results are shown in Figures 1 to 3.

[0288] Figure 1 demonstrates that eblasakimab was able to significantly inhibit IL-13 and IL-4 cytokine induced airway constriction compared to control.

[0289] Figure 2 demonstrates that while IL- 13 and IL-4 cytokine treatment enhanced MCh-induced airway constriction, eblasakimab was able to inhibit this effect

[0290] Figure 3 demonstrates that at 5 mins following formoterol administration, while IL-13 and IL-4 cytokine treatment inhibited formoterol-induced airway treatment, eblasakimab was able to overcome this effect. After 15 mins of formoterol treatment, the PCLS of all treatment groups relaxed fully (100% relaxation).

[0291] Conclusions The experiments showed that IL-4 and IL-13 combined pre-treatment of PCLS results in increases of bronchoconstriction of the airways tested in the PCLS with Methacholine. Both cytokines delay the kinetics of airway dilation to Formoterol, suggesting rapid changes of airway responsiveness with 48 hours of treatment

[0292] Surprisingly, eblasakimab was able to significantly block the IL-4 / IL-13 increased bronchoconstriction as well as rapidly improve the airway dilation response to Formoterol as compared to the cytokine-treated PCLS.

[0293] Going forward, the present inventors plan to perform a comparison between eblasakimab vs Dupixent® (dupilumab) using the same experiment setup.

[0294] Example 2 - Head-to-head comparison between eblasakimab and Dupixent (dupilumab) in healthy donor PCLS model

[0295] A follow-up experiment was conducted to compare the function of eblasakimab vs dupilumab in a PCLS model derived from a healthy donor.

[0296] Materials and Methods

[0297] A similar experimental set-up as Example 1 was used. PCLS were treated for 48h in presence of IL- 13 and IL-4 at 250 ng / ml each. Either eblasakimab or Dupixent® as co-administered at 500 pg / ml or 25 pg / ml was co-administered. The 500 ng / ml dose is estimated to be 20x higher than the Cmax for eblasakimab and >10x higher than the Cmax for Dupixent®. 25 pg / ml (25,000 ng / ml) is the predicted clinically relevant dose for eblasakimab based on the serum concentration data shown in Figure 10A, corresponding to an expected clinical dose between 300 and 600 mg.

[0298] The same 3 tests were carried out with slight adjustments:

[0299] 1. Eblasakimab's ability to inhibit cytokine-induced airway constriction

[0300] The % of contraction of the PCLS was compared between control (vehicle), IL-13 and IL-4 only, IL-13, IL-4 and eblasakimab. or IL-13, IL-4 and Dupixent®.

[0301] 2. Eblasakimab's ability to inhibit methacholine (MCh)-induced airway constriction Methacholine was administered at a lOuM dose (~EC90) and % of contraction of the PCLS after 20 minutes was compared between control (vehicle), IL-13 and IL-4 only, IL-13, IL-4 and eblasakimab, or IL-13, IL-4 and Dupixent®.

[0302] 3. Eblasakimab's ability to enhance acute airway dilation

[0303] Formoterol was administered acutely at a lOnM dose (-IC80) and the % relaxation of the PCLS after 5 and 15 minutes was compared between control (vehicle), IL-13 and IL-4 only, IL-13, IL-4 and eblasakimab, or IL-13, IL-4 and Dupixent®.

[0304] Results

[0305] The results are shown in Figures 4 to 6.

[0306] Figure 4 demonstrates that at the 500 pg / ml dose, eblasakimab was able to inhibit IL-13 and IL-4 cytokine induced airway constriction to a greater extent that Dupixent® at both the 25 pg / ml and 500 pg / ml doses. Figure 5A demonstrates that at 5 mins following formoterol administration, eblasakimab had superior dilatory effects in response to formoterol compared to Dupixent when comparing between 25 pg / ml eblasakimab and 25 pg / ml dupilumab.

[0307] Figure 5B shows that after 15 mins of formoterol treatment, all test groups showed 100% airway relaxation. This observation was in line with the previous results in Example 1.

