Asthma treatment by blocking IL-13 and TSLP

Abstract

The present invention provides compounds for use in the treatment of lung diseases (particularly asthma), which bind to the cytokines IL-13 and TSLP. Treatment according to the present invention can reduce exhaled nitric oxide (FeNO) levels by at least 18 ppb compared to placebo. Treatment according to the present invention can also reduce eosinophil count, increase FEV1, and / or reduce airway inflammation.

Description

[Technical Field]

[0001] 1. Field of the present invention This invention relates to the treatment of asthma by administering compounds that bind to IL-13 and TSLP. Blocking these two cytokines results in one or more significant effects, such as a reduction of at least 18 ppb in exhaled nitric oxide (FeNO) levels compared to a control such as placebo, and a reduction of at least 30% in blood eosinophil counts compared to a control such as placebo. The treatment may also reduce airway inflammation and small airway obstruction. [Background technology]

[0002] 2 Background While necessary for host defense, an unrestrained immune response can lead to a variety of inflammatory diseases, including asthma, atopic dermatitis, and rheumatoid arthritis. A series of immune responses mediated by the natural and adaptive arms of the immune system (e.g., antigen recognition, antigen processing, antigen presentation, cytokine production, antibody production, and target cell death) cause the development and progression of various immune disorders. Inflammatory diseases are often chronic and can even be life-threatening. Allergic diseases such as asthma and atopic diseases are often caused primarily by type 2 immune responses and are characterized by prominent features of type 2 immunity, such as high IgE production and eosinophilia.

[0003] Thymus-interstitial lymphocyte necrosis factor (TSLP) and interleukin-13 (IL-13) are soluble cytokine targets produced by stromal cells and / or immune cells (Ziegler & Artis, Nat Rev Immunol (2010) 11:289, Gieseck III et al., Nat Rev Immunol (2018) 18:62). Human TSLP and IL-13 drive different, overlapping, and synergistic aspects of immunity and autoimmunity, including type 2 inflammation.

[0004] TSLP signaling begins via a heterodimeric receptor complex composed of the thymic interstitial lymphocyte necrosis factor receptor (TSLPR) and the IL-7R alpha chain (IL-7Rα). Similarly, IL-13 signaling begins by binding to a heterodimeric receptor complex consisting of the alpha IL-4 receptor (IL-4Rα) and the alpha interleukin-13 receptor (IL-13R1α). The high affinity of IL-13 for IL-13R1 leads to their complex formation, which further increases the possibility of heterodimerization with IL-4Rα.

[0005] TSLP drives dendritic cell maturation, mast cell development and proliferation, and activates other immune cells such as basophils and innate lymphoid cells (ILC2). Similarly, IL-13 exerts various immunopathologies, including epithelial barrier disruption, mucus production from the mucosal epithelial surface, airway reorganization, and induction of eosinophils that recruit chemokines such as eotaxin. These mechanisms are central to the initiation and propagation of type 2 inflammatory responses and are central to the development of various immunopathologies in diseases such as atopic dermatitis and asthma.

[0006] Not all patients with moderate / severe asthma are adequately responding to currently available standard treatments, including biologics such as the anti-IL4Rα monoclonal antibody Dupixent (dupilumab; commercially available), anti-IL5s (commercially available), and anti-IgE monoclonal antibody Xolair (omalizumab; commercially available), and there are particularly unmet needs among asthma patients with a hypoeosinophilic phenotype. While antagonistic monoclonal antibodies against TSLP (tezepelumab; commercially available) and IL-13 (lebrikizumab) exist, no compounds targeting both TSLP and IL-13 are commercially available. Dual targeting of TSLP and IL-13 with a single compound may confer efficacy in both hypoeosinophilic and hypereosinophilic asthma, potentially conferring efficacy in subpopulations within these indications where monospecific drug therapy may not be sufficiently effective.

[0007] Targeting multiple disease factors can be achieved, for example, by the simultaneous administration or combined use of two separate biologics (e.g., antibodies that bind to different therapeutic targets). However, the simultaneous administration or combined use of separate biologics can be difficult from both a practical and commercial standpoint. For example, two injections of separate products result in a more inconvenient and painful treatment regimen for the patient, which can negatively impact compliance. Regarding single injections of two separate products, providing a formulation that allows for acceptable viscosity at the required concentration and favorable stability of both products can be difficult or impossible. In addition, simultaneous administration and co-formulation require the manufacture of two separate drugs, which can increase the overall cost. Bispecific antibodies capable of binding to two different antigens have been proposed as one strategy to address such limitations associated with the simultaneous administration or combined use of separate biologics, such as antibodies. [Overview of the project] [Problems that the invention aims to solve]

[0008] These factors hinder the development of multispecific asthma therapies. Therefore, there is a great need for alternative asthma treatments that target multiple pathological pathways. This invention satisfies this need by providing compounds that bind to both TSLP and IL-13 for use in the treatment of lung diseases (e.g., asthma). This invention is the first to demonstrate that simultaneous targeting of TSLP and IL-13 is highly effective in asthma patients. In particular, this invention shows that treatment with compounds that block both TSLP and IL-13 results in improvements to certain clinical parameters, such as FeNO levels, to a much higher degree than existing asthma medications. [Means for solving the problem]

[0009] 3. Outline of the present invention This invention is the first to demonstrate a potent effect of simultaneously blocking TSLP and IL-13 in human subjects suffering from lung diseases such as asthma. Specifically, the effect results in a reduction of FeNO levels of at least 18 ppb compared to baseline FeNO levels or placebo, and / or a reduction of eosinophil count of at least 30% compared to baseline eosinophil count or placebo, and / or an increase of at least 0.07 L in forced expiratory volume in one second (FEV1) compared to baseline FEV1 or placebo. This invention demonstrates that simultaneous blockade of TSLP and IL-13 in human subjects reduces airway inflammation and improves lung function.

[0010] In another aspect, the present invention relates to a prophylactic aspect. Since the present invention provides a method for significantly reducing FeNO levels compared to known treatments, this opens up the possibility of prophylactic administration to treat subjects with elevated FeNO levels to prevent further loss of lung function before further loss of lung function occurs. Prophylactic administration may be for asthma patients and subjects at risk of developing asthma, as well as patients with other lung diseases and subjects at risk of developing other lung diseases. Accordingly, the present invention relates to compounds for use in reducing FeNO levels in subjects, which prevent loss of lung function by reducing FeNO levels.

[0011] The present invention provides the following exemplary embodiments: [1] Compounds for use in the treatment of a target lung disease, which bind to IL-13 and TSLP, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) by at least 18 ppb compared to a control.

[0012] [2] The compound for use according to Embodiment [1], wherein the treatment reduces the level of FeNO by at least 20 ppb, at least 30 ppb, or at least 40 bppb compared to the control.

[0013] [3] The lung disease is asthma, the compound for use as described in Embodiment [1] or [2].

[0014] [4] The compound for use described in Embodiment [3] is for asthma, which is hypereosinophilic asthma.

[0015] [5] The compound for use described in Embodiment [3] is for hypoeosinophilic asthma.

[0016] [6] The control is a baseline, or the control is a placebo, and optionally, the baseline means the individual baseline of the compound for use according to any one of Embodiments [1] to [5].

[0017] [7] The compound for use according to any one of Embodiments [1] to [6], wherein the reduction in FeNO levels occurs within four weeks after administration of the compound, and optionally, the reduction in FeNO levels occurs within two weeks after administration of the compound, and optionally, the reduction in FeNO levels occurs within one week after administration of the compound.

[0018] [8] The compound for use according to any one of embodiments [1] to [7], wherein the compound that binds to IL-13 and TSLP is a polypeptide such as an antibody or antibody fragment.

[0019] [9] The polypeptide comprises or consists of at least four ISVDs, two of which bind specifically to IL-13 and two of which bind specifically to TSLP, each of the at least four ISVDs comprising three complementarity-determining regions (CDR1 to CDR3, respectively), and the at least four ISVDs are optionally linked by one or more peptide linkers. The first ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 7; CDR2, which is the amino acid sequence of SEQ ID NO: 12; and CDR3, which is the amino acid sequence of SEQ ID NO: 17. The second ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 8; CDR2, which is the amino acid sequence of SEQ ID NO: 13; and CDR3, which is the amino acid sequence of SEQ ID NO: 18. The third ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 9, CDR2, which is the amino acid sequence of SEQ ID NO: 14, and CDR3, which is the amino acid sequence of SEQ ID NO: 19. The fourth ISVD is, This includes CDR1, which is the amino acid sequence of SEQ ID NO: 11; CDR2, which is the amino acid sequence of SEQ ID NO: 16; and CDR3, which is the amino acid sequence of SEQ ID NO: 21. Compounds for use as described in Embodiment [8].

[0020]

[10] The polypeptide is a compound for use as described in Embodiment [8] or [9], comprising the amino acid sequence of SEQ ID NO: 1 or consisting of the amino acid sequence of SEQ ID NO: 1.

[0021]

[11] The subjects were those with a baseline FeNO level of at least 50 ppb and an eosinophil count of 0.3 × 10⁶ 9 A compound for use according to any one of embodiments [1] to

[10] , having a concentration of 1 or more cells / L.

[0022]

[12] Compounds for use in the treatment of a target lung disease, which bind to IL-13 and TSLP, wherein the treatment reduces the number of eosinophils in the blood by at least 30% compared to a control.

[0023]

[13] The compound for use according to Embodiment

[12] , wherein the reduction in eosinophil count occurs within 4 weeks after administration of the compound, and optionally, the reduction in eosinophil count occurs within 2 weeks after administration of the compound, and optionally, the reduction in eosinophil count occurs within 1 week after administration of the compound.

[0024]

[14] Compounds that bind to IL-13 and TSLP for use in the treatment of a target lung disease, wherein the treatment reduces airway inflammation.

[0025]

[15] The reduction of airway inflammation is characterized by a reduction of at least 18 ppb of FeNO, a reduction of at least 30% of eosinophil count, and / or an increase of at least 0.07 L of forced expiratory volume in one second (FEV1) compared to a control, as described in Embodiment

[14] of the compound.

[0026]

[16] The compound for use according to Embodiment

[15] , wherein the reduction of airway inflammation occurs within four weeks after administration of the compound, and optionally, the reduction of airway inflammation occurs within two weeks after administration of the compound, and optionally, the reduction of airway inflammation occurs within one week after administration of the compound.

[0027] In another aspect, the present invention provides the following exemplary embodiments:

[17] Compounds for use in reducing the FeNO level of a target, which bind to TSLP and / or IL-13, wherein the reduction in FeNO level prevents loss of lung function.

[0028]

[18] The reduction in FeNO level is a reduction of at least 18 ppb, the compound for use as described in Embodiment

[17] .

[0029]

[19] The reduction of the FeNO level is a reduction to a level of less than 25 ppb, the compound for use according to embodiment

[18] or

[19] .

[0030]

[20] The subject is a compound for use according to any one of the embodiments

[17] to

[19] , wherein the baseline FeNO level is at least 50 ppb, at least 35 ppb, or at least 25 ppb.

[0031]

[21] The subjects were those with a baseline FeNO level of at least 50 ppb and an eosinophil count of 0.3 × 10⁶ 9 A compound for use according to any one of the embodiments

[17] to

[20] , having a concentration of 1 or more cells / L.

[0032]

[22] The compound is a compound for use according to any one of the embodiments

[17] to

[21] , which binds to TSLP and IL-13.

[0033]

[23] The loss of lung function is related to asthma, and the compound is for use according to any one of the embodiments

[17] to

[22] . [Brief explanation of the drawing]

[0034] 4. Brief Description of the Drawings [Figure 1] Schedule of the clinical trial (PDY16622) for Example 1. The schedule shows the procedures / measurements performed at the specified time point ("D" representing "day") of the clinical trial. [Figure 1-1] Same as above. [Figure 1-2] Same as above. [Figure 2] FeNO measurements from the clinical trial (PDY16622) of Example 1. Shown is the change in exhaled nitric oxide levels (parts per billion, ppb) from baseline for the SAR443765 group (dashed line) and the placebo group (solid line). [Figure 3] FeNO measurements from the clinical trial (PDY16622) of Example 1, analyzed according to high / low eosinophil subgroups. Shown are the change in exhaled nitric oxide levels (parts per billion, ppb) from baseline for the high eosinophilic SAR443765 group (lower dashed line, dark gray), low eosinophilic SAR443765 group (lower solid line, dark gray), high eosinophilic placebo group (upper dashed line, light gray), and low eosinophilic placebo group (upper solid line, light gray). [Figure 4] Eosinophil counts in the clinical trial of Example 1 (PDY16622). Shown are the median changes in eosinophil counts compared to baseline at D29 (week 4) for the SAR443765 group (right) and the placebo group (left). [Figure 5]Eosinophil count (PDY16622, right bar) in the clinical trial of Example 1 compared with the following three other biologics on D29: lebrikizumab (left bar), tezeperumab (second bar from the left), and dupilumab (second bar from the right). [Figure 6] FEV1 measurements from the clinical trial (PDY16622) of Example 1. The figures show the change in FEV1 (in liters, compared to baseline) for the SAR443765 group (dashed line) and the placebo group (solid line). All measurements are included. [Figure 7] FEV1 measurements from the clinical trial (PDY16622) of Example 1. The changes in FEV1 (in liters, compared to baseline) are shown for the SAR443765 group (dashed line) and the placebo group (solid line). Only measurements meeting all quality criteria are included. [Figure 8] FEV1 measurements from the clinical trial (PDY16622) of Example 1. The figures shown are the changes in FEV1 (in liters, compared to baseline) as shown in Figure 7. The SAR443765 group and the placebo group were each divided into two subgroups according to their baseline percent predicted FEV1 (ppFEV1). These subgroups were: SAR443765, baseline ppFEV1 ≥ 80% (dark gray solid line); SAR443765, baseline ppFEV1 < 80% (dark gray dashed line); placebo, baseline ppFEV1 ≥ 80% (light gray solid line); placebo, baseline ppFEV1 < 80% (light gray dashed line). [Figure 9]The graph shows the measured values ​​of forced expiratory flow rate (FEF25-75) from the clinical trial (PDY16622) of Example 1. The graph shows the change in FEF25-75 (in liters / second, compared to baseline). The upper panel shows the change in FEF25-75 for the SAR443765 group (dashed line) and the placebo group (solid line). In the lower panel, the SAR443765 group and the placebo group were each divided into two subgroups according to their baseline percentage predicted FEV1 (ppFEV1). These subgroups are: SAR443765, baseline ppFEV1 ≥ 80% (dark gray solid line); SAR443765, baseline ppFEV1 < 80% (dark gray dashed line); placebo, baseline ppFEV1 ≥ 80% (light gray solid line); placebo, baseline ppFEV1 < 80% (light gray dashed line). [Figure 9-1] Same as above. [Figure 10] Measured values ​​of the difference in respiratory resistance (R5-20) at 5 Hz and 20 Hz in the clinical trial of Example 1 (PDY16622). Shown is the change in the difference between respiratory resistance at 5 Hz and respiratory resistance at 20 Hz (unit: cmH2O*s / L, compared to baseline). The upper panel shows the change in R5-20 for the SAR443765 group (dashed line) and placebo (solid line). In the lower panel, the SAR443765 group and the placebo group were each divided into two subgroups according to baseline percentage predicted FEV1 (ppFEV1). These subpopulations are: SAR443765, baseline ppFEV1 ≥ 80% (dark gray solid line); SAR443765, baseline ppFEV1 < 80% (dark gray dashed line); placebo, baseline ppFEV1 ≥ 80% (light gray solid line); placebo, baseline ppFEV1 < 80% (light gray dashed line). [Figure 10-1] Same as above. [Figure 11]Measured reactance area (AX) values ​​from the clinical trial (PDY16622) of Example 1. Shown is the change in reactance area (unit: cmH2O / L) compared to baseline. The upper panel shows the change in reactance area for the SAR443765 group (dashed line) and the placebo group (solid line). In the lower panel, the SAR443765 group and the placebo group are each divided into two subgroups according to baseline percentage predicted FEV1 (ppFEV1). These subgroups are: SAR443765, baseline ppFEV1 ≥ 80% (dark gray solid line); SAR443765, baseline ppFEV1 < 80% (dark gray dashed line); placebo, baseline ppFEV1 ≥ 80% (light gray solid line); placebo, baseline ppFEV1 < 80% (light gray dashed line). [Figure 11-1] Same as above. [Figure 12] Further biomarker measurements from the clinical trial of Example 1 (PDY16622). Shown are changes in serum IL-5 levels (upper left panel), changes in plasma CCL26 (eotaxin-3) levels (upper right panel), changes in serum IgE levels (lower left panel), and changes in serum TARC (CCL17) levels (lower right panel) compared to baseline. Each panel shows the placebo result (left side) and the SAR443765 result (right side). [Figure 13] Changes in cell type in nasal brushing samples from the clinical trial of Example 1 (PDY16622). Shown are the changes between samples from D1 (baseline, before administration of SAR443765 or placebo) and samples from D29. The change in the percentage of each cell type on the x-axis (shown as log2 of the fold change (FC)) is plotted against the p-value for the change on the y-axis (shown as -log10 of the p-value). [Figure 14]Changes in cell types in peripheral blood leukocyte (PBL) samples from the clinical trial of Example 1 (PDY16622). Shown are the changes between samples from D1 (baseline, before administration of SAR443765 or placebo) and samples from D29. The change in the percentage of each cell type on the x-axis (shown as log2 of the fold change (FC)) is plotted against the p-value for the change on the y-axis (shown as -log10 of the p-value). [Figure 15] Correlation between changes in NK cell percentage (in PBL samples) and changes in FeNO levels in the clinical trial of Example 1 (PDY16622). Shown are the changes between samples / measurements from D1 (baseline, before administration of SAR443765 or placebo) and samples / measurements from D29. Changes in FeNO on the x-axis are plotted against changes in NK cell type percentage (D29-D1) on the y-axis (shown as log10 of the magnification change (FC)). [Figure 16] CCL26 expression at D1 and D29 in nasal brushing samples from the clinical trial (PDY16622) of Example 1. In the SAR443765 group, there was a significant difference in CCL26 expression between D1 and D29 in terms of cell type epithelial basal, epithelial multiciliate, and epithelial secretion. [Figure 17] HBB expression in CD8 T effector memory (em) cells from PBL samples in the clinical trial of Example 1 (PDY16622). The graph shows the fold change in HBB gene expression relative to the p-value (D29 compared to D1). In the SAR443765 group (left), there is a much stronger downregulation of HBB expression compared to the placebo group (right). [Modes for carrying out the invention]

[0035] 5. Detailed Description of the Invention In a first aspect, the present invention relates to compounds that block TSLP and IL-13 for use in the treatment of a target lung disease (e.g., the treatment of asthma). The treatment is characterized by improvement of certain biomarkers, in particular by a reduction in FeNO levels and a reduction in eosinophil count.

[0036] In another aspect, the present invention relates to a compound for use in reducing a target FeNO level, wherein the reduction in FeNO level prevents loss of lung function, which may be associated with asthma or another lung disease.

[0037] 5.1 Definition Unless otherwise stated below, all terms used in this specification and in this application, including the claims, have the meanings commonly given to them in their respective scientific fields.

[0038] As used herein and in the appended claims, the indefinite articles “a,” “an,” and the definite article “the” include plural and singular references unless otherwise clearly indicated by the context.

[0039] In this application, all indications of time periods count the day of drug administration as day 1 ("D1"). This means that the day following drug administration is counted as day 2 ("D2"), and consequently, for example, a measurement taken 24 hours after drug administration is D2, and a measurement taken 72 hours after drug administration is D4. This also means that a one-week period ends at D8, a two-week period ends at D15, a three-week period ends at D22, a four-week period ends at D29, an eight-week period ends at D57, and a ten-week period ends at D71. In this disclosure, "day" is often abbreviated as "D". The terms "day" and "D" are used synonymously in closures.

[0040] Lung disease refers to diseases of the lungs. An example of lung disease is asthma.

