Anti-il-5 antibody in the treatment of chronic rhinosinusitis with nasal polyps

Abstract

Disclosed herein are antigen binding proteins, e.g. an antibody, which bind to IL-5, for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP), wherein the nasal polyps score and / or mean nasal obstruction score is improved.

Description

[0001] 70542W001

[0002] ANTI-IL-5 ANTIBODY IN THE TREATMENT OF CHRONIC RHINOSINUSITIS WITH

[0003] NASAL POLYPS

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to antigen binding proteins, e.g. an antibody, which bind to IL-5, for use in the treatment of chronic rhinosinusitis with nasal polyps, wherein the nasal polyps score and / or nasal obstruction score is reduced.

[0006] BACKGROUND TO THE INVENTION

[0007] Prolonged stimulation from chronic inflammation of the nasal / paranasal mucosa in chronic rhinosinusitis with nasal polyps (CRSwNP) can lead to tissue damage and aberrant tissue repair causing significant recurring symptoms and the growth of nasal polyps (NP) (Bachert et al., 2021; Gevaert et al., 2022; Shah et al., 2023).

[0008] Current standard of care (SoC) for CRSwNP involves maintenance intranasal corticosteroids (INCS; except Japan) and intranasal nasal douching with saline. Shortterm systemic CS (SCS) with / without antibiotics are used to manage flare-ups while endoscopic sinus surgery is an option to remove persistent polyps (Fokkens et al., 2023; Hellings et al., 2024; Shah et al., 2016). Short-term oral CS temporarily improve symptoms though repeat use can cause adverse events (AEs) (Bachert et al., 202). Surgical removal of nasal polyps also improves symptoms but may be associated with complications. Nasal polyp recurrence can be frequent, particularly in patients with an eosinophilic phenotype, as nasal polyp surgery does not address the underlying chronic inflammation (Bachert et al., 2021)

[0009] Patients with CRSwNP experience persistent symptoms, predominantly driven by type 2 inflammation in up to 85% of cases (Bachert et al., 2021; Gevaert et al., 2022); though this percentage varies by country, with a mixture of endotypes predominating in Asia (Wang et al., 2016). Type 2 inflammation is driven by Th2 cells and ILC2 cells, which produce type 2 cytokines such as interleukin (I L)-5, IL-4 and IL-13 (Maspero et al., 2022). High concentrations of these cytokines are present in NP tissue (Bachert et al., 2024); for IL-5, this is associated with increased disease severity (Gevaert et al., 2022). IL-5 stimulates eosinophil production and, in concert with IL-4 and IL-13, promotes eosinophil trafficking (Bachert et al., 2024). Collectively, they drive eosinophilic inflammation and orchestrate effects on a wide range of other immune and structural cells (Bachert et al., 2024). 70542W001

[0010] Biologies that target type 2 cytokines may help mitigate the impact of CRSwNP from chronic type 2 inflammation by rebalancing immune responses, impacting NP formation, and restoring epithelial integrity (Gevaert et al., 2022; Bergantini et al., 2023; Buchheit et al., 2021). The biologies mepolizumab (anti-IL-5), dupilumab (anti-IL-4R) and omalizumab (anti-lgE) have been approved as add-on therapy for the treatment of adults with severe uncontrolled CRSwNP, having demonstrated clinical benefit among patients with CRSwNP in both randomised clinical trials and real-world settings (Bachert et al., 2019; Han et al., 2021; Book et al., 2023). Whilst approved biologies have been shown to reduce the need for steroids and surgery and improve patient outcomes, they are required to be administered every 2 to 4 weeks (Bachert et al., 2019; Han et al., 2021).

[0011] In light of the above, there is a need for more effective and convenient treatments for CRSwNP.

[0012] SUMMARY OF THE INVENTION

[0013] The invention provides an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s nasal polyps score is reduced.

[0014] The invention also provides an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s nasal obstruction score is reduced.

[0015] The invention also provides a method of treating CRSwNP comprising administering to a patient an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region 70542W001 having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10, wherein the patient’s nasal polyps score is reduced.