[0308] Figure 6 demonstrates that eblasakimab was able to improve methacholine induced airway constriction qualitatively better than Dupixent®. This difference was particularly pronounced when comparing between the lower 25 pg / ml dose for eblasakimab and dupilumab.

[0309] Conclusions

[0310] The data suggest that:

[0311] • Eblasakimab may have the potential to outperform dupilumab in restoring lung disorder associated airway constrictions;

[0312] • Eblasakimab clinically relevant doses resulted in stronger dilatory effects to formoterol compared to dupilumab; and

[0313] • Targeting IL-13Ral with eblasakimab vs targeting IL-4Ra with dupilumab may provide stronger benefits restoring lung function in disorders associated with airway hyperresponsiveness (AHR), such as COPD and possibly other comorbidities. In particular, eblasakimab may provide stronger relief to address bronchoconstriction and improve dilatory function in COPD.

[0314] Example 3 - Head-to-head comparison between eblasakimab and Dupixent (dupilumab) in COPD donor PCLS model

[0315] A follow-up experiment was conducted to compare the function of eblasakimab vs dupilumab in PCLS samples derived from a COPD patient

[0316] Materials and Methods

[0317] The same experimental set-up as Example 2 was used. The difference from Example 2 is that the PCLS samples were derived from a COPD patient instead of a healthy donor, and that the samples were treated with 75 pg / ml eblasakimab or Dupixent® instead of 500 pg / ml eblasakimab or Dupixent®. The 75 pg / ml dose is the clinically relevant dose for dupilumab based on mean steady state concentrations as taught in the literature (see for example Li Z et al. Clinical Pharmacology in Drug Development, Aug; 9(6)742-755).

[0318] Results

[0319] The results are shown in Figures 7 to 9.

[0320] Figure 7 demonstrates that IL-4 / IL-13 induced basal constriction in COPD derived PCLS was significantly reversed with eblasakimab, and provides relief even beyond that of the control. In addition, eblasakimab appears to outperform dupilumab in restoring lung function at the 25 pg / ml, and also at dupilumab's clinically relevant dose of 75 pg / ml. Figure 8 demonstrates that eblasakimab provides superior relief to methacholine challenge compared to dupilumab at its predicted clinically relevant dose of 25 pg / ml and also at dupilumab’s clinically relevant dose of 75 pg / ml.

[0321] Figure 9 demonstrates that eblasakimab significantly improves dilatory function in response to formoterol in COPD derived PCLS at both the 25 pg / ml and 75 pg / ml doses. In comparison, dupilumab failed to significantly improve dilatory function in response to formoterol at all doses tested.

[0322] Conclusions

[0323] The results indicate that eblasakimab significantly reduced IL-13- and IL-4-induced bronchial airway constriction, significantly reduced sensitization by the constricting agent methacholine and enhanced airway dilation response to formoterol.

[0324] Surprisingly, eblasakimab appears to outperform dupilumab in restoring lung function to an even greater extent in COPD patient samples compared to healthy donor samples. For example, compare 25 pg / ml eblasakimab and 25 pg / ml dupilumab in Figure 7 with 25 pg / ml eblasakimab and 25 pg / ml dupilumab in Figure 4; and compare 25 pg / ml eblasakimab and 25 pg / ml dupilumab in Figure 8 with 25 pg / ml eblasakimab and 25 pg / ml dupilumab in Figure 6.

[0325] The results thus demonstrate a direct functional role of eblasakimab on airway hyperresponsiveness and a reduction of the pro-inflammatory-induced airway constriction responses driven by 1L-4 / IL- 13.

[0326] Furthermore, these head-to-head studies of eblasakimab against dupilumab suggest that eblasakimab may provide potentially stronger relief to address bronchoconstriction and improve dilatory function in COPD, and possibly in other Th2-driven lung disorders.