[0041] Inflammatory diseases are diseases characterized by autoinflammation. Inflammatory diseases of the lungs exist. One example of such a lung inflammatory disease is asthma.

[0042] Asthma is a lung disease characterized by chronic airway inflammation. Asthma involves airflow obstruction and induces bronchospasm. Symptoms often include wheezing, coughing, chest tightness, and shortness of breath. Types of asthma include allergic asthma, non-allergic asthma, high Th2 asthma, low Th2 asthma, high eosinophilic asthma, and low eosinophilic asthma.

[0043] Hypereosinophilic asthma, as used herein, refers to a patient with 0.3 × 10⁻⁶ saturation. 9 This refers to asthma characterized by an eosinophil count of more than 10 cells / L. An exemplary eosinophil count range in hypereosinophilic asthma is 0.3 × 10⁻⁶. 9 ~0.5 × 10 9 It is one cell / L.

[0044] Hypoeosinophilic asthma, as used herein, refers to a patient with 0.3 × 10⁻⁶ saturates. 9 This refers to asthma characterized by an eosinophil count of less than 0 cells / L. An exemplary eosinophil count range in hypoeosinophilic asthma is 0–0.3 × 10⁻⁶. 9 It is less than the number of cells / L.

[0045] Airway inflammation refers to inflammation located in the airways. Airway inflammation can be directly evaluated, for example, by analyzing induced sputum, bronchial lavage, bronchial biopsy, or by exhaled volatile markers such as FeNO, or indirectly by, for example, an increase in the number of eosinophils in the blood. Airway inflammation is characterized by elevated FeNO levels, elevated eosinophil counts in the blood, and decreased lung function (e.g., decreased FEV1).

[0046] Type 2 inflammation is an immune response characterized by the activation of type 2 T helper cells and / or type 2 innate lymphoid cells. The immune response of type 2 inflammation is characterized by the release of alarmins (IL-23, IL-33, TSLP) that lead to the activation of type 2 T helper cells and / or type 2 lymphoid cells. These cells secrete IL-4, IL-5, and IL-13, which promotes isotype switching to IgE in B cells and eosinophil recruitment. While type 2 inflammation may be useful in the body's defense against helminths, it is involved in various autoinflammatory diseases. Airway inflammation in asthma patients is often type 2 inflammation.

[0047] Exhaled nitric oxide (FeNO) is the percentage of nitric oxide (NO) in exhaled breath. It is measured in parts per billion (ppb). Elevated FeNO levels are a sign of airway inflammation. When this application refers to "reduction in FeNO levels compared to placebo," this refers to the average (in ppb) of the individual changes from baseline in FeNO levels of the compound group and the placebo group at a specific point in time. The difference (in ppb) between these two values ​​is the "reduction in FeNO levels compared to placebo."

[0048] When used herein, managing elevated FeNO levels means taking measures to reduce elevated FeNO levels, thereby potentially reducing airway inflammation and / or preventing its worsening.

[0049] When used herein, managing airway inflammation means administering measures to reduce airway inflammation, thereby reducing symptoms associated with airway inflammation and / or preventing the worsening of symptoms associated with airway inflammation.

[0050] As used herein, eosinophil count refers to the number of eosinophils. In the treatment according to the present invention, the eosinophil count is measured in whole blood. Methods for measuring the eosinophil count are known in the art, for example, flow cytometry or microscopic counting after H&E staining. The eosinophil count is measured in cells / L. When this application refers to "reduction of eosinophil count compared to placebo," this means measuring the change from baseline in the eosinophil count of the compound group (unit cells / L or %) and the change from baseline in the eosinophil count of the placebo group (unit cells / L or %) at a specific point in time after the start of treatment. The difference between these two values ​​(cells / L or %) is the "reduction of eosinophil count compared to placebo."

[0051] Forced expiratory volume in one second (FEV1) is the volume exhaled at the end of the second forced exhalation after maximum inspiration. FEV1 can be measured by vital capacity measurement. When this application refers to "increase in FEV1 compared to placebo," this means measuring the change from baseline (in L) of FEV1 in the compound group and the change from baseline (in L) of FEV1 in the placebo group at a specific point in time after the start of treatment. The difference (in L) between these two values ​​is the "increase in FEV1 compared to placebo."

[0052] As used herein, placebo refers to a treatment or a substance used in such a treatment that does not contain a pharmacologically active compound. In clinical trials, a placebo may be administered to a portion of participants to create a control group for the portion of participants that receive the pharmacologically active compound under test. To function as a proper control, the placebo treatment is identical to the treatment being compared, with the only exception being the administration of a placebo (e.g., an inactive pill such as a sugar pill) instead of a pharmacologically active compound.

[0053] In this invention, changes in biomarkers (e.g., FeNO, eosinophil count) are determined in comparison to a “control.” The control is either the “baseline” of the subject (i.e., the subject’s biomarker level before administration of the compound of the invention) or the “placebo” (i.e., the biomarker level after administration of a placebo instead of the compound of the invention). When determining changes in biomarker levels in comparison to a baseline, this means calculating the difference between the baseline biomarker level and the biomarker level at a specific point in time for each subject treated with the compound. The calculation may be performed for individual subjects and for control groups. When performed for individual subjects, the difference is directly shown as the change in biomarker level compared to baseline. When performed for control groups, the mean or median of all differences calculated for each individual subject is shown as the change in biomarker level compared to baseline.

[0054] When determining the change in biomarker levels compared to placebo, this means determining the change compared to baseline for the control group treated with the compound (as explained in the preceding paragraph) and determining the same value for the control group treated with placebo; the difference between these two values ​​is shown as the change in biomarker levels compared to placebo. This means that the change in biomarker levels compared to placebo is equal to the "change in biomarker levels compared to baseline" minus the change in biomarker levels in the placebo group.

[0055] Small airways, as generally defined in the literature, refer to airways with a diameter of 2 mm or less (see, for example, McNulty and Usmani, Eur Clin Respir J, 2014 and Stockley et al., Int J Chron Obstruct Pulmon Dis. 2017;12:2343-2353).

[0056] An airway is defined as an airway with a diameter greater than 2 mm.

[0057] The participants in the clinical trial of Example 1 (PDY16622) were all asthma patients (see Example 1 below). Therefore, the terms "participant" and "patient" are used synonymously throughout this application.

[0058] The expressions "treatment of the target disease" and "treatment of the disease" are used synonymously in this specification because it is clear that the treatment takes place within the target. The same applies to variations of these expressions; for example, "treatment of the target lung disease" is used synonymously with "treatment of lung disease."

[0059] 5.2 Treatment of the present invention The present invention provides compounds that bind to IL-13 and TSLP for use in the treatment of target lung diseases. The treatment is characterized by improvement of biomarkers and / or physiological characteristics, such as reduction of FeNO levels, reduction of eosinophil count in the blood, increase of FEV1, and / or reduction of airway inflammation.

[0060] The subjects of the treatment of the present invention may be any animal, and more specifically, mammals. Among mammals, humans and non-human mammals can be distinguished. Non-human animals may be, for example, companion animals (e.g., dogs, cats), livestock (e.g., cattle, horses, sheep, goats, or pigs), or animals commonly used for research purposes and / or antibody production (e.g., mice, rats, rabbits, cats, dogs, goats, sheep, horses, pigs, non-human primates, e.g., cynomolgus macaques or monkeys, or camelids, e.g., llamas or alpacas). In one embodiment, the subject is a human subject.

[0061] In relation to the preventive purpose of the present invention, the subject may be the same as that defined in the previous section. In one embodiment, the subject is a human subject.

[0062] The compounds (including polypeptides and nucleic acid molecules) or compositions according to the present invention may be administered to a subject by any preferred route of administration, for example, by enteral administration (e.g., orally or rectally) or parenteral administration (e.g., on the skin, sublingually, intrabuccally, intranasally, intraarticularly, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously (SC), percutaneously, or transmucosally). In one embodiment, the substance is administered by parenteral administration, for example, by intramuscular, subcutaneous, or intradermal administration. In one embodiment, subcutaneous administration is used.

[0063] To obtain the intended therapeutic effect, an effective amount of polypeptide, nucleic acid molecule, or a composition containing polypeptide or nucleic acid molecule may be administered to the target.

[0064] One or more doses may be administered. If multiple doses are administered, these doses may be given at appropriate intervals to maximize the effect of the polypeptide, composition, nucleic acid molecule, or vector.

[0065] In some embodiments, the dose of the compound that binds to TSLP and IL-13 is 400 mg. In some embodiments, the compound that binds to TSLP and IL-13 is administered subcutaneously (SC). In some embodiments, only a single dose of the compound that binds to TSLP and IL-13 is administered.

[0066] In some embodiments, the dose of the compound that binds to TSLP and IL-13 is 400 mg, and the compound that binds to TSLP and IL-13 is administered subcutaneously (SC). In some embodiments, the dose of the compound that binds to TSLP and IL-13 is 400 mg, and only a single dose of the compound that binds to TSLP and IL-13 is administered. In some embodiments, the compound that binds to TSLP and IL-13 is administered subcutaneously (SC), and only a single dose of the compound that binds to TSLP and IL-13 is administered. In some embodiments, the dose of the compound that binds to TSLP and IL-13 is 400 mg, and the compound that binds to TSLP and IL-13 is administered subcutaneously (SC), and only a single dose of the compound that binds to TSLP and IL-13 is administered.

[0067] 5.2.1 Reduction of FeNO levels A reduction in FeNO levels reflects a reduction in airway inflammation and is therefore beneficial for patients with lung diseases (e.g., asthma). In some embodiments, the lung disease is an inflammatory disease. In some embodiments, the lung disease is asthma. In some embodiments, the asthma is hypereosinophilic asthma. In some embodiments, the asthma is hypoeosinophilic asthma.

[0068] In this invention, the reduction in FeNO levels is determined in comparison to a control. The control is either the "baseline" of the subject (i.e., the subject's FeNO level before administration of the compound of the invention); or the "placebo" (i.e., the FeNO level after administration of a placebo instead of the compound of the invention). When determining the reduction in FeNO levels in comparison to a baseline, this means calculating the difference between the baseline FeNO level and the FeNO level at a specific point in time for each subject treated with the compound. The calculation may be performed for individual subjects and for groups of subjects. When performed for individual subjects, the difference is directly shown as the change in FeNO level compared to baseline. When performed for groups of subjects, the mean or median of all differences calculated for each individual subject is shown as the change in FeNO level compared to baseline.

[0069] When determining the reduction in FeNO levels compared to placebo, this means determining the reduction compared to baseline for the control group treated with the compound (as explained in the preamble) and determining the same value for the control group treated with placebo; the difference between these two values ​​is expressed as the reduction in FeNO levels compared to placebo. This means that the reduction in FeNO levels compared to placebo is equal to the "reduction in FeNO levels compared to baseline" minus the change in FeNO levels compared to baseline for the placebo group. In some embodiments, the reduction in FeNO levels is calculated with respect to the mean of the control group. In some embodiments, the reduction in FeNO levels is calculated with respect to the median of the control group.

[0070] In some embodiments of the present invention, the reduction in FeNO level is determined compared to a placebo. In some embodiments of the present invention, the reduction in FeNO level is determined compared to a baseline. In some embodiments of the present invention, the reduction in FeNO level is determined compared to a baseline, where the baseline refers to the individual baseline of the subject. In some embodiments of the present invention, the FeNO level is reduced by at least 18 ppb. In some embodiments of the present invention, the FeNO level is reduced by at least 20 ppb. In some embodiments of the present invention, the FeNO level is reduced by at least 25 ppb. In some embodiments of the present invention, the FeNO level is reduced by at least 30 ppb. In some embodiments of the present invention, the FeNO level is reduced by at least 35 ppb. In some embodiments of the present invention, the FeNO level is reduced by at least 40 ppb.

[0071] Exemplary ranges for FeNO level reduction are 18ppb~50ppb; 18ppb~40ppb; 18ppb~35ppb; 18ppb~30ppb; 18ppb~25ppb; 18ppb~20ppb; 20ppb~50ppb; 20ppb~40ppb; 20ppb~35ppb; 20ppb~30ppb; 20ppb~25ppb; 25ppb~50ppb; 25ppb~40ppb; 25ppb~35ppb; 25ppb~30ppb; 30ppb~50ppb; 30ppb~40ppb; 30ppb~35ppb; 35ppb~50ppb; 35ppb~40ppb; 40ppb~50ppb.

[0072] The reduction in FeNO levels can be evaluated at various points in time after administration of the compound of the present invention. In some embodiments, the reduction in FeNO levels is evaluated one week after administration of the compound of the present invention. In some embodiments, the reduction in FeNO levels is evaluated two weeks after administration of the compound of the present invention. In some embodiments, the reduction in FeNO levels is evaluated three weeks after administration of the compound of the present invention. In some embodiments, the reduction in FeNO levels is evaluated four weeks after administration of the compound of the present invention. In some embodiments, the reduction in FeNO levels is evaluated eight weeks after administration of the compound of the present invention.

[0073] The treatment of the present invention can be used to control the rise in FeNO levels. In some embodiments, controlling the FeNO level includes reducing the FeNO level to a value of less than 40 ppb. In some embodiments, controlling the FeNO level includes reducing the FeNO level to a value of less than 35. In some embodiments, controlling the FeNO level includes reducing the FeNO level to a value of less than 30. In some embodiments, controlling the FeNO level includes reducing the FeNO level to a value of less than 25. In some embodiments, controlling the FeNO level includes reducing the FeNO level to a value of less than 20.

[0074] The FeNO baseline level (i.e., the level before administration of the present compound) can also be a parameter of the treatment of the present invention. In some embodiments, the treatment of the present invention is used to manage an increase in the FeNO baseline level of at least 25 ppb. In some embodiments, the treatment of the present invention is used to manage an increase in the FeNO baseline level of at least 30 ppb. In some embodiments, the treatment of the present invention is used to manage an increase in the FeNO baseline level of at least 40 ppb. In some embodiments, the treatment of the present invention is used to manage an increase in the FeNO baseline level of at least 50 ppb. In some embodiments, the treatment of the present invention is used to manage an increase in the FeNO baseline level of at least 60 ppb. In some embodiments, the treatment of the present invention is used to manage an increase in the FeNO baseline level of at least 70 ppb.

[0075] In some embodiments, the treatment of the present invention is used to manage an increase in the FeNO baseline level of at least 50 ppb, where the subject also has an eosinophil count of 0.3×10 9 cells / L or more. Exemplary FeNO baseline level ranges are from 50 ppb to 150 ppb, and exemplary eosinophil count ranges are from 0.3×10 9 to 0.5×10 9 cells / L.

[0076] 5.2.2 Reduction of Eosinophil Count in Blood Reduction of eosinophil count in blood correlates with reduction of airway inflammation (particularly type 2 airway inflammation) and is thus beneficial to patients suffering from lung diseases (such as asthma). In some embodiments, the lung disease is an inflammatory disease. In some embodiments, the lung disease is asthma. In some embodiments, the asthma is eosinophilic asthma. In some embodiments, the asthma is non-eosinophilic asthma.

[0077] In this invention, the reduction in eosinophil count levels is determined in comparison to a control. The control is either the "baseline" of the subject (i.e., the number of eosinophils in the subject before administration of the compound of the invention); or the "placebo" (i.e., the number of eosinophils after administration of a placebo instead of the compound of the invention). When determining the reduction in eosinophil count in comparison to baseline, this means calculating the difference between the baseline eosinophil count and the eosinophil count at a specific point in time for each subject treated with the compound. The calculation may be performed for individual subjects and for control groups. When performed for individual subjects, the difference is directly shown as the change in eosinophil count compared to baseline. When performed for control groups, the mean or median of all differences calculated for each individual subject is shown as the reduction in eosinophil count compared to baseline. When determining the reduction in eosinophil count compared to placebo, this means determining the reduction compared to baseline for the control group treated with the compound (as explained in the preceding paragraph) and determining the same value for the control group treated with placebo; the difference between these two values ​​is shown as the reduction in eosinophil count compared to placebo. This means that the reduction in eosinophil count compared to placebo is equal to the "decrease in eosinophil count compared to baseline" minus the change in eosinophil count in the placebo group. In some embodiments, the reduction in eosinophil count refers to the median. In some embodiments, the reduction in eosinophil count refers to the mean. In some embodiments, the reduction in eosinophil count refers to the median change compared to baseline and is expressed as a percentage.

[0078] In some embodiments, a reduction in eosinophil count refers to the difference between the median change (expressed as a percentage) compared to baseline for the control group treated with the compound and the median change (expressed as a percentage) compared to baseline for the control group treated with placebo.

[0079] In some embodiments of the present invention, the reduction in eosinophil count (from baseline) is determined compared to placebo. In some embodiments of the present invention, the reduction in eosinophil count is determined compared to baseline. In some embodiments of the present invention, the reduction in FeNO levels (from baseline) is determined compared to baseline, where baseline refers to the individual baseline of the subject.

[0080] In some embodiments of the present invention, the eosinophil count is reduced by at least 30%. In some embodiments of the present invention, the eosinophil count is reduced by at least 30% with respect to the median of the control group. In some embodiments of the present invention, the eosinophil count is reduced by at least 30% with respect to the mean of the control group. In some embodiments of the present invention, the eosinophil count is reduced by at least 35%. In some embodiments of the present invention, the eosinophil count is reduced by at least 35% with respect to the median of the control group. In some embodiments of the present invention, the eosinophil count is reduced by at least 35% with respect to the mean of the control group. In some embodiments of the present invention, the eosinophil count is reduced by at least 40%. In some embodiments of the present invention, the eosinophil count is reduced by at least 40% with respect to the median of the control group. In some embodiments of the present invention, the eosinophil count is reduced by at least 40% with respect to the mean of the control group. Exemplary ranges of eosinophil count reduction are 30% to 80%; 35% to 80%; and 40% to 80%.

[0081] In some embodiments, a reduction in eosinophil count occurs within 4 weeks after administration of the compound. In some embodiments, a reduction in eosinophil count occurs within 2 weeks after administration of the compound. In some embodiments, a reduction in eosinophil count occurs within 1 week after administration of the compound. In some embodiments, a reduction in eosinophil count occurs within 3 days after administration of the compound. In some embodiments, a reduction in eosinophil count occurs within 1 day after administration of the compound.

[0082] In some embodiments, the compound that binds to IL-13 and TSLP and reduces eosinophil count is a polypeptide such as an antibody or antibody fragment. In some embodiments, the compound that binds to IL-13 and TSLP and reduces eosinophil count is a polypeptide, which comprises or consists of at least four ISVDs, two of which bind specifically to IL-13, and two of which bind specifically to TSLP, and each of the at least four ISVDs comprises three complementarity-determining regions (CDR1 to CDR3, respectively), and these at least four ISVDs are optionally linked by one or more peptide linkers. The first ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 7; CDR2, which is the amino acid sequence of SEQ ID NO: 12; and CDR3, which is the amino acid sequence of SEQ ID NO: 17. The second ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 8; CDR2, which is the amino acid sequence of SEQ ID NO: 13; and CDR3, which is the amino acid sequence of SEQ ID NO: 18. The third ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 9, CDR2, which is the amino acid sequence of SEQ ID NO: 14, and CDR3, which is the amino acid sequence of SEQ ID NO: 19. The fourth ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 11; CDR2, which is the amino acid sequence of SEQ ID NO: 16; and CDR3, which is the amino acid sequence of SEQ ID NO: 21.

[0083] In some embodiments, the compound that binds to IL-13 and TSLP and reduces eosinophil count contains or consists of the amino acid sequence of SEQ ID NO: 1.

[0084] 5.2.3 Increase in FEV1 An increase in FEV1 levels indicates improved lung function and is therefore beneficial for patients suffering from lung diseases (e.g., asthma). In some embodiments, the lung disease is an inflammatory disease. In some embodiments, the lung disease is asthma. In some embodiments, the asthma is hypereosinophilic asthma. In some embodiments, the asthma is hypoeosinophilic asthma.