[0016] The invention also provides a method of treating CRSwNP comprising administering to a patient an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10, wherein the patient’s nasal obstruction score is reduced.

[0017] BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIGURE 1. ANCHOR-2 Forest plot of least square mean (95% Cl) treatment difference in change from baseline in total endoscopic nasal polyps score at week 52 by subgroup.

[0019] FIGURE 2. ANCHOR-2 Forest plot of least square mean (95% Cl) treatment difference in change from baseline in mean nasal obstruction VRS score at weeks 49-52 by subgroup.

[0020] FIGURE 3. ANCHOR-1 Forest plot of least square mean (95% Cl) treatment difference in change from baseline in total endoscopic nasal polyps score at week 52 by subgroup.

[0021] FIGURE 4. ANCHOR-1 Forest plot of least square mean (95% Cl) treatment difference in change from baseline in mean nasal obstruction VRS score at weeks 49-52 by subgroup.

[0022] FIGURE 5. Forest plot of treatment difference by subgroup in change from baseline in total endoscopic nasal polyps score (Integrated analysis; Full Analysis Set).

[0023] FIGURE 6. Forest plot of treatment difference by subgroup in change from baseline in mean nasal obstruction VRS score over Weeks 49-52 (Integrated analysis; Full Analysis Set).

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] DEFINITIONS 70542W001

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0027] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. The term "plurality" refers to two or more. The term “at least one” refers to one or more.

[0028] Additionally, numerical limitations given with respect to concentrations or levels of a substance, such as solution component concentrations or ratios thereof, are intended to be approximate. Unless specified otherwise, where a numerical range is provided, it is inclusive, i.e. , the endpoints are included.

[0029] "About" as used herein when referring to a measurable value such as an amount and the like, is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0030] The term "antigen binding protein" as used herein refers to antibodies, antibody fragments and other protein constructs which are capable of binding to an antigen.

[0031] The term “antibody” is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanised, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g. a domain antibody (DAB)), antigen binding antibody fragments, Fab, F(ab’)2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABS, etc. and modified versions of any of the foregoing (for a summary of alternative “antibody” formats see Holliger and Hudson, Nature Biotechnology, 2005, Vol 23, No. 9, 1126-1136). Alternative antibody formats are also contemplated and include alternative scaffolds in which the one or more CDRs of the antigen binding protein can be arranged onto a suitable non-immunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer or an EGF domain. The antibody may be derived from rat, mouse, primate {e.g., cynomolgus, Old World monkey or Great Ape), human or other sources such as nucleic acids generated using molecular biology techniques which encode an antibody molecule.

[0032] The antigen binding protein may comprise a constant region, which may be of any isotype or subclass. The constant region may be of the IgG isotype, for example, IgGi, lgG2, IgGs, lgG4 or variants thereof. The antigen binding protein constant region may be IgGi. 70542W001

[0033] The antigen binding protein may comprise one or more modifications selected from a mutated constant domain such that the antibody has enhanced effector functions / ADCC and / or complement activation.

[0034] The antigen binding proteins of the invention can be used in any of the pharmaceutical compositions, dosage regimens, or method of treatments of the invention. The antigen binding proteins can be antibodies, for example I gGi antibodies.

[0035] The term “interleukin-5” or “IL- 5” as used herein includes human IL-5 comprising the amino acid sequence shown in SEQ ID NO: 11.

[0036] The term “interleukin-5 receptor” or “IL-5R” as used herein includes human IL-5 Receptor Subunit Alpha Isoform 1 comprising the amino acid sequence shown in SEQ ID NO: 12.

[0037] The term “binds”, as used herein in relation to antigen binding proteins means that the antigen binding protein binds to a target antigen as well as a discrete domain, or discrete amino acid sequence, within a target antigen with no or insignificant binding to other (for example, unrelated) proteins. This term, however, does not exclude the fact that the antigen binding proteins may also be cross-reactive with closely related molecules (for example, those with a high degree of sequence identity or from another genera or species). The antigen binding proteins described herein may bind to human IL-5 with at least 2, 5, 10, 50, 100, or 1000-fold greater affinity than they bind to closely related molecules.