Claims

Claims1. An antibody or antigen binding fragment thereof, which is an inhibitor of signalling through IL-13Ral, by binding the said receptor, for use in treating airway hyperresponsiveness (AHR) (also referred to as bronchial hyperresponsiveness) in a patient, for example a patient whose symptoms are not alleviated by a bronchodilator, such as a patient with chronic obstructive pulmonary disease (COPD), whereby the treatment improves respiratory airflow in the patient.1 An antibody or antigen binding fragment thereof, which is an inhibitor of signalling through IL-13Ral by binding the said receptor, for use in improving respiratory airflow in a patient in need thereof, for example a patient whose symptoms are not alleviated by a bronchodilator, such as a patient with chronic obstructive pulmonary disease (COPD).

2. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the airway hyperresponsiveness is caused by airway remodelling, for example wherein the structure of the small airways is altered.

3. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the airway hyperresponsiveness is caused by an airway obstruction, for example an airway constriction occurring in one or more parts of the respiratory tract4. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the airway constriction occurs in one or more of the following: the trachea, the bronchi, the bronchioles and / or the alveoli.

5. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the airway constriction occurs in the bronchial tubes and / or alveoli.

6. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the airway constriction is due to a loss of elasticity of tissue in the respiratory tract, for example a loss of elasticity of the bronchial tubes and / or the alveoli.

7. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the airway constriction is due to a thickening of the airway walls, for example a thickening of the bronchial tube walls.

8. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the airway obstruction is due to excessive mucus production.

9. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the airway hyperresponsiveness is caused by allergic inflammation, for example allergic inflammation mediated by one or more pro-inflammatory cytokines.

10. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the airway constriction is cytokine-induced, for example induced by one or more proinflammatory cytokines.

11. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the one or more cytokines are selected from the group comprising IL-13 and IL4, for example both IL- 13 and IL4.

12. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the airway constriction is induced by a bronchoconstrictor, such as methacholine.

13. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the airway hyperresponsiveness is reversible with a bronchodilator, for example asthma.

14. An antibody or antigen binding fragment thereof for use according to any one of claims 1 to 12, wherein the airway hyperresponsiveness is not reversible with a bronchodilator.

15. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient has a disease or condition associated with airway hyperresponsiveness, for example asthma, bronchiectasis, chronic pulmonary obstructive disease (COPD) or cystic fibrosis.

16. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient has COPD.

17. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient has non-severe COPD.

18. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient has chronic bronchitis and / or emphysema.

19. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient has asthma.

20. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient has both asthma and COPD (asthma-COPD).

21. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the airway hyperresponsiveness is in response to one or more stimuli.

22. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the treatment results in a reduction in airway responsiveness to one or more stimuli, for example wherein the treatment results in a reduction of 10% or more, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in the amount of stimuli required to produce a 20% fall in forced expired volume in 1 second (FEVi).

23. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the treatment results in a greater reduction in airway responsiveness to one or more stimuli, for example wherein the treatment results in a reduction of 10% or more, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in the amount of stimuli required to produce a 20% fall in forced expired volume in 1 second (FEVi), compared to when dupilumab is administered.

24. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the one or more stimuli is selected from the group comprising: acetylcholine, methacholine, histamine, propranolol, SO2, AMP, hyperventilation and fog.

25. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the one or more stimuli is one or more cytokines, for example IL- 13 and / or IL-4.

26. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the respiratory airflow is improved by reducing or preventing airway constriction and / or by increasing airway dilation, for example in response to a bronchodilator.

1. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the respiratory airflow is improved to a greater extent compared to when dupilumab is administered, for example by reducing or preventing airway constriction to a greater extentcompared to dupilumab and / or by increasing airway dilation to a greater extent, for example in response to a bronchodilator.

28. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the respiratory airflow is improved by an increase in and / or by preventing a loss of elasticity of tissue in the respiratory tract compared to baseline.

29. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the respiratory airflow is improved by an increase in elasticity of the bronchial tubes and / or the alveoli.

30. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the respiratory airflow is improved by an increase in elasticity of tissue in the respiratory tract compared to baseline, for example an increase of 10% or more, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in elasticity compared to baseline.

31. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the respiratory airflow is improved by a greater increase in elasticity of tissue in the respiratory tract compared to when dupilumab is administered, for example an increase of 10% or more in responsiveness, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in responsiveness compared to when dupilumab is administered.

32. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the respiratory airflow is improved by an increase in responsiveness to a bronchodilator, compared to baseline, for example an increase of 10% or more in responsiveness, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in responsiveness compared to baseline.

33. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the respiratory airflow is improved by an increased responsiveness to a bronchodilator, compared to when dupilumab is administered, for example an increase of 10% or more in responsiveness, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% in responsiveness compared to when dupilumab is administered.

34. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the bronchodilator is selected from the group comprising: a beta 2-agonist, such as formoterol, salbutamol, levalbuterol or pirbuterol; an anticholinergic, such as aclidinium bromide, tiotropium bromide, glycopyrrol ate, glycopyrronium bromide or umeclidinium bromide; and a xanthine derivative, such as theophylline.

35. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the airway dilation agent is formoterol.

36. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the patient has a reduced peak expiratory flow (PEF) compared to a control individual, for example a reduction of 10% or more in PEF, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% compared to a control individual.

37. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the respiratory airflow is improved by an increase in peak expiratory flow (PEF) compared to baseline, for example an increase of atleast 10% in PEF, such as a 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% increase in PEF.

38. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the respiratory airflow is improved by a greater increase in peak expiratory flow (PEF) compared to when dupihimab is administered, for example an increase of at least 10% in PEF, such as a 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% increase in PEF.

39. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the patient has a reduced forced expiratory volume in 1 second (FEVi) compared to a control, for example a reduction of 10% or more in FEVi, such as 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% compared to a control individual.

40. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the respiratory airflow is improved by an increase in FEVi compared to baseline, for example an increase of at least 10% in FEVi, such as a 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% increase in FEVi.

41. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the respiratory airflow is improved by a higher increase in FEVi compared to when dupilumab is administered, for example an increase of at least 10% in FEVi, such as a 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% increase in FEVi.

42. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the patient has a forced expiratory volume in 1 second / forced expiratory capacity [FEVi / FVC] ratio which is below 0.7.

43. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the respiratory airflow is improved by an increased FEVi / FVC ratio in the patient compared to baseline, for example wherein the treatment results in the patient having an FEVi / FVC ratio of 0.7 or higher.

44. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the respiratory airflow is improved by an increased FEVi / FVC ratio in the patient compared to when dupilumab is administered.

45. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the respiratory airflow is improved by a more consistent peak expiratory flow (PEF) in the patient compared to before treatment46. An antibody or antigen binding fragment thereof for use according to any preceding claim, wherein the respiratory airflow is improved by a more consistent peak expiratory flow (PEF) in the patient compared to when dupilumab is administered.

47. An antibody or antigen binding fragment thereof according to any preceding claim, wherein the respiratory airflow is improved by a more consistent FEVi compared to before treatment.

48. An antibody or antigen binding fragment thereof according to any preceding claim, wherein the respiratory airflow is improved by a more consistent FEVi compared to when dupilumab is administered.

49. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient is a highly allergic patient, for example where the baseline IgE levels have been established and are at a level of at least 10,000 KU / L + / - 2,000.

50. An antibody or antigen binding fragment thereof for use according to claim23 wherein the baseline IgE levels are in the range 10,000 + / - 2,000 to 30,000 + / - 6,000 KU / L.

51. An antibody or antigen binding fragment thereof for use according to any one of claims 23 to 24, wherein the treatment reduces the IgE levels by at least 15% from baseline.

52. An antibody or binding fragment thereof for use according to claim25, wherein the treatment reduces the IgE levels by atleast 20% from the baseline.

53. An antibody or binding fragment thereof for use according to claim25 or 26, wherein the treatment reduces the IgE levels by atleast 30% from baseline, for example reduces said levels 30 to 40%, such as 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40% from baseline.

54. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient has pruritus.

55. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the pruritus is mediated by one or more of the following: histamine, 5-HT (serotonin), acetylcholine, substance P (SP), leukotrienes, bradykinin, proteases (such as typsin, tryptase, cathepsin S, or kallikrein-related peptidases such as KLK4 or KLK14), IL-31, lysophosphatidic acid, autotaxin and / or toll-like receptor 7 (TLR7).

56. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the pruritus is mediated by histamine.

57. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the pruritus is mediated by IL-13, IL-4 or a combination of both.

58. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the pruritus is mediated by both IL- 13 and IL-4.

59. An antibody or antigen bindingfragment thereof for use according to any one of the preceding claims, wherein the patient has a skin condition, for example selected from the group comprising dermatitis; such as atopic dermatitis (AD), contact dermatitis, neurodermatitis or seborrheic dermatitis; eczema; hand-foot-and-mouth disease; hives (including urticaria associated with Lupus), psoriasis, an infection, such as a fungal or bacterial infection, for example impetigo or folliculitis; an allergic skin reaction; Ehlers- Danlos syndrome; asthma; and angioedema, such as hereditary angioedema (HAE).

60. An antibody or antigen bindingfragment thereof for use according to any one of the preceding claims, wherein the patient has dermatitis, for example atopic dermatitis (AD), contact dermatitis, neurodermatitis or seborrheic dermatitis.

61. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient has atopic dermatitis (AD), for example moderate to severe atopic dermatitis.

62. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient has Ehlers-Danlos syndrome (EDS), asthma or angioedema (such as HAE).

63. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient has asthma.

64. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient has angioedema.

65. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient does not have atopic dermatitis or psoriasis.

66. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient does not have atopic dermatitis.

67. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient does not have psoriasis.

68. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient was previously administered dupilumab.

69. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient had airway hyperresponsiveness that was poorly controlled by dupilumab.

70. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the patient has COPD that was poorly controlled by dupilumab.

71. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein an improvement in airflow is present after about two weeks from administration of the first dose (such as day 15).

72. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein an improvement in airflow is present after about four weeks from administration of the first dose (such as day 29).

73. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein an improvement in airflow is present after about six weeks from administration of the first dose (such as day 43).

74. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein an improvement in airflow is present after about eight weeks from administration of the first dose (such as day 57).

75. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the treatment is administered intravenously.

76. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the treatment is administered subcutaneously.

77. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein multiple doses are administered in a treatment cycle (for example wherein the treatment cycle is 4 to 8 weeks, such as 8 weeks).

78. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein multiple treatment cycles are administered, for example 2, 3, 4 or more treatment cycles are administered.

79. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein following the treatment cycle or cycles and disease modification, maintenance therapy is administered, for example the same dose administered less frequently (for example monthly), or a lower dose (such as 200mg) administered the same frequency or less frequently (such as about two weekly, about three weekly, or about four weekly.

80. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein said antibody or binding fragment thereof is administered approximately weekly, (in particular a single treatment cycle, especially 8 weeks).

81. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein said antibody or binding fragment thereof is administered once approximately every two weeks, (in particular a single treatment cycle, especially 8 weeks],82. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein said antibody or binding fragment thereof is administered once approximately every three weeks, (in particular a single treatment cycle, especially 8 weeks].

83. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or binding fragment thereof is administered once approximately every four weeks (for example monthly], (in particular a single treatment cycle, especially 8 weeks],84. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein a loading dose in the range 400 to 900mg, for example 400, 500, 600, 700, 800 or 900mg is employed before administration of the treatment cycle.

85. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein a loading dose of 600 mg is employed before administration of the therapeutic doses.

86. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the loading dose is administered for 1 to 3 weeks, such as 1, 2 or 3 weeks prior to administration of the therapeutic doses.

87. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the loading dose is administered only on week 0, for example 600 mg on week 0.

88. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the loading dose is administered on weeks 0 and 1, for example 600 mg on week 0 and 600 mg on week 1.

89. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the loading dose is administered on weeks 0, 1 and 2, for example 600 mg on week 0, 600 mg on week 1 and 600 mg on week 290. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the treatment does not comprise a loading dose.

91. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the dose, such as the therapeutic dose is in the range of 200 to 900 mg.

92. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the dose is in the range of 300 to 600 mg.

93. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the dose is 200mg.

94. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the dose is 300 mg, for example administered weekly.

95. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the dose is 400mg, for example administered bi-weekly or twice monthly.

96. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the dose is 600mg, for example administered monthly.

97. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the therapeutic dose of the anti-IL13R antibody or binding fragment thereof is 400 mg dosed every 2 weeks (400 mg Q2W).

98. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the therapeutic dose of the anti-IL13R antibody or binding fragment thereof is 600 mg dosed every 2 weeks (600 mg Q2W).

99. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the therapeutic dose of the anti-IL13R antibody or binding fragment thereof is 300 mg dosed every 2 weeks (300 mg Q2W).

100. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein a loading dose of 600 mg is administered during weeks 0 and 1, followed by therapeutic dosing of 300 mg dosed every 2 weeks (300 mg Q2W],101. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein a loading dose of 600 mg is administered during weeks 0 and 1, followed by therapeutic dosing of 400 mg dosed every 2 weeks (400 mg Q2W],102. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein a loading dose of 600 mg is administered during weeks 0, 1 and 2 followed by therapeutic dosing of 600 mg dosed every 4 weeks (400 mg Q4WJ.

103. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the treatment cycles comprises, a first dose at 600mg, followed by three weekly doses of 400mg, for example wherein the treatment cycle is repeated twice i.e. two treatment cycles lasting 8 weeks, in particular day 1 600mg, approximately day 8 400mg, approximately day 15 400mg, approximately day 22 400mg, approximately day 29 600mg, approximately day 36400mg, approximately day 43400mg, and approximately day 50400mg are administered.

104. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the disease modification occurs by day 8, wherein day 1 is the first administration of the antibody or binding fragment thereof.

105. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the disease modification is a reduction in the SD score of POEM, for example wherein the reduction is a percentage from base line in the range -50 to -100%.

106. An antibody or antigen binding fragment thereof for use according to claim80, wherein the disease modification in the range -50 to -100% is achieved by about day 57 following first administration on day 1, for example maximum disease modification is achieved by about day 57.

107. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen binding fragment binds an epitope FFYQ (for example same epitope as the antibody with a VH shown in SEQID NO: 51 and a VL shown in SEQID NO: 53, or a sequence at least 95% identical to any one of the same.

108. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen binding fragment thereof is an anti-IL13Ral antibody or antigen binding fragment thereof.

109. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen binding fragment thereof comprises a VH CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a VH CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a VH CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10.

110. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen binding fragment thereof comprises a VH domain comprising an amino acid sequence shown in SEQ ID NO: 51 or a sequence at least 95% identical thereto, in particular SEQ ID NO: 51.

111. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen binding fragment thereof comprises a VL CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 31, a VL CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 32, and a VL CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 45.

112. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen binding fragment thereof comprises a VL domain comprising an amino acid sequence shown in SEQ ID NO: 53 or a sequence at least 95% identical thereto, in particular SEQ ID NO: 53.

113. An antibody or antigen binding fragment thereof for use according to any one of the preceding claims, wherein the antibody comprises a VL domain comprising an amino acid sequence shown in SEQ ID NO: 53 or a sequence at least 95% identical thereto, in particular SEQ ID NO: 53, and a VH comprising an amino acid sequence shown in SEQ ID NO: 51 or a sequence at least 95% identical thereto, in particular SEQ ID NO: 51.

114. A pharmaceutical formulation comprising the antibody or binding fragment thereof for use according to any one of the preceding claims, said formulation comprising 150 to 210 mg / ml of an anti-IL-13R antibody or antigen binding fragment thereof, for example 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205 or 210 mg / ml, in particular 150 mg / ml, 175 mg / ml or 200 mg / ml;170 to 250 mM of arginine (such as Arg-HCl or Arg-Glu], for example 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245 or 250 mM, in particular 150 mM, 175 mM or 250 mM;20 to 50 mM histidine buffer, for example 20, 25, 30, 35, 40, 45 or 50 mM, such as 20 mM or 50 mM histidine buffer;0.01-0.03% of a non-ionic surfactant, such as 0.02% w / w; and wherein the pH of the formulation is in the range 6.0 to 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 6.5.