[0085] In this invention, the increase in FEV1 (from baseline) is determined by comparison with baseline or a control such as a placebo. In some embodiments of this invention, FEV1 increases by at least 0.05 L. In some embodiments of this invention, FEV1 increases by at least 0.07 L. In some embodiments of this invention, FEV1 increases by at least 0.1 L. In some embodiments of this invention, FEV1 increases by at least 0.15 L. In some embodiments of this invention, FEV1 increases by at least 0.2 L. In some embodiments of this invention, FEV1 increases by at least 0.25 L. In some embodiments of this invention, FEV1 increases by at least 0.3 L. An exemplary range in which FEV1 increases is 0.07 L to 0.3 L. An exemplary range in which FEV1 increases is 0.07 L to 0.3 L; 0.1 L to 0.3 L; 0.15 L to 0.3 L; 0.2 L to 0.3 L; and 0.25 L to 0.3 L.

[0086] The present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target lung disease, wherein FEV1 is increased by at least 0.05 L compared to placebo. The present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target lung disease, wherein FEV1 is increased by at least 0.07 L compared to placebo. The present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target lung disease, wherein FEV1 is increased by at least 0.1 L compared to placebo.

[0087] In some embodiments, the increase in FEV1 occurs within 4 weeks after administration of the compound. In some embodiments, the increase in FEV1 occurs within 2 weeks after administration of the compound. In some embodiments, the increase in FEV1 occurs within 1 week after administration of the compound.

[0088] In some embodiments, the compound that binds to IL-13 and TSLP and increases FEV1 is a polypeptide such as an antibody or antibody fragment. In some embodiments, the compound that binds to IL-13 and TSLP and increases FEV1 is a polypeptide, which comprises or consists of at least four ISVDs, two of which bind specifically to IL-13 and two of which bind specifically to TSLP, and each of the at least four ISVDs comprises three complementarity-determining regions (CDR1 to CDR3, respectively), and these at least four ISVDs are optionally linked by one or more peptide linkers. The first ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 7; CDR2, which is the amino acid sequence of SEQ ID NO: 12; and CDR3, which is the amino acid sequence of SEQ ID NO: 17. The second ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 8; CDR2, which is the amino acid sequence of SEQ ID NO: 13; and CDR3, which is the amino acid sequence of SEQ ID NO: 18. The third ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 9, CDR2, which is the amino acid sequence of SEQ ID NO: 14, and CDR3, which is the amino acid sequence of SEQ ID NO: 19. The fourth ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 11; CDR2, which is the amino acid sequence of SEQ ID NO: 16; and CDR3, which is the amino acid sequence of SEQ ID NO: 21.

[0089] In some embodiments, the compound that binds to IL-13 and TSLP and increases FEV1 contains or consists of the amino acid sequence of SEQ ID NO: 1.

[0090] 5.2.4 Reduction of airway inflammation A reduction in airway inflammation indicates better lung function and is therefore beneficial to patients suffering from lung diseases (e.g., asthma). In some embodiments, the airway inflammation is type 2 airway inflammation. In this invention, a reduction in airway inflammation can be determined by analyzing clinical parameters (in particular FeNO, eosinophil count, and FEV1). Reductions or increases in these parameters are determined compared to a control, which is either baseline or placebo (as described above with respect to the individual clinical parameters).

[0091] In some embodiments, airway inflammation is characterized by a reduction of at least 18 ppb in FeNO and a reduction of at least 30% in eosinophil count. In some embodiments, airway inflammation is characterized by a reduction of at least 18 ppb in FeNO and an increase of at least 0.07 L in forced expiratory volume per second (FEV1). In some embodiments, airway inflammation is characterized by a reduction of at least 30% in eosinophil count and an increase of at least 0.07 L in forced expiratory volume per second (FEV1). In some embodiments, airway inflammation is characterized by a reduction of at least 18 ppb in FeNO, a reduction of at least 30% in eosinophil count, and an increase of at least 0.07 L in forced expiratory volume per second (FEV1). An exemplary range is a reduction of 18 ppb to 70 ppb in FeNO, a reduction of 30% to 80% in eosinophil count, and an increase of 0.07 L to 0.3 L in FEV1.

[0092] In some embodiments, airway inflammation is characterized by a reduction of at least 20 ppb in FeNO and a reduction of at least 30% in eosinophil count. In some embodiments, airway inflammation is characterized by a reduction of at least 20 ppb in FeNO and an increase of at least 0.07 L in forced expiratory volume in one second (FEV1). In some embodiments, airway inflammation is characterized by a reduction of at least 20 ppb in FeNO, a reduction of at least 30% in eosinophil count and an increase of at least 0.07 L in forced expiratory volume in one second (FEV1).

[0093] In some embodiments, airway inflammation is characterized by a reduction of at least 30 ppb in FeNO and a reduction of at least 30% in eosinophil count. In some embodiments, airway inflammation is characterized by a reduction of at least 30 ppb in FeNO and an increase of at least 0.07 L in forced expiratory volume in one second (FEV1). In some embodiments, airway inflammation is characterized by a reduction of at least 30 ppb in FeNO, a reduction of at least 30% in eosinophil count and an increase of at least 0.07 L in forced expiratory volume in one second (FEV1).

[0094] In some embodiments, airway inflammation is characterized by a reduction of at least 40 ppb in FeNO and a reduction of at least 30% in eosinophil count. In some embodiments, airway inflammation is characterized by a reduction of at least 40 ppb in FeNO and an increase of at least 0.07 L in forced expiratory volume in one second (FEV1). In some embodiments, airway inflammation is characterized by a reduction of at least 40 ppb in FeNO, a reduction of at least 30% in eosinophil count and an increase of at least 0.07 L in forced expiratory volume in one second (FEV1).

[0095] In some embodiments, airway inflammation is characterized by a reduction of at least 18 ppb in FeNO, a reduction of at least 30% in eosinophil count, and an increase of at least 0.07 L in forced expiratory volume in one second (FEV1), as well as a reduction in one or more of the following: IL-5 levels, CCL26 (eotaxin-3) levels, TARC (CCL17) levels, and IgE levels (serum).

[0096] In some embodiments, airway inflammation is characterized by a reduction of at least 20 ppb in FeNO, a reduction of at least 30% in eosinophil count, and an increase of at least 0.07 L in forced expiratory volume in one second (FEV1), as well as a reduction in one or more of the following: IL-5 levels, CCL26 (eotaxin-3) levels, TARC (CCL17) levels, and IgE levels (serum).

[0097] In some embodiments, airway inflammation is characterized by a reduction of at least 30 ppb in FeNO, a reduction of at least 30% in eosinophil count, and an increase of at least 0.07 L in forced expiratory volume in one second (FEV1), as well as a reduction in one or more of the following: IL-5 levels, CCL26 (eotaxin-3) levels, TARC (CCL17) levels, and IgE levels.

[0098] In some embodiments, airway inflammation is characterized by a reduction of at least 40 ppb in FeNO, a reduction of at least 30% in eosinophil count, and an increase of at least 0.07 L in forced expiratory volume in one second (FEV1), as well as a reduction in one or more of the following: IL-5 levels, CCL26 (eotaxin-3) levels, TARC (CCL17) levels, and IgE levels (serum).

[0099] In some embodiments, a reduction in airway inflammation occurs within 4 weeks after administration of the compound. In some embodiments, a reduction in airway inflammation occurs within 2 weeks after administration of the compound. In some embodiments, a reduction in airway inflammation occurs within 1 week after administration of the compound.

[0100] In some embodiments, the compound that binds to IL-13 and TSLP and reduces airway inflammation is a polypeptide such as an antibody or antibody fragment. In some embodiments, the compound that binds to IL-13 and TSLP and reduces airway inflammation is a polypeptide, which comprises or consists of at least four ISVDs, two of which bind specifically to IL-13 and two of which bind specifically to TSLP, and each of the at least four ISVDs comprises three complementarity-determining regions (CDR1 to CDR3, respectively), and these at least four ISVDs are optionally linked by one or more peptide linkers. The first ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 7; CDR2, which is the amino acid sequence of SEQ ID NO: 12; and CDR3, which is the amino acid sequence of SEQ ID NO: 17. The second ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 8; CDR2, which is the amino acid sequence of SEQ ID NO: 13; and CDR3, which is the amino acid sequence of SEQ ID NO: 18. The third ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 9, CDR2, which is the amino acid sequence of SEQ ID NO: 14, and CDR3, which is the amino acid sequence of SEQ ID NO: 19. The fourth ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 11; CDR2, which is the amino acid sequence of SEQ ID NO: 16; and CDR3, which is the amino acid sequence of SEQ ID NO: 21.

[0101] In some embodiments, the compound that binds to IL-13 and TSLP and reduces airway inflammation contains or consists of the amino acid sequence of SEQ ID NO: 1.

[0102] 5.2.5 Management of airway inflammation The present invention can be used to manage airway inflammation. In some embodiments, managing airway inflammation includes reducing the FeNO level to less than 40 ppb. In some embodiments, managing airway inflammation includes reducing the FeNO level to less than 35. In some embodiments, managing airway inflammation includes reducing the FeNO level to less than 30. In some embodiments, managing airway inflammation includes reducing the FeNO level to less than 25. In some embodiments, managing airway inflammation includes reducing the FeNO level to less than 20.

[0103] In some embodiments, managing airway inflammation reduces FeNO levels to less than 40 ppb and 0.2 × 10⁻⁶ 9 This includes reducing the number of eosinophils in the blood to less than 10 cells / L. In some embodiments, managing airway inflammation involves reducing FeNO levels to less than 35 ppb and 0.2 × 10⁻⁶. 9This includes reducing the number of eosinophils in the blood to less than 0.2 × 10⁻¹⁶ cells / L. In some embodiments, managing airway inflammation involves reducing FeNO levels to less than 30 ppb and 0.2 × 10⁻¹⁶. 9 This includes reducing the number of eosinophils in the blood to less than 10 cells / L. In some embodiments, managing airway inflammation involves reducing FeNO levels to less than 25 ppb and 0.2 × 10⁻⁶. 9 This includes reducing the number of eosinophils in the blood to less than 0.2 × 10⁻¹⁶ cells / L. In some embodiments, managing airway inflammation involves reducing FeNO levels to less than 20 ppb and 0.2 × 10⁻¹⁶. 9 This includes reducing the number of eosinophils in the blood to less than one cell / L.

[0104] In some embodiments, managing airway inflammation further includes reducing one or more of the following: IL-5 levels, CCL26 (eotaxin-3) levels, TARC (CCL17) levels, and IgE levels.

[0105] The present invention can be used to manage type 2 airway inflammation. In some embodiments, managing type 2 airway inflammation includes reducing the FeNO level to less than 40 ppb. In some embodiments, managing type 2 airway inflammation includes reducing the FeNO level to less than 35. In some embodiments, managing type 2 airway inflammation includes reducing the FeNO level to less than 30. In some embodiments, managing type 2 airway inflammation includes reducing the FeNO level to less than 25. In some embodiments, managing type 2 airway inflammation includes reducing the airway inflammation to less than 20.

[0106] In some embodiments, managing type 2 airway inflammation reduces FeNO levels to less than 40 ppb and 0.2 × 10⁻⁶9 This includes reducing the number of eosinophils in the blood to less than 0.2 × 10⁻¹⁶ cells / L. In some embodiments, managing type 2 airway inflammation involves reducing FeNO levels to less than 35 ppb and 0.2 × 10⁻¹⁶. 9 This includes reducing the number of eosinophils in the blood to less than 10 cells / L. In some embodiments, managing type 2 airway inflammation involves reducing FeNO levels to less than 30 ppb and 0.2 × 10⁻⁶ 9 This includes reducing the number of eosinophils in the blood to less than 0.2 × 10⁻¹⁶ cells / L. In some embodiments, managing type 2 airway inflammation involves reducing FeNO levels to less than 25 ppb and 0.2 × 10⁻¹⁶. 9 This includes reducing the number of eosinophils in the blood to less than 0.2 × 10⁻¹⁶ cells / L. In some embodiments, managing type 2 airway inflammation involves reducing FeNO levels to less than 20 ppb and 0.2 × 10⁻¹⁶. 9 This includes reducing the number of eosinophils in the blood to less than one cell / L.

[0107] 5.3 Compounds for use according to the present invention Compounds that bind to TSLP and IL-13 for use in the present invention may be polypeptides. Preferred polypeptides are described in International Publication No. 2021116182 (which is incorporated herein in its entirety).

[0108] In some embodiments, the polypeptide is an antibody or antibody fragment. An exemplary polypeptide for use in the present invention is a polypeptide comprising an immunoglobulin single variable domain (ISVD). ISVDs that bind to TSLP and IL-13 can be found in Tables A-1 to A-6 of International Publication No. 2021116182.

[0109] In some embodiments, the polypeptide comprises or consists of at least four ISVDs, two of which bind specifically to IL-13 and two of which bind specifically to TSLP, and each of the at least four ISVDs comprises three complementarity-determining regions (CDR1 to CDR3, respectively), and these at least four ISVDs are optionally linked by one or more peptide linkers. The first ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 7; CDR2, which is the amino acid sequence of SEQ ID NO: 12; and CDR3, which is the amino acid sequence of SEQ ID NO: 17. The second ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 8; CDR2, which is the amino acid sequence of SEQ ID NO: 13; and CDR3, which is the amino acid sequence of SEQ ID NO: 18. The third ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 9, CDR2, which is the amino acid sequence of SEQ ID NO: 14, and CDR3, which is the amino acid sequence of SEQ ID NO: 19. The fourth ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 11; CDR2, which is the amino acid sequence of SEQ ID NO: 16; and CDR3, which is the amino acid sequence of SEQ ID NO: 21.

[0110] Sequence ID 7 is GRTFSSYRMG; Sequence ID 12 is ALSGDGYSTY; Sequence ID 17 is KLQYVSGWSYDYPY.

[0111] Sequence ID 8 is GFTFNNYAMK; Sequence ID 13 is SITTGGGSTD; Sequence ID 18 is VPFGYYSEHFSGLSFDY.

[0112] Sequence ID 9 is GSGFGVNILY; Sequence ID 14 is SITGGITN; Sequence ID 19 is RNIFDGTTE.

[0113] Sequence ID 11 is GFTFADYDYDIG; Sequence ID 16 is CISNRDGSTY; Sequence ID 21 is EIHCDDYGVENFDFD.

[0114] In some embodiments, the compound is The first ISVD containing the amino acid sequence of SEQ ID NO: 2, The second ISVD containing the amino acid sequence of SEQ ID NO: 3, A third ISVD containing the amino acid sequence of SEQ ID NO: 4, and The fourth ISVD containing the amino acid sequence of SEQ ID NO: 6 Includes.

[0115] In some embodiments, the order of the ISVDs described above indicates their relative positions to each other, considered from the N-terminus to the C-terminus of the polypeptide.

[0116] In some embodiments, the compound comprises a further ISVD that binds to human serum albumin, the further ISVD comprising CDR1, which is the amino acid sequence of SEQ ID NO: 10; CDR2, which is the amino acid sequence of SEQ ID NO: 15; and CDR3, which is the amino acid sequence of SEQ ID NO: 20. In some embodiments, the further ISVD is positioned between the third and fourth ISVDs described above.

[0117] In some embodiments, the compound is The first ISVD containing the amino acid sequence of SEQ ID NO: 2, The second ISVD containing the amino acid sequence of SEQ ID NO: 3, The third ISVD containing the amino acid sequence of SEQ ID NO: 4, The fourth ISVD containing the amino acid sequence of SEQ ID NO: 6, and Further ISVDs that bind to human serum albumin and contain the amino acid sequence of SEQ ID NO: 5 Includes.

[0118] An exemplary polypeptide that binds to TSLP and IL-13 is SAR443765 (also known as lunsekimig) (SEQ ID NO: 1). In some embodiments, the polypeptide that binds to TSLP and IL-13 is SAR443765 (SEQ ID NO: 1).

[0119] Sequence ID 1 is, [ka] That is the case.

[0120] 5.3.1 Immunoglobulin monovariable domains As described above, in some embodiments, the polypeptide for use in the present invention is a polypeptide comprising an immunoglobulin single variable domain (ISVD).

[0121] The term "Immunoglobulin Single Variable Domain" (ISVD), used synonymously with "Single Variable Domain," defines an immunoglobulin molecule in which the antigen-binding site resides on a single immunoglobulin domain and is formed by a single immunoglobulin domain. This distinguishes ISVDs from "conventional" immunoglobulins (e.g., monoclonal antibodies) or their fragments (e.g., Fab, Fab', F(ab')2, scFv, di-scFv) in which two immunoglobulin domains (particularly two variable domains) interact to form the antigen-binding site. Typically, in conventional immunoglobulins, the heavy chain variable domain (V) is present. H ) and light chain variable domain (V L ) interact to form an antigen-binding site. In this case, V H and V L Both complementarity-determining regions (CDRs) contribute to the antigen-binding site, meaning a total of six CDRs are involved in the formation of the antigen-binding site.

[0122] In light of the above definition, the antigen-binding domains of conventional four-chain antibodies (e.g., IgG, IgM, IgA, IgD, or IgE molecules known in the art), or Fv fragments such as Fab fragments, F(ab')2 fragments, disulfide-linked Fv fragments, or scFv fragments, or diabodies (all known in the art) derived from such conventional four-chain antibodies, are not usually considered ISVDs, because in these cases, binding to each epitope of the antigen does not usually occur by a single immunoglobulin domain, but rather by a pair of (related) immunoglobulin domains, such as light and heavy chain variable domains, i.e., the immunoglobulin domains that co-bind to each antigen's epitope. H -V L This is because it will occur in pairs.

[0123] In contrast, ISVD can specifically bind to the antigen epitope without pairing with an additional immunoglobulin variable domain. The binding site of ISVD is a single V H , single V HH , or a single V L It is formed by domains.

[0124] Therefore, a single variable domain can form a single antigen-binding unit (i.e., a functional antigen-binding unit that is essentially derived from a single variable domain, so that a single antigen-binding domain does not need to interact with another variable domain to form a functional antigen-binding unit) insofar as the single variable domain can form a single antigen-binding unit (e.g., V L - Sequence) or a preferred fragment thereof; or heavy chain variable domain sequence (e.g., V H - Array or V HH It may be an array or a preferred fragment thereof.

[0125] ISVD is, for example, a camelid V H or humanized V HH V H , V HH These can be heavy chain ISVDs. In one embodiment, this is camelid V Hor humanized V HH V including HH Heavy chain ISVD can be obtained from conventional four-chain antibodies or heavy chain antibodies.

[0126] For example, ISVD is a single-domain antibody (or an amino acid sequence suitable for use as a single-domain antibody), "dAb" or dAb (or an amino acid sequence suitable for use as a dAb), Nanobody® (as defined herein, V HH Examples include, but are not limited to; other single variable domains, or any suitable fragment of any one of these.

[0127] In particular, ISVD is Nanobody (registered trademark) (for example, humanized V HH Or Camelization V H V including HH ), or a suitable fragment. Nanobody®, Nanobodies®, and Nanoclone® are registered trademarks of Sanofi or its affiliates.

[0128] "V HH "Domain" is V HH , V HH Antigen fragments, and V HH Also known as antibodies, it was originally described as the antigen-binding immunoglobulin variable domain of "heavy chain antibodies" (i.e., "antibodies lacking a light chain"; Hamers-Casterman et al. Nature 363:446-448, 1993). HH The term "domain" refers to these variable domains as the heavy chain variable domains present in conventional four-chain antibodies (referred to as "V" in this specification). H (referred to as "domain") and the light chain variable domain present in conventional 4-chain antibodies (referred to as "V" in this specification). L It is chosen to distinguish it from what is called a "domain." HHFor further explanation, please refer to the review article by Muyldermans (Reviews in Molecular Biotechnology 74:277-302, 2001).

[0129] Typically, immunoglobulin production involves immunizing experimental animals, fusing immunoglobulin-producing cells to create hybridomas, and screening for desired specificity. Alternatively, immunoglobulins can be produced by screening naive or synthetic libraries, for example, by phage display.