[0038] By “isolated”, it is intended that the molecule, such as an antigen binding protein, is removed from the environment in which it may be found in nature. For example, the molecule may be purified away from substances with which it would normally exist in nature.

[0039] The terms “VH” and “VL” are used herein to refer to the heavy chain variable region and light chain variable region, respectively, of an antigen binding protein.

[0040] “CDRs” are defined as the complementarity determining region amino acid sequences of an antigen binding protein. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, "CDRs" as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least one CDR and wherein the at least one CDR is CDRH3. Framework regions follow each of these CDR regions. Acceptable heavy chain variable region and light chain variable region framework 1 , framework 2 and framework 3 regions are readily recognized by those of ordinary skill in the art. Acceptable heavy chain constant regions (including hinge regions) and light chain constant regions are readily 70542W001 recognized by those of ordinary skill in the art as well. Acceptable antibody isotypes are similarly readily recognized by those of ordinary skill in the art.

[0041] Throughout this specification, amino acid residues in variable domain sequences and full length antibody sequences are numbered according to the Kabat numbering convention. Similarly, the terms “CDR”, “CDRL1”, “CDRL2”, “CDRL3”, “CDRH1”, “CDRH2”, “CDRH3” used in the specification follow the Kabat numbering convention.

[0042] It will be apparent to those skilled in the art that there are alternative numbering conventions for amino acid residues in variable domain sequences and full length antibody sequences. There are also alternative numbering conventions for CDR sequences, for example those set out according to the Chothia numbering convention. The structure and protein folding of the antibody may mean that other residues are considered part of the CDR sequence and would be understood to be so by a skilled person.

[0043] Other numbering conventions for CDR sequences available to a skilled person include “AbM” (University of Bath) and “contact” (University College London) methods. The minimum overlapping region using at least two of the Kabat, Chothia, AbM and contact methods can be determined to provide the “minimum binding unit”. The minimum binding unit may be a sub-portion of a CDR.

[0044] The term “chronic rhinosinusitis with nasal polyps” or “CRSwNP” as used herein refers to the presence of two or more symptoms, one of which should be either nasal blockage / obstruction / congestion or nasal discharge (anterior / posterior nasal drip):

[0045] ± facial pain / pressure;

[0046] ± reduction or loss of smell; for >12 weeks; with validation by telephone or interview, and bilateral, endoscopically visualized polyps in middle meatus (European Position Paper on Rhinosinusitis and Nasal Polyps 2020, Fokkens et al.)

[0047] The term “chronic rhinosinusitis with nasal polyps” or “CRSwNP” as used herein may also refer to greater than or equal to 12 weeks of:

[0048] Two or more of the following symptoms:

[0049] Nasal discharge (rhinorrhea or post-nasal drip)

[0050] Nasal obstruction or congestion

[0051] Hyposmia

[0052] Facial pressure or pain

[0053] AND

[0054] One or more of the following objective findings: 70542W001

[0055] Evidence of inflammation on nasal endoscopy or computed tomography Evidence of purulence coming from paranasal sinuses or ostiomeatal complex

[0056] AND

[0057] The presence of nasal polyps (International consensus statement on allergy and rhinology: rhinosinusitis 2021 , Orlandi et al.)

[0058] The term “pharmaceutical composition” as used herein means a composition suitable for administration to a patient.

[0059] The term “therapeutically effective amount” as used herein means an amount of an agent (such as an antigen binding protein or a pharmaceutical composition), which provides a therapeutic benefit in the treatment or management of one or more symptoms of CRSwNP.