115. A pharmaceutical formulation comprising an antibody or binding fragment thereof for use according to any one of the preceding claims, said formulation comprising 175 to 250 mg / ml of an anti-IL-13R antibody or antigen binding fragment thereof, for example 175, 180, 185, 190, 195, 200, 205, 210, 215, 220 or 225 mg / ml, in particular 200 mg / ml, 225 mg / ml or 250 mg / ml;15 to 75 mM of tryptophan, such as 15 to 60 mM, in particular 25 to 50 mM tryptophan;190 to 270 mM of arginine (such as Arg-HCl or Arg-Glu), for example 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265 or 270 mM, in particular 200, 210, 225, 235, 250 or 260 mM;0.01-0.03% of a non-ionic surfactant, for example 0.01-0.03% w / w, such as 0.02% w / w; a buffer (such as histidine buffer); and wherein the pH of the formulation is in the range 6.0 to 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 6.4.

116. A pharmaceutical formulation comprising an antibody or binding fragment thereof for use according to any one of the preceding claims, said formulation comprising 175 to 250 mg / ml of an anti-IL-13R antibody or antigen binding fragment thereof, for example 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245 or 250 mg / ml, in particular 190, 200 mg / ml, 210 mg / ml, 225 mg / ml or 250 mg / ml, such as 200 mg / ml of an anti-IL-13R antibody or antigen binding fragment thereof;5 to 100 mM of tryptophan (including 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 mM), for example 15 to 75 mM of tryptophan, such as 15 to 60 mM, in particular 25 to 50 mM tryptophan, such as 20 mM, 50 or 80 mM tryptophan;140 to 290 mM of arginine (including 150 or 151 to 290nM), for example 160 to 290 mM of arginine (such as Arg-HCl or Arg-Glu), for example 160, 165, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280 285 or 290 mM, in particular 150, 185, 215, 225, 250, 260 or 280 mM arginine;0.01-0.03% of a non-ionic surfactant (such as polysorbate), for example 0.01-0.03% w / w, such as 0.01%, 0.015%, 0.020%, 0.025% or 0.030% in particular 0.02% w / w of a non-ionic surfactant; a buffer (such as histidine buffer), for example 15 to 55 mM of a buffer (including 25 or 26 to 55), such as 15, 20, 25, 30, 35, 40, 45, 50 or 55 mM of a histidine buffer; in particular 20, 35 or 50 mM histidine buffer; and wherein the pH of the formulation is in the range 5.5 to 7.2 (including 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, for example 6.0 to 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 5.8, 6.3, 6.4, 6.5, 6.6, 6.7 or 6.8.

117. A method of treating a patient having airway hyperresponsiveness (also referred to as bronchial hyperresponsiveness), for example a patient whose symptoms are not alleviated by a bronchodilator, such as a patient having chronic obstructive pulmonary disease (COPD), comprising administering a therapeutically effective amount of an antibody or antigen binding fragment thereof, which is an inhibitor of signalling through of the IL-13Ral by binding the said receptor, or a pharmaceutical formulation comprising the same, for example according to any one of the preceding claims, whereby the treatment improves respiratory airflow in the patient118. Use of an antibody or antigen binding fragment thereof, which is an inhibitor of signalling through of the IL-13Ral by binding the said receptor, or a pharmaceutical formulationcomprising the same, for example according to any one of the preceding claims, in the manufacture of a medicament for treating a patient having airway hyperresponsiveness (also referred to as bronchial hyperresponsiveness], such as a patient whose symptoms are not alleviated by a bronchodilator for example a patient having chronic obstructive pulmonary disease (COPD), whereby the treatment improves respiratory airflow in the patient.

Images