[0130] The generation of immunoglobulin sequences such as Nanobodies® has been widely described in various published literature, including, among others, International Publication No. 94 / 04678, Hamers-Casterman et al. 1993, and Muyldermans, 2001. In these methods, camelids are immunized with a target antigen to induce an immune response to the target antigen. The repertoire of nanobodies obtained from this immunization is further screened for nanobodies that bind to the target antigen.

[0131] In these examples, antibody production requires purified antigens for immunization and / or screening. Antigens can be purified from naturally occurring sources or during recombinant production processes.

[0132] Immunization and / or screening for immunoglobulin sequences can be performed using peptide fragments of such antigens.

[0133] The present invention may utilize immunoglobulin sequences of various origins, including those of mice, rats, rabbits, donkeys, humans, and camelids. The present invention may also utilize fully human sequences, humanized sequences, or chimeric sequences. For example, the present invention may utilize camelid immunoglobulin sequences and humanized camelid immunoglobulin sequences, or camelid domain antibodies (e.g., camelid dAbs as described by Ward et al.) (see, for example, International Publication No. 94 / 04678 and Davies and Riechmann (1994 and 1996)). Furthermore, in some embodiments, the present invention may also utilize fused immunoglobulin sequences (one or more V) that form, for example, polyvalent and / or multispecific constructs. HH For information regarding polyvalent and multispecific polypeptides containing domains, and their preparation, see Conrath et al., J. Biol. Chem., Vol. 276, 10. 7346-7350, 2001, and, for example, International Publication Nos. 96 / 34103 and 99 / 23221. Immunoglobulin sequences containing tags or other functional parts (e.g., toxins, labels, radiochemicals) that can be derived from the immunoglobulin sequences of the compounds used in the present invention are also used.

[0134] 5.3.2 Antibodies As described above, in some embodiments, the polypeptide for use in the present invention is an antibody. Antibodies that bind to TSLP and IL-13 can be found in Venkataramani et al. (Biochem Biophys Res Commun. 2018 Sep 26;504(1):19-24).

[0135] 5.3.3 Coupling / Blocking The compounds of the present invention bind to TSLP and IL-13. In some embodiments, the compounds of the present invention can block their target molecules. For example, the compounds can block the interaction between IL-13 and IL-13Rα1 (interleukin 13 receptor, alpha-1), and / or the interaction between the IL-13 / IL-13Rα1 complex and IL-4Rα (alpha-interleukin 4 receptor), and / or the interaction between TSLP, TSLPR (TSLP receptor) and / or the TSLP / TSLPR complex and IL-7Rα (interleukin 7 receptor subunit alpha). In some embodiments, the compounds of the present invention can block the interaction between IL-13 and IL-13Rα1 (interleukin 13 receptor, alpha-1), and / or the interaction between the IL-13 / IL-13Rα1 complex and IL-4Rα (alpha-interleukin 4 receptor), and can block the interaction between TSLP, TSLPR (TSLP receptor) and / or the TSLP / TSLPR complex and IL-7Rα (interleukin 7 receptor subunit alpha).

[0136] In some embodiments, the compounds for use in the present invention may bind to human IL-13 (Uniprot accession P35225) and human TSLP (Uniprot accession Q969D9). In some embodiments, the compounds for use in the present invention may bind to IL-13 and TSLP derived from other mammals, such as mice, rats, rabbits, cats, dogs, goats, sheep, horses, pigs, non-human primates, such as cynomolgus macaques (also referred to herein as "cyno"), or camelids (e.g., llamas or alpacas).

[0137] In relation to the compounds of the present invention, binding to IL-13 and TSLP means specific binding to IL-13 and TSLP. The binding of a compound to its target can be determined based on affinity. Affinity indicates the strength or stability of molecular interactions. Affinity is generally expressed by the KD or dissociation constant, which has units of mol / liter (or M). Affinity can also be expressed as the association constant KA, where KA is equal to 1 / KD, (mol / liter) -1 (or M -1 It has units of ).

[0138] Affinity is an indicator of the binding strength between a given part of a molecule and a binding site on the target molecule. The smaller the KD value, the stronger the binding strength between the target molecule and the targeting site.

[0139] Typically, the bonding units used in the present invention are 10 -5 ~10 -12 moles / liter or less, or 10 -7 ~10 -12 moles / liter or less, or 10 -8 ~10 -12 The dissociation constant (KD) in moles / liter (i.e., 10 5 ~10 12 Liters / moles or more, or 10 7 ~10 12 Liters / moles or more, or 10 8 ~10 12 It binds to the target of the binding unit with an association constant (KA) of liters / moles.

[0140] 10 -4 Any KD value exceeding mol / liter (or 10 4 Any KA value less than liters / mol is generally considered to indicate nonspecific interactions.

[0141] The KD of biological interactions considered specific, such as the binding of immunoglobulin sequences to antigens, is typically 10. -5 moles / liter (10000 nM or 10 μM) ~ 10 -12 The concentration is within the range of moles / liter (0.001 nM or 1 pM) or less.

[0142] Therefore, specific / selective binding can be determined by using the same measurement method, e.g., SPR, for a compound of 10 -5 ~10 -12 It binds to IL13 and / or TSLP with a KD value of 10 moles / liter or less, and -4 A KD value exceeding moles / liter may indicate binding to the relevant cytokine. An example of an IL13-related target is human IL4. An example of a TSLP-related cytokine is human IL7. Therefore, in some embodiments, the compounds used in the present invention are 10 -5 ~10 -12 It binds to IL13 with a KD value of 10 moles / liter or less, and -4 It binds to the same type of IL4 with a KD value exceeding mol / liter, and 10 -5 ~10 -12 It binds to TSLP with a KD value of 10 moles / liter or less, and 10 -4 It binds to the same species of human IL7 at a KD value exceeding moles / liter.

[0143] In some embodiments, the polypeptide used in the present invention has at least half the binding affinity to human IL13 and human TSLP compared to the polypeptide consisting of the amino acids of SEQ ID NO: 1, and the binding affinity is measured using the same method (e.g., SPR).

[0144] Specific binding to a specific target originating from a particular species does not preclude the possibility that the binding unit may also specifically bind to similar targets originating from different species. For example, specific binding to human IL-13 does not preclude the possibility that the binding unit (or polypeptide containing it) may also specifically bind to IL-13 from cynomolgus monkeys. Similarly, specific binding to human TSLP does not preclude the possibility that the binding unit (or polypeptide containing it) may also specifically bind to TSLP from cynomolgus monkeys ("cyno").

[0145] The specific binding of the binding unit to a specified target can be determined by any suitable method known in itself, including, for example, scatchard analysis and / or competitive binding assays, such as radioimmunoassays (RIAs), enzyme immunoassays (EIAs), and sandwich competitive assays, as well as various variations thereof known in the art; and other techniques referred to herein.

[0146] The dissociation constant may be the actual dissociation constant or the apparent dissociation constant, as will be obvious to those skilled in the art. Methods for determining the dissociation constant are obvious to those skilled in the art, and include, for example, the techniques mentioned below. In this regard, 10 -4 moles / liter or 10 -3 moles / liter (for example, 10 -2 It will also be apparent that dissociation constants exceeding moles / liter may be unmeasurable. In some cases, as will be apparent to those skilled in the art, the (actual or apparent) dissociation constant can be calculated based on the (actual or apparent) association constant (KA) using the relation [KD = 1 / KA].

[0147] The affinity of molecular interactions between two molecules can be measured by various self-known techniques, such as the well-known surface plasmon resonance (SPR) biosensor technique (see, e.g., Ober et al. 2001, Intern. Immunology 13:1551-1559). The term "surface plasmon resonance," as used herein, refers to an optical phenomenon that enables real-time analysis of biospecific interactions by detecting changes in protein concentration within a biosensor matrix, where one molecule is immobilized on a biosensor chip and the other molecule passes over the immobilized molecule under flow conditions, k on , k off Measured value, therefore K D (or K AThis yields a value. This can be done, for example, using the well-known BIAcore® system (BIAcore International AB, a GE Healthcare company, Uppsala, Sweden and Piscataway, NJ). For further explanation, see Jonsson et al. (1993, Ann. Biol. Clin. 51:19-26), Jonsson et al. (1991 Biotechniques 11:620-627), Johnson et al. (1995, J. Mol. Recognit. 8:125-131), and Johnson et al. (1991, Anal. Biochem. 198:268-277).

[0148] Another well-known biosensor technique for determining the affinity of biomolecular interactions is biolayer interferometry (BLI) (see, e.g., Abdiche et al. 2008, Anal. Biochem. 377:209-217). The terms “biolayer interferometry” or “BLI,” as used herein, refer to a label-free optical technique that analyzes the interference patterns of light reflected from two surfaces: an internal reference layer (reference beam) and a layer of immobilized proteins on a biosensor chip (signal beam). A change in the number of molecules bound to the tip of the biosensor causes a shift in the interference pattern, reported as a wavelength shift (nm), the magnitude of which is a direct measure of the number of molecules bound to the tip surface of the biosensor. Because interactions can be measured in real time, association and dissociation rates, as well as affinity, can be determined. BLI can be performed, for example, using the well-known Octet® Systems (ForteBio, a division of Pall Life Sciences, Menlo Park, USA).

[0149] Alternatively, affinity can be measured using a kinetic exclusion assay (KinExA) (see, e.g., Drake et al. 2004, Anal. Biochem., 328:35-43) with the KinExA® platform (Sapidyne Instruments Inc, Boise, USA). As used herein, the term "KinExA" refers to a solution-based method for measuring the true equilibrium binding affinity and kinetics of an unmodified molecule. An equilibrium solution of the antibody / antigen complex is passed through a column containing beads pre-coated with the antigen (or antibody) to bind the free antibody (or antigen) to the coated molecule. Detection of the thus captured antibody (or antigen) is achieved using a fluorescently labeled protein that binds to the antibody (or antigen).

[0150] The GYROLAB® immunoassay system provides a platform for automated bioanalysis and rapid sample turnaround (Fraley et al. 2013, Bioanalysis 5:1765-74).

[0151] 5.3.4 Nucleic acid molecules In some embodiments, the present invention relates to nucleic acids for use in the treatment of a target lung disease, encoding compounds that bind to IL-13 and TSLP, and the treatment reduces exhaled nitric oxide (FeNO) levels by at least 18 ppb compared to placebo. In some embodiments, the lung disease is an inflammatory disease. In some embodiments, the lung disease is asthma. In some embodiments, the asthma is hypereosinophilic asthma. In some embodiments, the asthma is hypoeosinophilic asthma.

[0152] A "nucleic acid molecule" (used synonymously with "nucleic acid") is a chain of nucleotide monomers linked together via a phosphate backbone to form a nucleotide sequence. Nucleic acids can be used to transform / transfect host cells or host organisms for, for example, polypeptide expression and / or production. Suitable hosts or host cells for production purposes will be obvious to those skilled in the art. For example, they may be any suitable fungal, prokaryotic, or eukaryotic cell or cell lineage, or any suitable fungal, prokaryotic, or eukaryotic organism. Hosts or host cells containing nucleic acids encoding the polypeptides of the present invention are also included in the present invention.

[0153] Nucleic acids can be, for example, DNA, RNA, or hybrids thereof, and may also include (e.g., chemically) modified nucleotides such as PNA. They can be single-stranded or double-stranded. In one embodiment, this is in the form of double-stranded DNA. For example, the nucleotide sequence of the present invention may be genomic DNA or cDNA.

[0154] The nucleic acids of the present invention can be prepared or obtained by methods known in themselves, and / or isolated from suitable natural sources. Nucleotide sequences encoding naturally occurring (poly)peptides can be subjected to site-directed mutagenesis, for example, to provide nucleic acid molecules encoding polypeptides with sequence mutations. As will be apparent to those skilled in the art, several nucleotide sequences, for example, at least one nucleotide sequence encoding a targeting moiety and nucleic acids encoding, for example, one or more linkers, can be linked and integrated in a suitable manner to prepare nucleic acids.

[0155] Nucleic acid generation techniques will be apparent to those skilled in the art. Examples, but not limited to, include automated DNA synthesis, site-directed mutagenesis, combination of two or more naturally occurring and / or synthetic sequences (or two or more parts thereof), introduction of mutations resulting in the expression of truncated expression products, introduction of one or more restriction sites (e.g., creation of cassettes and / or regions that can be readily digested and / or ligated using suitable restriction enzymes), and / or introduction of mutations using PCR reactions with one or more "mismatch" primers.

[0156] 5.3.5 Composition The present invention also provides a pharmaceutical composition for use in the present invention, comprising at least one compound that binds to TSLP and IL-13, and / or at least one nucleic acid molecule encoding the compound that binds to TSLP and IL-13. The composition may further comprise at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and may optionally comprise one or more further pharmaceutically active polypeptides and / or compounds.

[0157] In some embodiments, the present invention provides a pharmaceutical composition for use in the treatment of a target lung disease, comprising a compound that binds to IL-13 and TSLP, further comprising at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally comprising one or more further pharmaceutically active polypeptides and / or compounds, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) by at least 18 ppb compared to placebo. In some embodiments, the lung disease is an inflammatory disease. In some embodiments, the lung disease is asthma. In some embodiments, the asthma is hypereosinophilic asthma. In some embodiments, the asthma is hypoeosinophilic asthma.

[0158] In some embodiments, the present invention provides a pharmaceutical composition for use in the treatment of a target lung disease, comprising a compound that binds to IL-13 and TSLP, further comprising at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally comprising one or more further pharmaceutically active polypeptides and / or compounds, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) by at least 20 ppb compared to placebo. In some embodiments, the lung disease is an inflammatory disease. In some embodiments, the lung disease is asthma. In some embodiments, the asthma is hypereosinophilic asthma. In some embodiments, the asthma is hypoeosinophilic asthma.

[0159] In some embodiments, the present invention provides a pharmaceutical composition for use in the treatment of a target lung disease, comprising a compound that binds to IL-13 and TSLP, further comprising at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally comprising one or more further pharmaceutically active polypeptides and / or compounds, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) by at least 30 ppb compared to placebo. In some embodiments, the lung disease is an inflammatory disease. In some embodiments, the lung disease is asthma. In some embodiments, the asthma is hypereosinophilic asthma. In some embodiments, the asthma is hypoeosinophilic asthma.

[0160] In some embodiments, the present invention provides a pharmaceutical composition for use in the treatment of a target lung disease, comprising a compound that binds to IL-13 and TSLP, further comprising at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally comprising one or more further pharmaceutically active polypeptides and / or compounds, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) by at least 40 ppb compared to placebo. In some embodiments, the lung disease is an inflammatory disease. In some embodiments, the lung disease is asthma. In some embodiments, the asthma is hypereosinophilic asthma. In some embodiments, the asthma is hypoeosinophilic asthma.

[0161] 5.4 Embodiments of the Invention The following exemplary embodiments of the present invention are provided for illustrative purposes only.

[0162] 5.4.1 Compounds that bind to IL-13 and TSLP for use in the treatment of lung diseases These embodiments relate to compounds that bind to IL-13 and TSLP for use in the treatment of target lung diseases, wherein the treatment reduces exhaled nitric oxide (FeNO) levels by at least 18 ppb compared to a control.

[0163] FeNO level+ point In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 18 ppb compared to placebo within 4 weeks after administration of the compound.

[0164] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 18 ppb compared to placebo within two weeks after administration of the compound.

[0165] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 18 ppb compared to placebo within one week after administration of the compound.

[0166] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 20 ppb compared to placebo within 4 weeks after administration of the compound.

[0167] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 20 ppb compared to placebo within two weeks of administering the compound.

[0168] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 20 ppb compared to placebo within one week after administration of the compound.

[0169] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 25 ppb compared to placebo within 4 weeks after administration of the compound.

[0170] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 25 ppb compared to placebo within two weeks after administration of the compound.

[0171] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 25 ppb compared to placebo within one week after administration of the compound.

[0172] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 30 ppb compared to placebo within 4 weeks after administration of the compound.

[0173] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 30 ppb compared to placebo within two weeks after administration of the compound.

[0174] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 30 ppb compared to placebo within one week after administration of the compound.

[0175] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 35 ppb compared to placebo within 4 weeks after administration of the compound.

[0176] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 35 ppb compared to placebo within two weeks after administration of the compound.

[0177] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 35 ppb compared to placebo within one week after administration of the compound.

[0178] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 40 ppb compared to placebo within 4 weeks after administration of the compound.

[0179] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 40 ppb compared to placebo within two weeks after administration of the compound.

[0180] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 40 ppb compared to placebo within one week after administration of the compound.

[0181] FeNO baseline level In some embodiments, the treatment is applied to subjects whose baseline (before administration of the compound) FeNO level is at least 25.

[0182] In some embodiments, the treatment is applied to subjects whose baseline (before administration of the compound) FeNO level is at least 30.

[0183] In some embodiments, the treatment is applied to subjects whose baseline (before administration of the compound) FeNO level is at least 40.

[0184] In some embodiments, the treatment is applied to subjects whose baseline (before administration of the compound) FeNO level is at least 50.

[0185] In some embodiments, the treatment is applied to subjects whose baseline (before administration of the compound) FeNO level is at least 60.

[0186] In some embodiments, the treatment is applied to subjects whose baseline (before administration of the compound) FeNO level is at least 70.

[0187] In some embodiments, the treatment is applied to the subject to control baseline (pre-administration of the compound) FeNO levels, which are at least 25.

[0188] In some embodiments, the treatment is applied to the subject to control baseline (pre-administration of the compound) FeNO levels, which are at least 30.

[0189] In some embodiments, the treatment is applied to the subject to control baseline (pre-administration of the compound) FeNO levels, which are at least 40.

[0190] In some embodiments, the treatment is applied to the subject to control baseline (pre-administration of the compound) FeNO levels, which are at least 50.

[0191] In some embodiments, the treatment is applied to the subject to control baseline (pre-administration of the compound) FeNO levels, which are at least 60.

[0192] In some embodiments, the treatment is applied to the subject to control baseline (pre-administration of the compound) FeNO levels, which are at least 70.

[0193] Eosinophil count + time point In some embodiments of the present invention, the eosinophil count is reduced by at least 30% compared to placebo within 4 weeks after administration of the compound.

[0194] In some embodiments of the present invention, the eosinophil count is reduced by at least 30% compared to placebo within two weeks after administration of the compound.

[0195] In some embodiments of the present invention, the eosinophil count is reduced by at least 30% compared to placebo within one week after administration of the compound.

[0196] In some embodiments of the present invention, the eosinophil count is reduced by at least 30% compared to placebo within 3 days after administration of the compound.

[0197] In some embodiments of the present invention, the eosinophil count is reduced by at least 30% compared to placebo within 1 day after administration of the compound.

[0198] In some embodiments of the present invention, the eosinophil count is reduced by at least 35% compared to placebo within 4 weeks after administration of the compound.

[0199] In some embodiments of the present invention, the eosinophil count is reduced by at least 35% compared to placebo within two weeks after administration of the compound.

[0200] In some embodiments of the present invention, the eosinophil count is reduced by at least 35% compared to placebo within one week after administration of the compound.

[0201] In some embodiments of the present invention, the eosinophil count is reduced by at least 35% compared to placebo within 3 days after administration of the compound.

[0202] In some embodiments of the present invention, the eosinophil count is reduced by at least 35% compared to placebo within 1 day after administration of the compound.

[0203] In some embodiments of the present invention, the eosinophil count is reduced by at least 40% compared to placebo within 4 weeks after administration of the compound.

[0204] In some embodiments of the present invention, the eosinophil count is reduced by at least 40% compared to placebo within two weeks after administration of the compound.

[0205] In some embodiments of the present invention, the eosinophil count is reduced by at least 40% compared to placebo within one week after administration of the compound.

[0206] In some embodiments of the present invention, the eosinophil count is reduced by at least 40% compared to placebo within 3 days after administration of the compound.

[0207] In some embodiments of the present invention, the eosinophil count is reduced by at least 40% compared to placebo within 1 day after administration of the compound.