[0060] Examples of such treatment or management of one or more symptoms of CRSwNP include:

[0061] 1. Improvement / reduction in the nasal polyps score, including total endoscopic nasal polyps score

[0062] 2. Improvement / reduction in the nasal obstruction score, including mean nasal obstruction score

[0063] 3. Improvement / reduction in the rhinorrhea score, including mean rhinorrhea score

[0064] 4. Improvement / reduction in the loss of smell score, including mean loss of smell score

[0065] 5. Improvement / reduction in the Lund Mackay CT score

[0066] 6. Improvement / reduction in the SNOT-22 total score

[0067] 7. Time to first nasal surgery (optionally, actual or entry on waiting list)

[0068] 8. Reduction in systemic corticosteroid use

[0069] 9. Improvement / reduction in Asthma Control Questionnaire (ACQ-5) score

[0070] Therapeutically effective amounts and treatment regimens are generally determined empirically and may be dependent on factors, such as the age, weight, and health status of the patient and disease or disorder to be treated. Such factors are within the purview of the attending physician.

[0071] As used herein, the term “treatment” refers to ameliorating or stabilising the specified condition, reducing or eliminating the symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying reoccurrence of the condition in a previously afflicted patient or subject. As is recognised in the art, drugs 70542W001 employed as therapeutic agents in methods of treatment may reduce the severity of a given disease state, but need not abolish every manifestation of the disease to be regarded as useful therapeutic agents. Simply reducing the impact of a disease (for example, by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or reducing the likelihood that the disease will occur (for example by delaying the onset of the disease) or worsen in a subject, is sufficient.

[0072] As used herein, the term "patient" refers to a human. The terms “individual”, “subject” and “patient” are used herein interchangeably. The patient may be an adult (>18 years).

[0073] As used herein, the phrase “once every 6 months” means that in a typical 6 month period consisting of about 183 days, a subject is administered a dose of the antigen binding protein of the invention on one day only and on the other days the subject is not administered a dose of the antigen binding protein of the invention. Administration of once every 6 months may also be referred to as “Q26W” (which refers to administration once every 26 weeks). References herein to “about once every 6 months” refer to an intended dosage regime of once every 6 months, but with the allowance of patient compliance, therefore allowing up to a four week variation depending upon patient scheduling.

[0074] As used herein, the term “total endoscopic nasal polyps score” refers to a grading based on nasal polyps size and recorded as the sum of the right and left nostril scores with a range of 0 to 8; with higher scores indicating worse status. Total endoscopic nasal polyps score may be performed by trained health care professionals (typically an ENT surgeon). Image recordings of endoscopies are used for blinded nasal polyps scoring.

[0075] As used herein, the term “nasal obstruction score” refers to a patient-reported evaluation of nasal obstruction symptoms severity using a 4-point verbal rating scale (VRS). Patients are asked to record their symptom severity over the past 24 hours in a daily diary. Response options using a 0-3 point scale include: ‘No symptoms’, ‘Mild symptoms’, ‘Moderate symptoms’ and ‘Severe symptoms’.

[0076] As used herein, the term “Lund-Mackay Computed Tomography” or Lund-Mackay CT” or “LMK-CT” refers to a scoring system based on localisation with points given for degree of opacification: 0 = normal, 1 = partial opacification, 2 = total opacification. These points are applied to the maxillary, anterior ethmoid, posterior ethmoid, sphenoid, frontal sinus on each side. The osteomeatal complex (OC) is graded as 0 = not occluded, or 2 = occluded and the maximum score is 12 per side. Image recordings of CT scans are used for Lund Mackay CT scoring. 70542W001

[0077] As used herein, the term “SNOT-22” refers to a 22-item measure of disease specific health-related quality of life (HRQoL). Participants are asked to rate the severity of their condition on each of the 22 items over the previous 2 weeks using a 6-point rating scale of 0 to 5 including: 0 = not present / no problem; 1 = very mild problem; 2 = mild or slight problem; 3 = moderate problem; 4 = severe problem; 5 = problem as “bad as it can be”. The total score range for the SNOT-22 is 0 to 110, where higher scores indicated greater disease impact.