[0208] FENO level + eosinophil count + time point In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 18 ppb and eosinophil counts by at least 30% compared to placebo, within 4 weeks after administration of the compound.

[0209] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 20 ppb and eosinophil counts by at least 30% compared to placebo, within 4 weeks after administration of the compound.

[0210] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 30 ppb and eosinophil counts by at least 30% compared to placebo, within 4 weeks after administration of the compound.

[0211] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 40 ppb and eosinophil counts by at least 30% compared to placebo, within 4 weeks after administration of the compound.

[0212] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 18 ppb and eosinophil counts by at least 30% compared to placebo, within two weeks after administration of the compound.

[0213] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 20 ppb and eosinophil counts by at least 30% compared to placebo, within two weeks after administration of the compound.

[0214] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 30 ppb and eosinophil counts by at least 30% compared to placebo, within two weeks after administration of the compound.

[0215] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 40 ppb and eosinophil counts by at least 30% compared to placebo, within two weeks after administration of the compound.

[0216] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 18 ppb and eosinophil counts by at least 30% compared to placebo, within one week after administration of the compound.

[0217] In some embodiments, the treatment reduces exhaled nitric oxide (FeNO) levels by at least 20 ppb and eosinophil counts by at least 30% compared to placebo, within one week after administration of the compound.

[0218] In some embodiments, treatment results in at least a 30 ppb reduction in the level of exhaled nitric oxide (FeNO) and at least a 30% reduction in the eosinophil count within one week after administration of the compound, compared to placebo.

[0219] In some embodiments, treatment results in at least a 40 ppb reduction in the level of exhaled nitric oxide (FeNO) and at least a 30% reduction in the eosinophil count within one week after administration of the compound, compared to placebo.

[0220] SEQ ID NO: 1 + asthma In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in treating asthma in a subject, which is a polypeptide comprising or consisting of the amino acids of SEQ ID NO: 1.

[0221] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in treating eosinophilic asthma in a subject, which is a polypeptide comprising or consisting of the amino acids of SEQ ID NO: 1.

[0222] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in treating non-eosinophilic asthma in a subject, which is a polypeptide comprising or consisting of the amino acids of SEQ ID NO: 1.

[0223] SEQ ID NO: 1 + asthma + FeNO level In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in treating asthma in a subject, wherein treatment results in at least an 18 ppb reduction in the level of exhaled nitric oxide (FeNO) compared to placebo, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0224] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce exhaled nitric oxide (FeNO) levels by at least 20 ppb compared to placebo, wherein the compounds are polypeptides comprising or consisting of the amino acid sequence of SEQ ID NO 1.

[0225] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce exhaled nitric oxide (FeNO) levels by at least 30 ppb compared to placebo, wherein the compounds are polypeptides comprising or consisting of the amino acid sequence of SEQ ID NO 1.

[0226] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce exhaled nitric oxide (FeNO) levels by at least 40 ppb compared to placebo, and the compounds are polypeptides comprising or consisting of the amino acid sequence of SEQ ID NO 1.

[0227] Sequence ID 1 + Asthma + FeNO level + Time point In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce exhaled nitric oxide (FeNO) levels by at least 18 ppb compared to a control, wherein the reduction in FeNO levels occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0228] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce exhaled nitric oxide (FeNO) levels by at least 20 ppb compared to a control, wherein the reduction in FeNO levels occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0229] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce exhaled nitric oxide (FeNO) levels by at least 30 ppb compared to a control, wherein the reduction in FeNO levels occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0230] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, wherein the treatment reduces exhaled nitric oxide (FeNO) levels by at least 40 ppb compared to a control, the reduction in FeNO levels occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0231] Sequence ID 1 + Asthma + FeNO level + Time point + Placebo In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce exhaled nitric oxide (FeNO) levels by at least 18 ppb compared to placebo, wherein the reduction in FeNO levels occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0232] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce exhaled nitric oxide (FeNO) levels by at least 20 ppb compared to placebo, wherein the reduction in FeNO levels occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0233] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce exhaled nitric oxide (FeNO) levels by at least 30 ppb compared to placebo, wherein the reduction in FeNO levels occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0234] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce exhaled nitric oxide (FeNO) levels by at least 40 ppb compared to placebo, wherein the reduction in FeNO levels occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0235] Sequence ID 1 + Asthma + FeNO level + Time point + Baseline In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces exhaled nitric oxide (FeNO) levels by at least 18 ppb compared to baseline, the reduction in FeNO levels occurring within 4 weeks after administration of the compound, the compound being a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO 1, and baseline meaning the individual baseline of the target.

[0236] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces exhaled nitric oxide (FeNO) levels by at least 20 ppb compared to baseline, the reduction in FeNO levels occurring within 4 weeks after administration of the compound, the compound being a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO 1, and baseline meaning the individual baseline of the target.

[0237] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces exhaled nitric oxide (FeNO) levels by at least 30 ppb compared to baseline, the reduction in FeNO levels occurring within 4 weeks after administration of the compound, the compound being a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO 1, and baseline meaning the individual baseline of the target.

[0238] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces exhaled nitric oxide (FeNO) levels by at least 40 ppb compared to baseline, the reduction in FeNO levels occurring within 4 weeks after administration of the compound, the compound being a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO 1, and baseline meaning the individual baseline of the target.

[0239] Sequence ID 1 + Asthma + FeNO Level + Human + Baseline In some embodiments, the present invention provides compounds that bind to IL-13 and TSLP for use in the treatment of asthma in human subjects, wherein the treatment reduces exhaled nitric oxide (FeNO) levels by at least 18 ppb compared to baseline, and the compounds are polypeptides comprising or consisting of the amino acid sequence of SEQ ID NO: 1, where baseline refers to the individual baseline of the subject.

[0240] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of asthma in a human subject, wherein treatment results in a reduction in the level of exhaled nitric oxide (FeNO) of at least 20 ppb compared to baseline, the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1, and baseline means the individual baseline of the subject.

[0241] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of asthma in a human subject, wherein treatment results in a reduction in the level of exhaled nitric oxide (FeNO) of at least 30 ppb compared to baseline, the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1, and baseline means the individual baseline of the subject.

[0242] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of asthma in a human subject, wherein treatment results in a reduction in the level of exhaled nitric oxide (FeNO) of at least 40 ppb compared to baseline, the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1, and baseline means the individual baseline of the subject.

[0243] SEQ ID NO: 1 + Asthma + FeNO Level + Human + Time Point + Baseline In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of asthma in a human subject, wherein treatment results in a reduction in the level of exhaled nitric oxide (FeNO) of at least 18 ppb compared to baseline, the reduction in the FeNO level occurs within 4 weeks after administration of the compound, the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1, and baseline means the individual baseline of the subject.

[0244] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of asthma in human subjects, wherein the treatment reduces exhaled nitric oxide (FeNO) levels by at least 20 ppb compared to baseline, the reduction in FeNO levels occurring within 4 weeks after administration of the compound, the compound being a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO 1, and baseline meaning the individual baseline of the subject.

[0245] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of asthma in human subjects, wherein the treatment reduces exhaled nitric oxide (FeNO) levels by at least 30 ppb compared to baseline, the reduction in FeNO levels occurring within 4 weeks after administration of the compound, the compound being a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO 1, and baseline meaning the individual baseline of the subject.

[0246] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of asthma in human subjects, wherein the treatment reduces exhaled nitric oxide (FeNO) levels by at least 40 ppb compared to baseline, the reduction in FeNO levels occurring within 4 weeks after administration of the compound, the compound being a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO 1, and baseline meaning the individual baseline of the subject.

[0247] Sequence ID 1 + Asthma + Eosinophil count + Time point In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce the number of eosinophils in the blood by at least 30% compared to a control, wherein the reduction in the number of eosinophils occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0248] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce the number of eosinophils in the blood by at least 35% compared to a control, wherein the reduction in the number of eosinophils occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0249] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce the number of eosinophils in the blood by at least 40% compared to a control, wherein the reduction in the number of eosinophils occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0250] Sequence ID 1 + Asthma + Eosinophil Count + Time Point + Placebo In some embodiments, the present invention provides compounds that bind to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces the number of eosinophils in the blood by at least 30% compared to placebo, the reduction in the number of eosinophils occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0251] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce the number of eosinophils in the blood by at least 35% compared to placebo, wherein the reduction in the number of eosinophils occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0252] In some embodiments, the present invention provides compounds for use in the treatment of a target asthma, which bind to IL-13 and TSLP, and which, upon treatment, reduce the number of eosinophils in the blood by at least 40% compared to placebo, wherein the reduction in the number of eosinophils occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0253] Sequence ID 1 + Asthma + Eosinophil Count + Time Point + Baseline In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces the number of eosinophils in the blood by at least 30% compared to baseline, the reduction in the number of eosinophils occurring within 4 weeks after administration of the compound, the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1, and baseline means the individual baseline of the target.

[0254] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces the number of eosinophils in the blood by at least 35% compared to baseline, the reduction in eosinophil count occurs within 4 weeks after administration of the compound, the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1, and baseline means the individual baseline of the target.

[0255] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces the number of eosinophils in the blood by at least 40% compared to baseline, the reduction in the number of eosinophils occurring within 4 weeks after administration of the compound, the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1, and baseline means the individual baseline of the target.

[0256] Sequence ID 1 + Asthma + Airway inflammation + Time point In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces airway inflammation, characterized by a reduction of at least 18 ppb in FeNO, at least 30% in eosinophil count, and / or an increase of at least 0.07 L in forced expiratory volume in one second (FEV1) compared to a control, wherein the reduction in airway inflammation occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0257] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces airway inflammation, characterized by a reduction of at least 20 ppb in FeNO, at least 30% in eosinophil count, and / or an increase of at least 0.07 L in forced expiratory volume in one second (FEV1) compared to a control, wherein the reduction in airway inflammation occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0258] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces airway inflammation, characterized by a reduction of at least 30 ppb in FeNO, at least 30% in eosinophil count, and / or an increase of at least 0.07 L in forced expiratory volume in one second (FEV1) compared to a control, wherein the reduction in airway inflammation occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0259] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces airway inflammation, characterized by a reduction of at least 40 ppb in FeNO, at least 30% in eosinophil count, and / or an increase of at least 0.07 L in forced expiratory volume in one second (FEV1) compared to a control, wherein the reduction in airway inflammation occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0260] Sequence ID 1 + Asthma + Airway Inflammation + Time Point + Placebo In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces airway inflammation, characterized by a reduction of at least 18 ppb in FeNO, at least 30% in eosinophil count, and / or an increase of at least 0.07 L in forced expiratory volume in one second (FEV1) compared to placebo, wherein the reduction in airway inflammation occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0261] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces airway inflammation, characterized by a reduction of at least 20 ppb of FeNO, at least 30% of eosinophil count, and / or an increase of at least 0.07 L of forced expiratory volume in one second (FEV1) compared to placebo, wherein the reduction of airway inflammation occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0262] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces airway inflammation, characterized by a reduction of at least 30 ppb in FeNO, at least 30% in eosinophil count, and / or an increase of at least 0.07 L in forced expiratory volume in one second (FEV1) compared to placebo, wherein the reduction in airway inflammation occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0263] In some embodiments, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target asthma, wherein the treatment reduces airway inflammation, characterized by a reduction of at least 40 ppb in FeNO, at least 30% in eosinophil count, and / or an increase of at least 0.07 L in forced expiratory volume in one second (FEV1) compared to placebo, wherein the reduction in airway inflammation occurs within 4 weeks after administration of the compound, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0264] 5.4.2 Treatment methods for lung diseases The present invention also provides a method for treating a target lung disease, comprising administering an effective amount of a compound that binds to IL-13 and TSLP to the target, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) compared to a control.

[0265] In some embodiments, the present invention provides a method for treating a target lung disease, comprising administering an effective amount of a compound that binds to IL-13 and TSLP to the target, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) by at least 18 ppb compared to a control.

[0266] All the above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a target lung disease, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) compared to a control, can be translated into a method for treating a target lung disease, comprising administering an effective amount of the compound that binds to IL-13 and TSLP to a subject, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) compared to a control. This applies particularly to the reduction of FeNO levels, timing, properties of the compound, type of lung disease, and control. For example, in some embodiments, the present invention provides a method for treating a target lung disease, comprising administering an effective amount of the compound that binds to IL-13 and TSLP to a subject, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) by at least 20 ppb, at least 30 ppb, or at least 40 ppb compared to a control.

[0267] The present invention also provides a method for treating a target lung disease, comprising administering an effective amount of a compound that binds to IL-13 and TSLP to the target, wherein the treatment reduces the number of eosinophils in the blood compared to a control.

[0268] In some embodiments, the present invention provides a method for treating a target lung disease, comprising administering an effective amount of a compound that binds to IL-13 and TSLP to the target, wherein the treatment reduces the number of eosinophils in the blood by at least 30% compared to a control.

[0269] All the above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a target lung disease, wherein the treatment reduces the number of eosinophils in the blood compared to a control, can be translated into a method for treating a target lung disease, comprising administering an effective amount of the compound that binds to IL-13 and TSLP to a subject, wherein the treatment reduces the number of eosinophils in the blood compared to a control. This applies particularly to the reduction of eosinophil count, the timing, the properties of the compound, the type of lung disease, and the control. For example, in some embodiments, the present invention provides a method for treating a target lung disease, comprising administering an effective amount of the compound that binds to IL-13 and TSLP to a subject, wherein the treatment reduces the number of eosinophils in the blood by at least 35% or at least 40% compared to a control.

[0270] The present invention also provides a method for treating a target lung disease, comprising administering an effective amount of a compound that binds to IL-13 and TSLP to the target, wherein the treatment reduces airway inflammation. All of the above embodiments and examples relating to a compound that binds to IL-13 and TSLP for use in the treatment of a target lung disease, wherein the treatment reduces airway inflammation, can be translated into a method for treating a target lung disease, comprising administering an effective amount of a compound that binds to IL-13 and TSLP to the target, wherein the treatment reduces airway inflammation. This applies in particular to the definition of reduction of airway inflammation, the timing, the properties of the compound, the type of lung disease, and the control.

[0271] 5.4.3 Use of compounds that bind to IL-13 and TSLP in the preparation of pharmaceutical compositions for the treatment of lung diseases The present invention also provides the use of compounds that bind to IL-13 and TSLP in the preparation of pharmaceutical compositions for the treatment of target lung diseases, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) compared to a control.

[0272] In some embodiments, the present invention provides the use of compounds that bind to IL-13 and TSLP in the preparation of a pharmaceutical composition for the treatment of a target lung disease, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) by at least 18 ppb compared to a control.

[0273] All the above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of target lung diseases, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) compared to a control, can be translated into uses of compounds that bind to IL-13 and TSLP in the preparation of pharmaceutical compositions for the treatment of target lung diseases, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) compared to a control. This applies particularly to the reduction of FeNO levels, timing, properties of the compound, type of lung disease, and control. For example, in some embodiments, the present invention provides uses of compounds that bind to IL-13 and TSLP in the preparation of pharmaceutical compositions for the treatment of target lung diseases, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) by at least 20 ppb, at least 30 ppb, or at least 40 ppb compared to a control.

[0274] The present invention also provides the use of compounds that bind to IL-13 and TSLP in the preparation of a pharmaceutical composition for the treatment of a target lung disease, wherein the treatment reduces the number of eosinophils in the blood compared to a control.

[0275] In some embodiments, the present invention provides the use of compounds that bind to IL-13 and TSLP in the preparation of a pharmaceutical composition for the treatment of a target lung disease, wherein the treatment reduces the number of eosinophils in the blood by at least 30% compared to a control.

[0276] All the above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a target lung disease, wherein the treatment reduces the number of eosinophils in the blood compared to a control, can be translated into uses of compounds that bind to IL-13 and TSLP in the preparation of a pharmaceutical composition for the treatment of a target lung disease, wherein the treatment reduces the number of eosinophils in the blood compared to a control. This applies particularly to the reduction of eosinophil count, timing, properties of the compound, type of lung disease, and control. For example, in some embodiments, the present invention provides uses of compounds that bind to IL-13 and TSLP in the preparation of a pharmaceutical composition for the treatment of a target lung disease, wherein the treatment reduces the number of eosinophils in the blood by at least 35% or at least 40% compared to a control.

[0277] The present invention also provides the use of compounds that bind to IL-13 and TSLP in the preparation of pharmaceutical compositions for the treatment of target lung diseases, wherein the treatment reduces airway inflammation. All of the above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of target lung diseases, wherein the treatment reduces airway inflammation, can be translated into the use of compounds that bind to IL-13 and TSLP in the preparation of pharmaceutical compositions for the treatment of target lung diseases, wherein the treatment reduces airway inflammation. This applies in particular to the definition of reduction of airway inflammation, the timing, the properties of the compounds, the type of lung disease, and the controls.

[0278] 5.4.4 Use of compounds that bind to IL-13 and TSLP for the treatment of lung diseases The present invention also provides the use of compounds that bind to IL-13 and TSLP for the treatment of a target lung disease, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) compared to a control.

[0279] In some embodiments, the present invention provides the use of compounds that bind to IL-13 and TSLP for the treatment of a target lung disease, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) by at least 18 ppb compared to a control.

[0280] All the above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of target lung diseases, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) compared to a control, can be translated into uses of compounds that bind to IL-13 and TSLP for the treatment of target lung diseases, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) compared to a control. This applies particularly to the reduction of FeNO levels, timing, properties of the compound, type of lung disease, and control. For example, in some embodiments, the present invention provides uses of compounds that bind to IL-13 and TSLP for the treatment of target lung diseases, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) by 20 ppb, at least 30 ppb, or at least 40 ppb compared to a control.

[0281] The present invention also provides the use of compounds that bind to IL-13 and TSLP for the treatment of a target lung disease, wherein the treatment reduces the number of eosinophils in the blood compared to a control.

[0282] In some embodiments, the present invention provides the use of compounds that bind to IL-13 and TSLP for the treatment of a target lung disease, wherein the treatment reduces the number of eosinophils in the blood by at least 30% compared to a control.

[0283] All the above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a target lung disease, wherein the treatment reduces the number of eosinophils in the blood compared to a control, can be translated into uses of compounds that bind to IL-13 and TSLP for the treatment of a target lung disease, wherein the treatment reduces the number of eosinophils in the blood compared to a control. This applies particularly to the reduction in eosinophil count, the timing, the properties of the compound, the type of lung disease, and the control. For example, in some embodiments, the present invention provides uses of compounds that bind to IL-13 and TSLP for the treatment of a target lung disease, wherein the treatment reduces the number of eosinophils in the blood by at least 35% or at least 40% compared to a control.

[0284] The present invention also provides the use of compounds that bind to IL-13 and TSLP for the treatment of target lung diseases, wherein the treatment reduces airway inflammation. All of the above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of target lung diseases, wherein the treatment reduces airway inflammation, can be translated into the use of compounds that bind to IL-13 and TSLP for the treatment of target lung diseases, wherein the treatment reduces airway inflammation. This applies in particular to the definition of reduction of airway inflammation, the timing, the properties of the compounds, the type of lung disease, and the controls.

[0285] 5.4.5 Methods to reduce FeNO levels The present invention also provides compounds for use in reducing the target FeNO level, and methods for reducing the target FeNO level.

[0286] In some embodiments, the present invention provides compounds that bind to IL-13 and TSLP for use in reducing the level of exhaled nitric oxide (FeNO) in a target, wherein the compound reduces the FeNO level by at least 18 ppb compared to a control. The above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a target lung disease, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) in a target compared to a control, can be applied to compounds that bind to IL-13 and TSLP for use in reducing the level of exhaled nitric oxide (FeNO) in a target. This applies particularly to the reduction of FeNO levels, timing, properties of the compound, and control. For example, in some embodiments, the present invention provides compounds that bind to IL-13 and TSLP for use in reducing the level of exhaled nitric oxide (FeNO) in a target, wherein the compound reduces the FeNO level by at least 20 ppb, at least 30 ppb, or at least 40 ppb compared to a control.

[0287] In some embodiments, the present invention provides a method for reducing the level of exhaled nitric oxide (FeNO) in a target, wherein the compound reduces the FeNO level by at least 18 ppb compared to a control. The above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a target lung disease, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) compared to a control, can be translated into a method for reducing the level of exhaled nitric oxide (FeNO) in a target. This applies particularly to the reduction of FeNO levels, timing, properties of the compound, and controls. For example, in some embodiments, the present invention provides a method for reducing the level of exhaled nitric oxide (FeNO) in a target, wherein the compound reduces the FeNO level by at least 20 ppb, at least 30 ppb, or at least 40 ppb compared to a control.

[0288] 5.5 Preventive reduction of FeNO levels In another aspect, the present invention relates to a preventative aspect. Since the present invention provides a method for significantly reducing FeNO levels compared to known treatments, this opens up the possibility of prophylactic administration to subjects with elevated FeNO levels to prevent further loss of lung function before further loss of lung function occurs. Prophylactic administration may be for asthmatic patients and subjects at risk of developing asthma, as well as patients with other lung diseases and subjects at risk of developing other lung diseases. Accordingly, the present invention also provides compounds for use in reducing the FeNO levels of subjects, and methods for reducing the FeNO levels of subjects, wherein the reduction in FeNO levels prevents loss of lung function.

[0289] FeNO level The prophylactic reduction of FeNO levels according to the present invention relates to subjects whose FeNO levels (hereinafter referred to as baseline FeNO levels) are elevated before the initiation of prophylactic administration. Elevated baseline FeNO levels are those greater than 25 ppb (see, for example, Miskoff et al., Cureus. 2019 Jun;11(6):e4864).

[0290] In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 90 ppb, wherein the reduction in FeNO level prevents loss of lung function. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 80 ppb, wherein the reduction in FeNO level prevents loss of lung function. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 75 ppb, wherein the reduction in FeNO level prevents loss of lung function. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 70 ppb, wherein the reduction in FeNO level prevents loss of lung function. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 65 ppb, wherein the reduction in FeNO level prevents loss of lung function. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 60 ppb, wherein the reduction in FeNO level prevents loss of lung function. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 55 ppb, wherein the reduction in FeNO level prevents loss of lung function. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in FeNO level prevents loss of lung function. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 45 ppb, wherein the reduction in FeNO level prevents loss of lung function.In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 40 ppb, wherein the reduction in the FeNO level prevents loss of lung function. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 35 ppb, wherein the reduction in the FeNO level prevents loss of lung function. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 30 ppb, wherein the reduction in the FeNO level prevents loss of lung function. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 25 ppb, wherein the reduction in the FeNO level prevents loss of lung function.

[0291] In some embodiments, the present invention relates to compounds for use in reducing the FeNO level of a subject where the baseline FeNO level is at least 50 ppb, and the subject also has an eosinophil count of 0.3 × 10⁶. 9 The present invention provides a compound with a concentration of more than one cell / L, which prevents loss of lung function by reducing FeNO levels.

[0292] FeNO reduction In some embodiments, the reduction in the FeNO level is a reduction of at least 18 ppb. In some embodiments, the reduction in the FeNO level is a reduction of at least 20 ppb. In some embodiments, the reduction in the FeNO level is a reduction of at least 25 ppb. In some embodiments, the reduction in the FeNO level is a reduction of at least 30 ppb. In some embodiments, the reduction in the FeNO level is a reduction of at least 35 ppb. In some embodiments, the reduction in the FeNO level is a reduction of at least 40 ppb. In some embodiments, the reduction in the FeNO level is a reduction to a normal level, meaning a reduction to a level of less than 25 ppb.

[0293] FeNO level + FeNO reduction In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, and the reduction in the FeNO level is at least 25 ppb. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, and the reduction in the FeNO level is at least 20 ppb. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, and the reduction in the FeNO level is at least 18 ppb. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, and the reduction in the FeNO level is at least 25 ppb.

[0294] In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 35 ppb, wherein the reduction in the FeNO level prevents loss of lung function, and the reduction in the FeNO level is at least 25 ppb. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 35 ppb, wherein the reduction in the FeNO level prevents loss of lung function, and the reduction in the FeNO level is at least 20 ppb. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 35 ppb, wherein the reduction in the FeNO level prevents loss of lung function, and the reduction in the FeNO level is at least 18 ppb. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a target whose baseline FeNO level is at least 35 ppb, wherein the reduction in the FeNO level prevents loss of lung function, and the reduction in the FeNO level is at least 25 ppb.

[0295] In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a subject whose baseline FeNO level is at least 25 ppb, wherein the reduction in the FeNO level prevents loss of lung function, and the reduction in the FeNO level is at least 25 ppb. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a subject whose baseline FeNO level is at least 25 ppb, wherein the reduction in the FeNO level prevents loss of lung function, and the reduction in the FeNO level is at least 20 ppb. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a subject whose baseline FeNO level is at least 25 ppb, wherein the reduction in the FeNO level prevents loss of lung function, and the reduction in the FeNO level is at least 18 ppb. In some embodiments, the present invention provides compounds for use in reducing the FeNO level of a subject whose baseline FeNO level is at least 25 ppb, wherein the reduction in the FeNO level prevents loss of lung function, and the reduction in the FeNO level is at least 25 ppb.

[0296] Compounds for use in the precautionary reduction of FeNO levels In some embodiments, the compound is a compound that binds to IL-13. Exemplary compounds that bind to IL-13 include the antibodies anlukinzumab, lebrikizumab, and tralokinumab.

[0297] In some embodiments, the compound is a compound that binds to TSLP. An exemplary compound that binds to TSLP is the antibody tezeperumab.

[0298] In some embodiments, the compound is a compound that binds to IL-13 and TSLP. Exemplary compounds that bind to IL-13 and TSLP are shown above (Section 5.3). In some embodiments, the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0299] FeNO level + FeNO reduction + compounds In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is at least 25 ppb, and the compound is a compound that binds to IL-13 and TSLP. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is at least 25 ppb, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is at least 25 ppb, and the compound is tezepermab.

[0300] In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is to a level of less than 25 ppb, and the compound is a compound that binds to IL-13 and TSLP. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is to a level of less than 25 ppb, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is to a level of less than 25 ppb, and the compound is tezepermab.

[0301] In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 35 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is at least 18 ppb, and the compound is a compound that binds to IL-13 and TSLP. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 35 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is at least 18 ppb, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 35 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is at least 18 ppb, and the compound is tezepermab.

[0302] In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 35 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is to a level of less than 25 ppb, and the compound is a compound that binds to IL-13 and TSLP. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 35 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is to a level of less than 25 ppb, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 35 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is to a level of less than 25 ppb, and the compound is tezepermab.

[0303] In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 25 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is at least 18 ppb, and the compound is a compound that binds to IL-13 and TSLP. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 25 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is at least 18 ppb, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 25 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is at least 18 ppb, and the compound is tezepermab.

[0304] Causes of lung function loss Elevated FeNO levels are associated with several lung diseases, including asthma and idiopathic pulmonary fibrosis (Cameli et al., Int J Mol Sci. 2020 Sep;21(17):6187). Individuals with elevated baseline FeNO levels may already be exhibiting symptoms of asthma from another lung disease, or are at risk of developing symptoms of asthma or another lung disease. These symptoms include loss of lung function. Loss of lung function can be prevented by the prophylactic reduction of FeNO levels according to the present invention.

[0305] In some embodiments, the reduction of FeNO levels according to the present invention prevents loss of lung function associated with asthma. In some embodiments, the reduction of FeNO levels according to the present invention prevents loss of lung function associated with non-asthmatic lung diseases.

[0306] FeNO levels + FeNO reduction + compounds + causes of lung function loss In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is to a level of less than 25 ppb, the compound is a compound that binds to IL-13 and TSLP, and the loss of lung function is associated with asthma. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is to a level of less than 25 ppb, the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1, and the loss of lung function is associated with asthma. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a subject whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is to a level of less than 25 ppb, the compound is tezepermab, and the loss of lung function is associated with asthma.

[0307] In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is to a level of less than 25 ppb, the compound is a compound that binds to IL-13 and TSLP, and the loss of lung function is associated with a lung disease other than asthma. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target whose baseline FeNO level is at least 50 ppb, wherein the reduction in the FeNO level prevents loss of lung function, the reduction in the FeNO level is to a level of less than 25 ppb, the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1, and the loss of lung function is associated with a lung disease other than asthma. In some embodiments, the present invention provides a compound for use in reducing the FeNO level of a target, where the baseline FeNO level is at least 50 ppb, the reduction of the FeNO level prevents loss of lung function, the reduction of the FeNO level is to a level of less than 25 ppb, the compound is tezeperumab, and the loss of lung function is associated with a lung disease other than asthma.

[0308] The present invention also provides a method for reducing the FeNO level of a target, wherein the reduction in the FeNO level prevents loss of lung function. All of the above embodiments and examples relating to compounds for use in reducing the FeNO level of a target, wherein the reduction in the FeNO level prevents loss of lung function, can be translated into a method for reducing the FeNO level of a target, wherein the reduction in the FeNO level prevents loss of lung function.

[0309] The present invention also provides the use of a compound for preventing loss of lung function in a subject, wherein the compound reduces the FeNO level of the subject. All of the above embodiments and examples relating to a compound for use in reducing the FeNO level of a subject, wherein the reduction in the FeNO level prevents loss of lung function, can be translated into the use of a compound for preventing loss of lung function in a subject, wherein the compound reduces the FeNO level of the subject.

[0310] 5.6 Other aspects of the present invention 5.6.1 Treatment of small airway obstruction The present invention also provides compounds for use in the treatment of target lung diseases, wherein the treatment reduces small airway obstruction. Thus, the present invention offers the possibility of specifically treating patients suffering from small airway obstruction (for example, a subgroup of asthma patients suffering from small airway obstruction).

[0311] Accordingly, the present invention provides a compound that binds to IL-13 and TSLP for use in the treatment of a target lung disease, wherein the treatment reduces exhaled nitric oxide (FeNO) levels by at least 18 ppb compared to a control, and the treatment reduces small airway obstruction. In some embodiments, the lung disease is asthma. In some embodiments, the control is a placebo. In some embodiments, the compound is a polypeptide comprising or consisting of the amino acids of SEQ ID NO: 1. In some embodiments, the lung disease is asthma, and the control is a placebo. In some embodiments, the lung disease is asthma, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1. In some embodiments, the control is a placebo, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1. In some embodiments, the lung disease is asthma, the control is a placebo, and the compound is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0312] 5.6.2 Reduction of eosinophil count The present invention also provides compounds for use in reducing the number of eosinophils in the blood of a subject, and a method for reducing the number of eosinophils in the blood of a control.

[0313] In some embodiments, the present invention provides compounds that bind to IL-13 and TSLP for use in reducing the level of exhaled nitric oxide (FeNO) in a target, wherein the treatment reduces the number of eosinophils in the blood by at least 30% compared to a control. The above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a target lung disease, wherein the treatment reduces the number of eosinophils in the blood by at least 30% compared to a control, can be applied to compounds that bind to IL-13 and TSLP for use in reducing the number of eosinophils in a target. This applies particularly to the reduction of eosinophil count, timing, properties of the compound, and control. For example, in some embodiments, the present invention provides compounds that bind to IL-13 and TSLP for use in reducing the level of exhaled nitric oxide (FeNO) in a target, wherein the treatment reduces the number of eosinophils in the blood by at least 35% or at least 40% compared to a control.

[0314] In some embodiments, the present invention provides a method for reducing the number of eosinophils in a subject, wherein the treatment reduces the number of eosinophils in the blood by at least 30% compared to a control. The above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a lung disease in a subject, wherein the treatment reduces the number of eosinophils in the blood compared to a control, can be translated into a method for reducing the number of eosinophils in a subject. This applies particularly to the reduction of eosinophil count, timing, properties of the compound, and control. For example, in some embodiments, the present invention provides a method for reducing the number of eosinophils in a subject, wherein the treatment reduces the number of eosinophils in the blood by at least 35% or at least 40% compared to a control.

[0315] 5.6.3 Reduction of the proportion of non-classical monocytes The present invention also provides compounds for use in reducing the proportion of non-classical monocytes in a target airway, and a method for reducing the proportion of non-classical monocytes in a control airway.

[0316] Monocytes are a heterogeneous cell population with the potential to be activated, to infiltrate tissues from the blood, and to differentiate into macrophages. When activated, monocytes and macrophages release many inflammatory cytokines involved in the pathogenesis of asthma, and monocyte activation and respiratory tissue infiltration have been explained in numerous studies in asthma, suggesting an important role of cell type in disease pathobiology (Li et al., Tomita et al.). Monocytes have been observed to rapidly accumulate in the nasal mucosa after local allergen loading, where they promote the recruitment of Th2 cells and eosinophils. Recent single-cell RNA-seq analysis of bronchoalveolar lavage fluid has further identified increased monocyte clusters and monocyte-derived macrophage subpopulations in patients with asthma exacerbations. Another recent study has shown that monocytes accumulate in the lungs of children and adolescents with fatal asthma attacks (Eguiluz-Gracia et al., Clin Exp Allergy. 2018 Dec;48(12):1631-1639). These results also strongly support the idea that monocytes are directly involved in the immunopathology of asthma as pro-inflammatory cells, and suggest that preventing their entry into respiratory tissues with SAR may have a beneficial effect in preventing asthma symptoms and exacerbations.

[0317] Therefore, reducing the proportion of monocyte subpopulations (e.g., non-classical monocytes) may be useful in treating asthma. The present invention can achieve such a reduction, as shown in the Examples section below.

[0318] In some embodiments, the present invention provides compounds that bind to IL-13 and TSLP for use in reducing the level of exhaled nitric oxide (FeNO) in a subject, wherein the treatment reduces the proportion of non-classical monocytes in the subject's blood. The above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a subject's lung disease can be transferred to compounds that bind to IL-13 and TSLP for use in reducing the proportion of non-classical monocytes in the subject's blood. This applies particularly to the timing and properties of the compounds. For example, in some embodiments, the compounds that bind to IL-13 and TSLP are polypeptides comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0319] In some embodiments, the present invention provides a method for reducing the proportion of non-classical monocytes in the blood of a subject. The above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a target lung disease can be translated into a method for reducing the proportion of non-classical monocytes in the blood of a subject. This applies particularly to the time and properties of the compounds. For example, in some embodiments, the compounds that bind to IL-13 and TSLP are polypeptides comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0320] 5.6.4 Decrease in the proportion of NK cells The present invention also provides compounds for use in reducing the proportion of NK cells in the blood of a target, and methods for reducing the proportion of NK cells in the blood of a target.

[0321] In some embodiments, the present invention provides compounds that bind to IL-13 and TSLP for use in reducing the level of exhaled nitric oxide (FeNO) in a target, wherein the treatment reduces the proportion of NK cells in the target's blood. The above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a target lung disease can be transferred to compounds that bind to IL-13 and TSLP for use in reducing the proportion of NK cells in the target's blood. This applies particularly to the timing and properties of the compound. For example, in some embodiments, the compound that binds to IL-13 and TSLP is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0322] In some embodiments, the present invention provides a method for reducing the proportion of NK cells in the blood of a subject. The above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a target lung disease can be translated into a method for reducing the proportion of NK cells in the blood of a subject. This applies particularly to the time and properties of the compound. For example, in some embodiments, the compound that binds to IL-13 and TSLP is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0323] 5.6.5 Reduction of CCL26 expression in endothelial cells The present invention also provides compounds for use in reducing CCL26 expression in target endothelial cells (e.g., basal epithelial cells, multiciliated epithelial cells, and secretory epithelial cells), as well as methods for reducing CCL26 expression in target endothelial cells (e.g., basal epithelial cells, multiciliated epithelial cells, and secretory epithelial cells).

[0324] In some embodiments, the present invention provides compounds that bind to IL-13 and TSLP for use in reducing the level of exhaled nitric oxide (FeNO) in a target, wherein the treatment reduces CCL26 expression in the target endothelial cells. The above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of a target lung disease can be transferred to compounds that bind to IL-13 and TSLP for use in reducing CCL26 expression in the target endothelial cells. This applies particularly to the timing and properties of the compound. For example, in some embodiments, the compound that binds to IL-13 and TSLP is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0325] In some embodiments, the present invention provides a method for reducing CCL26 expression in target endothelial cells. The above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of target lung diseases can be translated into a method for reducing CCL26 expression in target endothelial cells. This applies particularly to the time and properties of the compounds. For example, in some embodiments, the compounds that bind to IL-13 and TSLP are polypeptides comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0326] 5.6.6 Reduction of HBB expression in T cells The present invention also provides compounds for use in reducing HBB expression in target T cells (e.g., CD8 T effector memory (em) cells), and methods for reducing HBB expression in target T cells (e.g., CD8 T effector memory (em) cells).

[0327] In some embodiments, the present invention provides compounds that bind to IL-13 and TSLP for use in reducing the level of exhaled nitric oxide (FeNO) in a target, wherein the treatment reduces HBB expression in the target T cells. The above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in treating a target lung disease can be transferred to compounds that bind to IL-13 and TSLP for use in reducing HBB expression in the target T cells. This applies particularly to the timing and properties of the compound. For example, in some embodiments, the compound that binds to IL-13 and TSLP is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0328] In some embodiments, the present invention provides a method for reducing HBB expression in target T cells. The above embodiments and examples relating to compounds that bind to IL-13 and TSLP for use in the treatment of target lung diseases can be translated into a method for reducing HBB expression in target T cells. This applies particularly to the time and properties of the compounds. For example, in some embodiments, the compounds that bind to IL-13 and TSLP are polypeptides comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

[0329] 5.7 Industrial Applicability The compounds for use according to the present invention can be used in the treatment of subjects suffering from lung diseases such as asthma. [Examples]

[0330] 6 Examples 6.1 Example 1: PDY16622 - A double-blind, randomized, placebo-controlled, parallel-design single-dose asthma trial at three sites. The efficacy of SAR443765 for the treatment of asthma was tested in a Phase I trial (PDY16622) detailed below. The trial schedule is shown in Figure 1.

[0331] 6.1.1 Method Patient cohort A total of up to 36 participants with mild to moderate asthma were enrolled in the study. These participants were randomized to either the SAR443765 group or the placebo group (24 SAR443765s and 12 placebos). These participants received a single dose at the safest and most tolerable dose level (400 mg SCmax), as initially assessed in the healthy adult participant portion of the study.

[0332] These participants had to meet the following criteria: • A diagnosis of asthma for at least 12 months, confirmed by screening based on the Global Initiative for Asthma (GINA) 2020 Guidelines, at all steps except steps 4 and 5, using high-dose inhaled corticosteroids (ICS). Controlled asthma, defined as an Asthma Control Questionnaire (ACQ)-5 score of less than 1.5. Participants using, as needed, short-acting beta-agonists (SABAs), ICS-natured, or existing stable treatment (for at least 3 months prior to screening) with low to moderate daily doses of ICS (500 mcg or less of fluticasone propionate or equivalent total daily dose of ICS), potentially in combination with long-acting beta-agonists (LABAs) and / or long-acting muscarinic agonists (LAMAs) as a second controller, and / or potentially in combination with stable daily leukotriene receptor antagonists, leukotriene synthesis inhibitors, and / or chromones. Participants with elevated FeNO levels defined as 25 ppb or higher at screening and baseline. • Participants whose FEV1 before bronchodilator administration at the time of screening is 60% or higher of the predicted normal value. • Recovery of at least 12% and 200 mL in FEV1 or forced vital capacity (FVC) after four single doses (400 mcg) of albuterol / salbutamol or levalbuterol / levosalbutamol during screening, or a record of a recovery test meeting these criteria within 5 years prior to screening, or a record of a positive response to metacholine loading (20% reduction in FEV1 to less than 8 mg / mL [PC20]) within 5 years prior to the screening visit. • Normal or clinically acceptable vital signs (pulse rate, SBP, and DBP) after a 10-minute supine rest at screening and baseline. • Normal or clinically acceptable standard 12-lead electrocardiogram (ECG) parameters and traces after a 10-minute supine rest at screening and baseline; a normal ECG trace unless the investigator determines that the abnormality of the ECG trace is not clinically significant. • Laboratory parameters within the normal range (or the screening threshold defined at the investigator's institution) at screening and baseline, unless the investigator determines the abnormality is clinically insignificant; however, serum creatinine, alkaline phosphatase, and liver enzymes (aspartate aminotransferase, alanine aminotransferase) should not exceed 1.25 times the upper limit of the laboratory value. Total bilirubin outside the normal range may be acceptable if the total bilirubin does not exceed 1.5 times the upper limit of the normal conjugated bilirubin value (unless the participant has documented Gilbert's syndrome). • Weight at screening and baseline: 50.0–105.0 kg (including both ends) for males, and 40.0–95.0 kg (including both ends) for females, 18.0 kg / m² 2 ~32.0 kg / m 2 The obesity index (including both ends).