[0078] As used herein, the term “loss of smell score” refers to a patient-reported evaluation of loss of smell symptoms severity using a 4-point verbal rating scale (VRS). Patients are asked to record their symptom severity over the past 24 hours in a daily diary. Response options using a 0-3 point scale include: ‘No symptoms’, ‘Mild symptoms’, ‘Moderate symptoms’ and ‘Severe symptoms’.

[0079] As used herein, the term “rhinorrhea score” or “runny nose score” refers to a patient-reported evaluation of rhinorrhea or runny nose symptoms severity using a 4-point verbal rating scale (VRS). Patients are asked to record their symptom severity over the past 24 hours in a daily diary. Response options using a 0-3 point scale include: ‘No symptoms’, ‘Mild symptoms’, ‘Moderate symptoms’ and ‘Severe symptoms’.

[0080] “Mean nasal obstruction score”, “mean rhinorrhea score”, and “mean loss of smell score” are mean scores derived as averages of daily responses across a diary period (4- weeks) for each individual VRS symptom item.

[0081] If desired, the effective dose of an antibody or antigen binding protein of the disclosure (e.g., as a pharmaceutical composition) may be administered as a unit dosage form.

[0082] STATEMENT OF THE INVENTION

[0083] The present invention includes an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s nasal polyps score is reduced.

[0084] The present invention includes a method of treating CRSwNP comprising administering to a patient an antigen binding protein which binds to human IL-5 70542W001 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10, wherein the patient’s nasal polyps score is reduced.

[0085] The present invention includes an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 for use in a method of reducing nasal polyps score in a patient with CRSwNP.

[0086] The present invention includes a method of reducing nasal polyps score in patient with CRSwNP comprising administering to a patient a therapeutic amount of an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0087] In one embodiment, the nasal polyps score is the total endoscopic nasal polyps score. In one embodiment, the patient’s total endoscopic nasal polyps score is reduced. In one embodiment, the patient’s nasal polyps score is significantly reduced. In one embodiment, the patient’s total endoscopic nasal polyps score is significantly reduced. In one embodiment, the patient’s nasal polyps score is significantly reduced compared to baseline or untreated control levels. In one embodiment, the patient’s total endoscopic nasal polyps score is significantly reduced compared to baseline or untreated control levels. In one embodiment, the reduction in nasal polyps score is measured by a change from baseline in nasal polyps score at week 52 following treatment with the antigen binding protein. In one embodiment, the reduction in total endoscopic nasal polyps score is measured by a change from baseline in total endoscopic nasal polyps score at week 52 following treatment with the antigen binding protein. In one embodiment, the reduction in nasal polyps score is measured by a change from baseline in nasal polyps score at week 52 following treatment with the antigen binding protein versus placebo. In one 70542W001 embodiment, the reduction in total endoscopic nasal polyps score is measured by a change from baseline in total endoscopic nasal polyps score at week 52 following treatment with the antigen binding protein versus placebo.

[0088] The present invention includes an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s nasal obstruction score is reduced.

[0089] The present invention includes a method of treating CRSwNP comprising administering to a patient an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10, wherein the patient’s nasal obstruction score is reduced.

[0090] The present invention includes an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 for use in a method of reducing nasal obstruction score in a patient with CRSwNP.

[0091] The present invention includes a method of reducing nasal obstruction score in patient with CRSwNP comprising administering to a patient a therapeutic amount of an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10. 70542W001

[0092] In one embodiment, the nasal obstruction score is the mean nasal obstruction score. In one embodiment, the patient’s mean nasal obstruction score is reduced. In one embodiment, the patient’s nasal obstruction score is significantly reduced. In one embodiment, the patient’s mean nasal obstruction score is significantly reduced. In one embodiment, the patient’s nasal obstruction score (by verbal response scale [VRS]) is reduced. In one embodiment, the patient’s mean nasal obstruction score (by verbal response scale [VRS]) is reduced. In one embodiment, the patient’s nasal obstruction score is significantly reduced compared to baseline or untreated control levels. In one embodiment, the patient’s mean nasal obstruction score is significantly reduced compared to baseline or untreated control levels. In one embodiment, the reduction in nasal obstruction score is measured by a change from baseline in nasal obstruction score from week 49 through to week 52 following treatment with the antigen binding protein. In one embodiment, the reduction in mean nasal obstruction score is measured by a change from baseline in mean nasal obstruction score from week 49 through to week 52 following treatment with the antigen binding protein. In one embodiment, the reduction in nasal obstruction score is measured by a change from baseline in nasal obstruction score from week 49 through to week 52 following treatment with the antigen binding protein versus placebo. In one embodiment, the reduction in mean nasal obstruction score is measured by a change from baseline in mean nasal obstruction score from week 49 through to week 52 following treatment with the antigen binding protein versus placebo.