[0333] Administration Participants were administered the drug at least every 10 minutes in subgroups of up to four participants, with at least two days between subgroups. The asthma cohort was initiated based on blinded safety and PK data from an earlier trial part in healthy adult participants.

[0334] All participants were screened within 28 days to confirm they met the study requirements. Eligible participants were hospitalized the day before each dose, and participants included in the study remained hospitalized for 1 day after administration of the study drug in the asthma cohort, taking into account new safety, PK, and PD data. Prior to administration of each drug, participants were evaluated for SARS-CoV-2 infection and underwent intensive monitoring including physical examination, AE assessment, vital signs, ECG, and periodic laboratory assessments (complete blood count with differential, chemistry, aPTT, PT-INR, high-sensitivity cardiac troponin T, and urinalysis). After the hospitalization period, participants underwent clinical assessments including vital signs, ECG, routine laboratory assessments, and ADA assessments at various intervals until the completion of the study. Therefore, considering the half-life range of serum albumin-binding nanobodies, the observation period for adverse events occurring with the study treatment ended 70 days after the last dose.

[0335] Analysis of exhaled nitric oxide (FeNO) levels Exhaled nitric oxide (FeNO) was measured at the time points specified in the study schedule (Figure 1) (i.e., baseline, D8, D15, D29, and D57). FeNO is a measure of NO production by lung epithelial cells and is considered a biomarker of airway inflammation in asthma.

[0336] FeNO levels (ppb) were collected in-situ using a dedicated medical device, such as a commercially available handheld device (NIOX VERO®). The FeNO test must be completed before impulse oscillometry and vital capacity measurements to avoid any influence on nitric oxide measurements. Considering the diurnal variation of FeNO, assessments should be performed at approximately the same time of day (±2 hours) throughout the study. Participants should not eat or drink for one hour before FeNO measurement, as this may affect the results. All carbonated beverages and nitrate-rich foods (e.g., vegetable juices, salads, lettuce, radish, celery, broccoli, cauliflower, spinach, radish, beet, parsley, leeks, cabbage, fennel, turnip, carrot, processed meat, sausage, bacon) should be avoided for at least two hours before FeNO measurement. ICS, if present, should be avoided for at least four hours before FeNO measurement. Participants should be seated during the FeNO test, but may stand if seating is not possible. Participants should maintain the same posture (seated or standing) throughout the test. Participants will inhale to their total lung volume via a handheld device (NIOX VERO®) and then exhale at 50 mL / second for 10 seconds (assisted by visual and auditory cues).

[0337] Eosinophil count The eosinophil count in whole blood was determined using flow cytometry at the time points specified in the study schedule (Figure 1) (i.e., baseline, and D2 (24 hours), D4 (72 hours), D8 (1 week), D15 (2 weeks), D29 (4 weeks), D57 (8 weeks), and D71 (10 weeks)).

[0338] Lung capacity measurement (FEV1 and FEF25-75) FEV1 and FEF25-75 were determined by measuring vital capacity at the points specified in the test schedule (Figure 1).

[0339] Vital capacity measurements were performed according to the American Thoracic Society (ATS) / European Respiratory Society (ERS) guidelines (2019 revision). Measurement parameters such as FEV1, peak expiratory flow rate (PEF), FVC, and forced expiratory flow rate (FEF) 25%–75% were measured after the bronchodilator washout period, according to the duration of action detailed in the ATS guidelines. For example, the bronchodilator retention time is at least 6 hours for SABA, at least 24 hours for LABA, and 36–48 hours for LAMA. Chromone must be withheld for at least 24 hours before vital capacity measurement. ICS, leukotriene receptor antagonists, and leukotriene synthesis inhibitors do not need to be withheld before vital capacity measurement, however, ICS must be withheld before FeNO evaluation.

[0340] At every visit, vital capacity (SVC) measurements were preferably performed in the morning, with afternoon measurements permitted only in exceptional circumstances where morning measurements could not be performed. SVC measurements were performed approximately simultaneously at each visit throughout the study (±2 hours). The same spirometer and standard SVC measurement techniques, including calibration, were used for all SVC measurements, and whenever possible, the same person performed the measurements. Three measurements meeting the ATS acceptance and reproducibility criteria should be obtained at each visit.

[0341] Recovery was determined by measuring vital capacity after bronchodilator administration. Recovery was defined as the increase in absolute FEV1 and / or FVC after bronchodilator administration, and was measured by vital capacity measurement as the increase in post-bronchodilator FEV1 or FVC as a percentage of pre-bronchodilator FEV1 or FVC, respectively. After measuring vital capacity to determine pre-bronchodilator FEV1, participants were administered four single puffs of albuterol / salbutamol or levalbuterol / levosalbutamol from a primed metered dose inhaler (MDI). Post-bronchodilator vital capacity measurement should be performed after a waiting period of at least 10 minutes and can be repeated several times within approximately 30 minutes after bronchodilator administration.

[0342] Impulse oscillometry measurement (R5-20 and AX) R5-20 and AX were determined by oscillometry at the points specified in the test schedule (Figure 1).

[0343] Oscillometry is a complementary technique to vital capacity measurement, which determines the mechanical properties of the lungs. While vital capacity measurement is the most commonly used technique for examining airway function, it cannot sensitively assess the small airways, and abnormalities are only detected when approximately 75% of the small airways are obstructed. Oscillometry is more sensitive in detecting small airway disorders, which correlate with poor disease control and type 2 inflammation. Therefore, oscillometry makes it possible to assess the relative contribution of the airways and small airways in asthma. Oscillometry was performed during a single breath using a Tremoflo® device (Thorasys, Montreal, Canada) in accordance with ERS recommended guidelines (Oostveen et al., Eur Respir J. 2003;22(6):1026-41). Oscillometry was performed immediately before vital capacity measurement, according to the test protocol.

[0344] Multi-frequency signals ranging from 5 to 37 Hz were superimposed on the participants' spontaneous respiration to measure oscillatory pressure and flow rate. Measurements were repeated for 20 seconds with approximately 20-second breaks. Artificial results due to coughing or glottal closure were automatically rejected by software. A minimum of three records achieving a coefficient of variation of 15% or less were required for quality control (Peters et al., Appl Physiol Nutr Metab. 2016;41(5):538-47). Only these data were used for data analysis.

[0345] Low frequencies (e.g., 5 Hz) reach the small airways and reflect the entire airway, while high frequencies (e.g., 20 Hz) do not reach the small airways and thus reflect only the central airways. Respiratory resistance (Rrs) reflects the energy required to propagate a pressure wave through the airway and expand the lung parenchyma. Total airway resistance is mainly determined by the central airways (80%) and to a lesser extent by the smaller airways (20%). Therefore, in health, there is a low-frequency dependence of Rrs (Pride, Thorax. 1992;47(4):317-20), and R5-20 (the difference between Rrs at 5 Hz (R5) and Rrs at 20 Hz (R20)) is low. Central airway flow obstruction, which is a component of airflow limitation in asthma, increases Rrs at all frequencies (i.e., increases both R5 and R20), and R5-R20 is low (Landser et al., Chest. 1982;81(5):586-91). In small airway diseases, which are also frequently seen in asthma, Rrs increases frequency-dependently at low frequencies (i.e., R5 increases beyond R20). (Clement et al., Chest. 1983;83(2):215-20). Therefore, the frequency dependence of Rrs (referred to as R5-R20; the difference between Rrs at 5 Hz and Rrs at 20 Hz) reflects airway non-uniformity and increases associated with small airway obstruction (Otis et al., J Appl Physiol. 1956;8(4):427-43).

[0346] Respiratory reactance (Xrs) is driven by the capacitance (contractility) characteristics of the respiratory system at low frequencies and reflects soft tissue and lung parenchyma. However, at higher frequencies, Xrs is driven by the inertia of the moving air column within the conducting airways. The resonant frequency (f res ) is the point at which the magnitudes of the capacitive reactance and the inertial reactance are equal; f res increases in both obstructive and restrictive lung diseases (Pride, Thorax. 1992;47(4):317-20, Clement et al., Chest. 1983;83(2):215-20). AX is from 5 Hz to f resIt is the integral exponent of total respiratory reactance at all frequencies (area under the reactance curve), has units of elastance, and is a measure of small airway disease and occlusion, as seen in asthma.

[0347] R5, R5-R20, and AX are the most sensitive oscillometric metrics for small airway function (Goldman et al., Respir Physiol Neurobiol. 2005;148(1-2):179-94, Oostveen et al., Eur Respir J. 2003;22(6):1026-41, Oostveen et al., Eur Respir J. 2013;42(6):1513-23). ​​Therefore, AX, R5, and R5-R20 were the focus of analysis for detecting treatment effects.

[0348] Transcriptome analysis To facilitate understanding the effects of SAR443765 at the cellular level, single-cell RNA sequencing (scRNA-seq) was utilized. This technique allows for the examination of gene expression patterns at the individual cell level, enabling more detailed and comprehensive analysis. By comparing gene expression patterns before and after SAR443765 treatment, and between the SAR443765 treatment and placebo groups, specific cellular changes associated with SAR443765 treatment can be identified.

[0349] In this study, scRNAseq was performed on nasal brushing (NB) samples and peripheral blood leukocyte (PBL) samples collected from the SAR443765 group and the placebo group on D1 (before administration of SAR443765 or placebo) and D29.

[0350] scRNAseq was performed as described in the literature (see, for example, Haque et al., Genome Med. 2017 Aug 18;9(1):75, and Slovin et al., Methods Mol Biol. 2021;2284:343-365). The analysis was performed separately for nasal brushing and PBL data. Cell population and gene expression results from various samples were compared as follow-up analyses to assess consistency between samples.

[0351] Using SignacX v2.2.4, we annotated cell types B.memory, B.naive, macrophage, Mon.classical, Mon.nonclassical, neutrophil, eosinophil, NK, plasma, CD4.T.memory, CD4.T.naive, CD8.T.CM, CD8.T.EM, CD8.T.naive, Treg, fibroblast, endothelial cell, and epithelial cell types (Chamberlain et al.). While SignacX provides detailed algorithmic annotation for multiple immunotypes, it only provides a general classification for non-immune cell types. Therefore, Louvain clustering performed during SPRING pretreatment, followed by marker gene expression analysis, was applied to the annotation of NB non-immune epithelial cell subtypes, dendritic cell subtypes (Villani et al.), and mast cells and eosinophils. Manual annotation of nasal epithelium was performed based on cluster-level expression of previously published marker sets and ranked expression of marker gene sets (Deprez et al., Am J Respir Crit Care Med. 2020 Dec 15;202(12):1636-1645, Legebeke et al., Front Cell Dev Biol. 2022 Jun 15;10:907511, Vieira Braga et al., Nat Med. 2019 Jul;25(7):1153-1163). SPRING pipeline annotated objects were converted to data structures in common scRNAseq format (Seurat and SingleCellExperiment objects) and used as input to other single-cell data analysis packages for further analysis.

[0352] To summarize the results of preprocessing and annotation, clustering and cell type annotation, including the identification of novel cell types and subtypes, were performed using dimensionality reduction of normalized count data. The summary output shows the distribution of cell type abundances in terms of ratios and percentages, and reports the top marker genes for each cell type to confirm the assignment. These outputs are shown graphically.

[0353] We analyzed samples collected at baseline to assess the presence of cell subsets and / or gene signatures that potentially predict FeNO reduction. FeNO levels at week 4 (D29) and / or changes in FeNO from baseline were used for correlation analysis. In particular, cell types that were prominently identified by scRNASeq analysis were subjected to Spearman correlation analysis with FeNO levels at week 4 (D29) and / or changes in FeNO between D29 and D1 (baseline). Various correlation analyses were performed, including changes in cell type ratios from baseline versus changes in FeNO, and gene expression at baseline versus changes in FeNO. For these analyses, correlation values, along with p-values, are reported.

[0354] To gain further insights into the biological significance of the data generated above and its relevance to asthma, the gene sets identified by differential expression analysis (D29 vs. D1) were tested using an integrated knowledge database and pathway analysis performed with provided software such as Ingenuity Pathway Analysis (Qiagen) and Gene Set Enrichment Analysis (GSEA) (e.g., scGSEA). These tools made it possible to identify pathway activation or inhibition through pathway module score analysis. A specific list of genes was investigated in relation to allergies and asthma and / or the biology of the TSLP / IL13 pathway, including but not limited to genes in the TSLP and IL-13 pathways (e.g., IL-4, IL-13, IFNa, IFNg) (Giovannini-Chami et al., Eur Respir J. 2012; 39(5): 1197-205, Kramer et al., Bioinformatics. 2014; 30(4): 523-30, Adhikary et al., Pharmacol Ther. 2021; 217: 107648).

[0355] 6.1.2 Results The following data were collected at the points shown in Figure 1: FeNO levels (Figures 2 and 3), eosinophil count in blood (Figures 4 and 5), FEV1 (Figures 6, 7, and 8), FEF25-75 (Figure 9), R5-20 (Figure 10), AX (Figure 11), other biomarkers in serum / plasma (Figure 12), and transcriptome analysis (Figures 13, 14, 15, and 16).

[0356] FeNO level Figure 2 shows the change from baseline in FeNO levels of participants treated with SAR443765 (dashed line) or placebo (solid line). The dose of SAR443765 was 400 mg, and FeNO levels were measured at 1 week (D8), 2 weeks (D15), 4 weeks (D29), and 8 weeks (D57) after administration of SAR443765 or placebo. Table 1 shows the results of these FeNO level measurements. Baseline values ​​are defined as the most recent available value immediately prior to the first dose of the investigational drug. The SAR443765 treatment was determined to reduce FeNO levels by 31.1 ppb (-31.9 ppb - -0.8 ppb) after 1 week (D8) compared to placebo, by 54.0 ppb (-35.2 ppb - 18.8 ppb) after 2 weeks (D15), by 39.9 ppb (-39.1 ppb - 0.8 ppb) after 4 weeks (D29), and by 35.9 ppb (-32.0 ppb - 3.9 ppb) after 8 weeks (D57).

[0357] In the SAR443765 group, 37% of participants had normal FeNO levels (less than 25 ppb) at the end of the trial, compared to only 8% in the placebo group.

[0358] [Table 1]

[0359] Table 2 shows baseline FeNO levels and reductions after 4 weeks (D29) in this study, as well as results from several published studies using other biologics, including tezeperumab (anti-TSLP), leburikizumab (anti-IL-13), tralokinumab (anti-IL-13), benralizumab (anti-IL-5Ra), dupilumab (anti-IL4Ra), and itepecimab (anti-IL-33). SAR443765 showed a more potent reduction in FeNO levels compared to all other compounds, with a reduction more than twice as high as the maximum reduction achieved in studies using another compound (18 ppb in the leburikizumab study). This study demonstrates that administration of compounds that block both IL-13 and TSLP can significantly increase FeNO reduction by approximately 2 to 4 times compared to a single-specific approach.

[0360] [Table 2]

[0361] [Table 3]

[0362] Subgroup analysis Figure 3 shows the same measurements as in Figure 2, separated according to the participants' baseline eosinophil count. The following groups are shown: high baseline eosinophil count (0.3 × 10⁻⁶) 9 (Cells per liter or more) SAR443765 (lower dashed line), low baseline eosinophil count (0.3 × 10⁻¹⁰) 9 (less than individual cells / L) SAR443765 (lower solid line), high baseline eosinophil count (0.3 × 10⁻⁶) 9 Placebo (upper dashed line) with a low baseline eosinophil count (0.3 × 10⁻¹⁰ cells / L or higher), compared to a low baseline eosinophil count (0.3 × 10⁻¹⁰ cells / L or higher). 9 Placebo (upper solid line) with less than one cell / L. The results for these four groups at D29 (4 weeks) are also shown in Table 3.

[0363] [Table 4]

[0364] This treatment resulted in a significant reduction in FeNO levels in both groups. In participants with high eosinophil counts, the reduction compared to placebo was 53.0 ppb (64.34% of baseline), while in participants with low eosinophil counts, the reduction compared to placebo was 33.5 ppb (47.58% of baseline). This indicates that this treatment resulted in a similar relative FeNO reduction in both participant groups to that observed with any other biologic (see Table 2).

[0365] Eosinophil count Figure 4 shows the change in eosinophil count at D29 (4 weeks) in participants treated with SAR443765 (right column) or placebo (left column). The median change in eosinophil count was -42.42% in the SAR443765 group, compared to -0.38% in the placebo group. This demonstrates that SAR443765 results in a potent reduction in eosinophil count compared to placebo. Figure 5 shows the change in eosinophil count at D29 for SAR443765 and other biologics (lebrikizumab, tezeperumab, and dupilumab). SAR443765 shows a reduction within the same range as tezeperumab. Note that dupilumab, which blocks IL-13 signaling like SAR443765, shows an increase in eosinophil count here. Such eosinophilia was not observed in SAR443765.

[0366] Table 4 shows the eosinophil count results after SAR443765 treatment on days D2, D4, D8, D15, D29, D57, and D71.

[0367] [Table 5]

[0368] FEV1 FEV1 (Forced Expiratory Volume in One Second) is the maximum amount of air that can be exhaled in the first second of exhalation, starting from maximum inspiration. In the study, FEV1 was determined by the vital capacity measurement described above. Figure 6 shows the change in FEV1 (compared to baseline) for participants treated with SAR443765 (dashed line) or placebo (solid line). The dose of SAR443765 was 400 mg. Figure 6 shows all available FEV1 measurements. Figure 7 shows the same measurements, but values ​​that did not meet all quality criteria (meaning the difference between two of the three maximum FEV1 values ​​exceeded 0.150 L) have been excluded. From the results in Figure 6, this treatment increased FEV1 by approximately 0.25 L after 1 week (D8), approximately 0.2 L after 2 weeks (D15), and approximately 0.07 L after 4 weeks (D29) and 8 weeks (D57) compared to placebo. The results in Figure 7 are similar for D8 and D29, but show a smaller difference for D15 and no significant difference for D57. These results suggest that SAR443765 improves FEV1. However, further trials with a larger patient cohort at baseline and with more impaired FEV1 are needed to support these findings.

[0369] To gain deeper insights into various patient subgroups, we analyzed FEV1 improvement for subgroups with normal lung function and subgroups with lung dysfunction at baseline. The criterion for classifying participants into one of these groups was "percent predicted FEV1" at baseline (i.e., before the initiation of treatment with SAR443765 or placebo). Percent predicted FEV1 (abbreviated as "ppFEV1") is the ratio (in %) of a participant's actual FEV1 to their reference FEV1, reflecting the mean of a person based on the participant's demographics such as age, sex, and body composition. Participants with a baseline ppFEV1 of 80% or higher were classified into the normal baseline lung function subgroup, and participants with a baseline ppFEV1 of less than 80% were classified into the baseline lung dysfunction subgroup. Therefore, data from both the SAR443765 group and the placebo group were split into two subgroups according to the criterion. The FEV1 results for these four subgroups are shown in Figure 8. These results suggest that the overall improvement in FEV1 observed in Figure 7 (particularly on D8, D15, and D29 after SAR443765 treatment) is primarily due to improvement in the subpopulation with baseline pulmonary impairment (ppFEV1 <80%), while the subpopulation with normal baseline pulmonary function (ppFEV1 ≥80%) showed little improvement, likely due to a ceiling effect.

[0370] FEF25-75 FEF25-75 (Forced Expiratory Flow Rate 25-75%) refers to the percentage of FVC (Forced Vital Capacity), which is the maximum amount of air a patient can exhale after maximum inhalation. FEF25-75 is calculated by dividing the percentage of FVC exhaled between 25% and 75% of FVC by the time it is exhaled. Impairment of FEF25-75 may indicate small airway obstruction. In the study, FEF25-75 was determined by the vital capacity measurement described above.

[0371] Figure 9 shows the FEF25-75 for the entire patient population (upper panel) and the FEF25-75 for subpopulations of normal baseline lung function (ppFEV1 ≥80%) and baseline lung impairment (ppFEV1 <80%) as described above regarding the FEV1 results in Figure 8 (lower panel). SAR443765 improved FEF25-75 in the entire patient population, particularly on D8 and D15 (left panel). The subpopulation results (right panel) show that the overall improvement in FEF25-75 seen in the left panel is mainly attributable to the SAR443765 subpopulation with baseline lung impairment (ppFEV1 <80%), which shows an improvement of approximately 0.4–0.5 L / s, while the normal baseline lung function subpopulation (ppFEV1 ≥80%) showed little improvement compared to baseline. The results provide evidence that the SAR443765 treatment reduces small airway obstruction in asthma patients.

[0372] R5-20 As mentioned above, R5-20 is the difference between the respiratory resistance at 5 Hz and the respiratory resistance at 20 Hz. The resistance at 5 Hz represents the resistance of the entire respiratory system (small airway and atmospheric airway), while the resistance at 20 Hz represents the resistance within the atmospheric airway. Therefore, an increase in R5-20 indicates an increase in resistance (and consequently obstruction) of the small airway. R5-20 was determined by the impulse oscillometry described above.

[0373] Figure 10 shows R5-20 for the entire patient population (upper panel) and R5-20 for subsets of normal baseline lung function (ppFEV1 of 80% or more) and baseline lung function impairment (ppFEV1 less than 80%) as described above with respect to the FEV1 results in Figure 8 (lower panel). R5-20 was reduced in the entire patient population, with the reduction exceeding the value of 0.31 cmH2O*s / L (0.03 kPa*s / L), which is considered a clinically significant threshold (Foy B, et al. Am J Respir Crit Care. 2019;200(8):982-991). The effect was most prominent at D8 and D15. In the subset of normal baseline lung function (ppFEV1 of 80% or more), there was substantially no effect of SAR443765, but in the subset of baseline lung function impairment (ppFEV1 less than 80%), there was a significant reduction in R5-20. This indicates that SAR443765 treatment reduces small airway obstruction, particularly in asthmatic patients with lung function impairment.

[0374] As described above, the reactance area (AX) is calculated from the lung reactance measurement (see also Desiraju and Agrawal, 2016). This includes the total area occupied by capacitance and reflects the capacitance (contractility) characteristics of the lung. Reactance and f res As seen, AX also increases in any disease of the lung periphery. AX was determined by impulse oscillometry as described above.

[0375] Figure 11 shows the AX for the entire patient population (upper panel) and the AX for the subpopulations of normal baseline lung function (ppFEV1 ≥80%) and baseline lung impairment (ppFEV1 <80%) as described above, with respect to the FEV1 results in Figure 8 (lower panel). SAR443765 reduced AX in the entire patient population, and the reduction exceeded the clinically significant threshold of 6.65 cmH2O / L (0.65 kPa / L) (Abdo et al. Eur Respir J. 2023;61(5):2201793). The effect was most pronounced on days 8 and 15. There was virtually no effect in the subpopulation of normal baseline lung function (ppFEV1 ≥80%), but there was a significant reduction with SAR443765 administration in the subpopulation of baseline lung impairment (ppFEV1 <80%). This indicates that the SAR443765 treatment reduces small airway obstruction, particularly in asthma patients with impaired pulmonary function.

[0376] Further biomarkers In addition to the parameters described above, the following biomarkers were determined in the clinical trial using SAR443765: serum IL-5 levels; plasma CCL26 (eotaxin-3) levels; serum TARC (CCL17) levels; and serum IgE levels. The determination of these biomarker levels was performed according to methods commonly known in the art. The results at D29 are shown in Figure 12. Treatment with SAR443765 resulted in a reduction from baseline for all observed biomarkers.

[0377] Transcriptome analysis Transcriptome analysis was performed by single-cell RNA sequencing (scRNAseq). Using scRNAseq, gene expression at the single-cell level was determined in nasal brushing samples (NB) and peripheral blood leukocyte (PBL) samples. Samples were collected on D1 (baseline, before administration of SAR443765 or placebo) and D29. Analysis of gene expression allowed for the identification of cell types and their proportions (Figures 13, 14), the correlation between changes in proportions and changes in FeNO levels (Figure 15), and the analysis of single gene expression per cell type (Figure 16).

[0378] Figure 13 shows the various cell types found in nasal brushing samples. The change in the proportion of each cell type on the x-axis (D29 compared to D1; shown as log2 of the magnification change (FC)) is plotted against the p-value for the change on the y-axis (shown as -log10 of the p-value). In the analysis, p-values ​​of 0.05 or less (corresponding to a value of at least approximately 1.3 on the y-axis) were considered significant. Reduced ("downregulated") cell types are shown as triangles, unchanged cell types as dots, and increased ("upregulated") cell types as squares. It was found that the proportion of non-classical monocytes was significantly reduced in the SAR443765 group, but there was no significant change in the placebo group. Since nasal brushing samples can be considered to represent the entire airway, this is the first indicator that the proportion of non-classical monocytes can also be reduced in the pulmonary airways. The reduction of airway inflammation by SAR443765 may include a reduction in the proportion of non-classical monocytes in the airways.

[0379] In either the SAR443765 group or the placebo group, there were no significant changes regarding other identified immune cell types.

[0380] Figure 14 shows the various cell types found in peripheral blood leukocyte (PBL) samples. The change in the percentage of each cell type on the x-axis (D29 compared to D1; shown as log2 of the fulcrum change (FC)) is plotted against the p-value for the change on the y-axis (shown as -log10 of the p-value). In the analysis, p-values ​​of 0.05 or less (corresponding to a value of at least 1.3 on the y-axis) were considered significant. In the SAR443765 group, the percentage of NK cells and CD8 T effector memory (em) cells was found to be significantly reduced. The percentage of neutrophils increased significantly, but additional measurements showed that the total number of neutrophils did not increase. This is evidence of immune system rebalancing due to a reduction in type 2 inflammation, and consequently, a reduction in the number of cells associated with type 2 inflammation. There were no significant changes in the placebo group. This suggests that the anti-inflammatory effect of SAR443765 may include a reduction in the percentage of NK cells and CD8 T em cells.

[0381] In either the SAR443765 group or the placebo group, there were no significant changes regarding other identified immune cell types.

[0382] Figure 15 shows the correlation between changes in FeNO levels (D29 compared to D1) and changes in the percentage of NK cells (D29 compared to D1) in PBL samples. The y-axis shows the change in the percentage of NK cells (log10 factor change (FC)), and the x-axis shows the change in FeNO levels (unit: bbb). Each point represents the value for one participant. The left panel shows the SAR443765 group and the placebo group, while the right panel shows the SAR443765 group only. It is clear that the correlation between changes in FeNO levels and changes in the percentage of NK cells is much better in the SAR443765 group alone compared to the SAR443765 group combined with the placebo group. This suggests that there may be a relationship between SAR443765-induced FeNO reduction and a reduction in the percentage of NK cells in the blood, which may be part of the therapeutic effect of SAR443765.

[0383] Figure 16 shows the changes in CCL26 gene expression across various cell types in nasal brushing samples (D29 compared to D1). For each cell type, two bars are present; the left bar corresponds to D1, and the right bar corresponds to D29. CCL26 expression was not significantly reduced in the placebo group (upper panel), but was significantly reduced in basal epithelial cells, polyciliated epithelial cells, and secretory epithelial cells after SAR443765 treatment (lower panel). The results for polyciliated epithelial cells are shown again in an enlarged view in the upper right corner of the figure. These results support the findings regarding CCL26 / eotaxin-3 at the protein level (see Figure 12).

[0384] As shown above (see Figure 14), SAR443765 treatment reduced the proportion of CD8 T effector memory (em) cells in PBL samples. In addition, SAR443765 resulted in significant (adj p-value < 0.05) downregulation of the HBB gene encoding β-globin in CD8 T em cells (Figure 17). High HBB expression has been explained as being associated with low FEV1 in asthma. Therefore, the reduction in HBB expression may be an indicator of treatment success.

[0385] Path analysis As described above, in the PBL sample, the proportion of neutrophils significantly increased in the SAR443765 group, but additional measurements showed no increase in the total number of neutrophils (Figure 14). To investigate the activation state of neutrophils, gene expression data from scRNAseq were subjected to pathway analysis. Lists of genes for specific pathways are known from the literature (Giovannini-Chami et al., Kramer et al., Adhikary et al.), and these can be grouped into so-called "pathway modules." Pathway modules for IL-4, IL-13, interferon-alpha (IFNα), and interferon-gamma (IFNg) were determined. Each pathway module was assigned a score corresponding to the expression of the module's genes at each time point (D1 and D29). The difference in pathway module scores from D29 and D1 (Δ score) indicates upregulation or downregulation of each pathway. Table 5 shows the differences in these scores for SAR443765 and placebo.

[0386] [Table 6]

[0387] Regarding SAR443765, the Il-4, IFNa, and IFNg pathway modules show a negative score difference, indicating a reduction in Il-4, IFNa, and IFNg pathway activity in peripheral blood neutrophils. Since this reduction is not observed with placebo, SAR443765 may be a contributing factor to the effect.

[0388] References Abdiche et al.Anal Biochem.2008 Jun 15;377(2):209-17 Abdo et al.,2023 Eur Respir J.2023 May 5;61(5):2201793 Adhikary et al.,Pharmacol Ther.2021;217:107648 American Thoracic Society(ATS) / European Respiratory Society(ERS)Guidelines,2019 update:Graham et al.,Am J Respir Crit Care Med.2019 Oct 15;200(8):e70-e88 Cameli et al.,Int J Mol Sci.2020 Sep;21(17):6187 Castro et al.,Lancet Respir Med.2014 Nov;2(11):879-890 Chamberlain et al.,fortune Journals 2023 ;6(3),152-177 Clement et al.,Chest.1983;83(2):215-20 Conrath et al.,J Biol Chem.2001 Mar 9;276(10):7346-50 Corren et al.,N Engl J Med.2011 Sep 22;365(12):1088-98 Corren et al.,N Engl J Med.2017 Sep 7;377(10):936-946 Davies and Riechmann,Protein Eng.1996 Jun;9(6):531-7 Deprez et al.Am J Respir Crit Care Med.2020 Dec 15;202(12):1636-1645 Desiraju and Agrawal,Lung India.2016 Jul-Aug;33(4):410-416. Drake et al.,Anal Biochem.2004 May 1;328(1):35-43 Eguiluz-Gracia et al.,Clin Exp Allergy.2018 Dec;48(12):1631-1639 Foy B, et al.Am J Respir Crit Care.2019;200(8):982-991 Fraley et al., Bioanalysis. 2013 Jul;5(14):1765-74 Gauvreau et al., N Engl J Med. 2014 May 29;370(22):2102-10 Gieseck III et al., Nat Rev Immunol. 2018 Jan;18(1):62-76 Giovannini-Chami et al., Eur Respir J. 2012;39(5):1197-205 Global Initiative for Asthma 2020 Guidelines: Global strategy for asthma management and prevention, 2020 [cited 2021 May 07]. Available from: URL: www.ginasthma.org. Goldman et al., Respir Physiol Neurobiol. 2005;148(1-2):179-94 Hamers-Casterman et al., Nature. 1993 Jun 3;363(6428):446-8 Haque et al., Genome Med. 2017 Aug 18;9(1):75 Johnson et al. Anal Biochem. 1991 Nov 1;198(2):268-77 Johnsson et al., J Mol Recognit. 1995 Jan-Apr;8(1-2):125-31 Joensson et al., Ann Biol Clin (Paris). 1993;51(1):19-26 Joensson et al., Biotechniques.1991 Nov;11(5):620-7. Korenblat et al.,Respir Med.2018 Jan;134:143-149 Kramer et al.,Bioinformatics.2014;30(4):523-30 Landser et al.,Chest.1982;81(5):586-91 Legebeke et al.,Front Cell Dev Biol.2022 Jun 15;10:907511 Li et al.,J Allergy Clin Immunol.2021 Mar;147(3):941-954 McNulty and Usmani,Eur Clin Respir J,2014;1:10.3402 / ecrj.v1.25898 Menzies-Gow et al.,N Engl J Med.2021 May 13;384(19):1800-1809 Miskoff et al.,Cureus.2019 Jun;11(6):e4864 Muyldermans,J Biotechnol.2001 Jun;74(4):277-302 Ober et al.,Int Immunol.2001 Dec;13(12):1551-9 Oostveen E,et al.Eur Respir J.2013;42(6):1513-23 Oostveen et al.,Eur Respir J.2003;22(6):1026-41 Ordovas-Montanes et al.,Nature.2018;560(7720):649-54. Otis et al.,J Appl Physiol.1956;8(4):427-43 Panettieri et al.,Immunotherapy.2018 Mar 1;10(6):473-490 Panettieri et al.,Lance Respir Med.2018 Jul;6(7):511-525 Peters et al.,Appl Physiol Nutr Metab.2016;41(5):538-47 Pride,Throat.1992;47(4):317-20 Russell et al.,Lancet Respir Med.2018 Jul;6(7):499-510 Slovin et al.,Methods Mol Biol.2021;2284:343-365 Stockley et al.,Int J Chron Obstruct Lung Dis.2017;12:2343–2353 Tomita et al.,J Allergy Clin Immunol.1995 Aug;96(2):230-8 Venkataramani et al.,Biochem Biophys Res Commun.2018 Sep 26;504(1):19-24 Vieira Braga et al.,Nat Med.2019 Jul;25(7):1153-1163 Villani et al.,Science.2017 Apr 21;356(6335) Wechsler et al.,Lancet Respir Med.2022 Jul;10(7):650-660 Wechsler et al.,N Engl J Med.2021 Oct 28;385(18):1656-1668 Wenzel et al.,Lancet.2016 Jul 2;388(10039):31-44 WO 94 / 04678-IMMUNOGLOBULINS DEVOID OF LIGHT CHAINS WO 96 / 34103-VARIABLE FRAGMENTS OF IMMUNOGLOBULINS-USE FOR THERAPEUTIC OR VETERINARY PURPOSES WO 99 / 23221-MULTIVALENT ANTIGEN-BINDING PROTEINS WO 2021116182-POLYPEPTIDES COMPRISING IMMUNOGLOBULIN SINGLE VARIABLE DOMAINS TARGETING IL-13 AND TSLP Ziegler & Artis,Nat Rev Immunol(2010)11:289-93

Claims

1. Compounds for use in the treatment of target lung diseases, comprising compounds that bind to IL-13 and TSLP, wherein the treatment reduces the level of exhaled nitric oxide (FeNO) by at least 18 ppb compared to a control.

2. The compound for use according to claim 1, wherein the treatment reduces the level of FeNO by at least 20 ppb, at least 30 ppb, or at least 40 ppb compared to the control.

3. The compound for use according to claim 1 or 2, wherein the lung disease is asthma.

4. The compound for use according to claim 3, wherein the asthma is hypereosinophilic asthma.

5. The compound for use according to claim 3, wherein the asthma is hypoeosinophilic asthma.

6. The compound for use according to any one of claims 1 to 5, wherein the control is a baseline, or the control is a placebo, and optionally, the baseline means the individual baselines of the subject.

7. The compound for use according to any one of claims 1 to 6, wherein the reduction in FeNO levels occurs within four weeks after administration of the compound, optionally, the reduction in FeNO levels occurs within two weeks after administration of the compound, optionally, the reduction in FeNO levels occurs within one week after administration of the compound.

8. The compound for use according to any one of claims 1 to 7, wherein the compound that binds to IL-13 and TSLP is a polypeptide such as an antibody or antibody fragment.

9. The polypeptide comprises or consists of at least four ISVDs, two of which bind specifically to IL-13, two of which bind specifically to TSLP, each of the at least four ISVDs comprises three complementarity-determining regions (CDR1 to CDR3, respectively), and the at least four ISVDs are optionally linked by one or more peptide linkers. The first ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 7; CDR2, which is the amino acid sequence of SEQ ID NO: 12; and CDR3, which is the amino acid sequence of SEQ ID NO:

17. The second ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 8; CDR2, which is the amino acid sequence of SEQ ID NO: 13; and CDR3, which is the amino acid sequence of SEQ ID NO:

18. The third ISVD is, It includes CDR1, which is the amino acid sequence of SEQ ID NO: 9; CDR2, which is the amino acid sequence of SEQ ID NO: 14; and CDR3, which is the amino acid sequence of SEQ ID NO:

19. The fourth ISVD is, This includes CDR1, which is the amino acid sequence of SEQ ID NO: 11; CDR2, which is the amino acid sequence of SEQ ID NO: 16; and CDR3, which is the amino acid sequence of SEQ ID NO:

21. The compound for use according to claim 8.

10. The compound for use according to claim 8 or 9, wherein the polypeptide comprises or consists of the amino acid sequence of SEQ ID NO:

1.

11. The subjects described above have a baseline FeNO level of at least 50 ppb and an eosinophil count of 0.3 × 10⁻⁶. ９ A compound for use according to any one of claims 1 to 10, wherein the concentration is 1 cell / L or more.

12. Compounds for use in the treatment of target lung diseases, which bind to IL-13 and TSLP, wherein the treatment reduces the number of eosinophils in the blood by at least 30% compared to a control.

13. The compound for use according to claim 12, wherein the reduction in eosinophil count occurs within four weeks after administration of the compound, and optionally, the reduction in eosinophil count occurs within two weeks after administration of the compound, and optionally, the reduction in eosinophil count occurs within one week after administration of the compound.

14. A compound that binds to IL-13 and TSLP for use in the treatment of a target lung disease, wherein the treatment reduces airway inflammation.

15. The compound according to claim 14, wherein the reduction of airway inflammation is characterized by a reduction of at least 18 ppb in FeNO, a reduction of at least 30% in eosinophil count, and / or an increase of at least 0.07 L in forced expiratory volume in one second (FEV1) compared to a control.

16. The compound for use according to claim 15, wherein the reduction of airway inflammation occurs within four weeks after administration of the compound, and optionally, the reduction of airway inflammation occurs within two weeks after administration of the compound, and optionally, the reduction of airway inflammation occurs within one week after administration of the compound.

17. Compounds for use in reducing target FeNO levels, wherein the reduction in FeNO levels prevents loss of lung function.

18. The compound for use according to claim 17, wherein the reduction in the FeNO level is a reduction of at least 18 ppb.

19. The compound for use according to claim 17 or 18, wherein the reduction of the FeNO level is a reduction to a level of less than 25 ppb.

20. The subject is a compound for use according to any one of claims 17 to 19, wherein the baseline FeNO level is at least 50 ppb, at least 35 ppb, or at least 25 ppb.

21. The subjects described above have a baseline FeNO level of at least 50 ppb and an eosinophil count of 0.3 × 10⁻⁶. ９ A compound for use according to any one of claims 17 to 20, wherein the concentration is 1 or more cells / L.

22. The compound for use according to any one of claims 17 to 21, wherein the compound binds to TSLP and IL-13.

23. The compound for use according to any one of claims 17 to 21, wherein the loss of lung function is related to asthma.

Images