[0093] In one embodiment, the nasal polyps score is reduced by about 10% to about 50%, by about 20% to about 40%, or by about 25% to about 30%. In one embodiment, the nasal polyps score is reduced by about 10% to about 30%. In one embodiment, the nasal polyps score is reduced by about 10% to about 20%. In one embodiment, the nasal polyps score is reduced by at least about 10%. In one embodiment, the nasal polyps score is reduced by at least about 15%. In one embodiment, the nasal polyps score is reduced by at least about 20%. In one embodiment, the nasal polyps score is reduced by at least about 25%. In one embodiment, the nasal polyps score is reduced by at least about 30%. In one embodiment, the nasal polyps score is reduced by at least about 35%. In one embodiment, the nasal polyps score is reduced by at least about 40%. In one embodiment, the nasal polyps score is reduced by at least about 45%. In one embodiment, the nasal polyps score is reduced by at least about 50%. In one embodiment, the nasal polyps score is reduced by about 10%. In one embodiment, the nasal polyps score is reduced by about 20%.

[0094] In one embodiment, the nasal polyps score is reduced by at least about 0.4, at least about 0.45, at least about 0.5, at least about 0.55, at least about 0.6, at least about 70542W001

[0095] 0.65, at least about 0.7, at least about 0.75, at least about 0.8, at least about 0.85, at least about 0.9, at least about 0.95, or at least about 1.0. In one embodiment, the nasal polyps score is reduced by at least about 0.4, at least about 0.45, at least about 0.5, at least about 0.55, at least about 0.6, at least about 0.65, at least about 0.7, at least about 0.75, at least about 0.8, at least about 0.85, or at least about 0.9. In one embodiment, the nasal polyps score is reduced by at least about 0.4. In one embodiment, the nasal polyps score is reduced by at least about 0.5. In one embodiment, the nasal polyps score is reduced by at least about 0.55. In one embodiment, the nasal polyps score is reduced by at least about 0.6. In one embodiment, the nasal polyps score is reduced by at least about 0.65. In one embodiment, the nasal polyps score is reduced by at least about 0.7. In one embodiment, the nasal polyps score is reduced by at least about 0.8. In one embodiment, the nasal polyps score is reduced by at least about 0.85. In one embodiment, the nasal polyps score is reduced by at least about 0.9. In one embodiment, the nasal polyps score is reduced by at least about 0.95. In one embodiment, the nasal polyps score is reduced by at least about 1.0. In one embodiment, the nasal polyps score is reduced by at least about 1.1.

[0096] In one embodiment, the nasal polyps score is reduced by about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, about 0.95, or about 1.0. In one embodiment, the nasal polyps score is reduced by about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, or about 0.9. In one embodiment, the nasal polyps score is reduced by about 0.4. In one embodiment, the nasal polyps score is reduced by about 0.5. In one embodiment, the nasal polyps score is reduced by about 0.55. In one embodiment, the nasal polyps score is reduced by about 0.6. In one embodiment, the nasal polyps score is reduced by about 0.65. In one embodiment, the nasal polyps score is reduced by about 0.7. In one embodiment, the nasal polyps score is reduced by about 0.8. In one embodiment, the nasal polyps score is reduced by about 0.85. In one embodiment, the nasal polyps score is reduced by about 0.9. In one embodiment, the nasal polyps score is reduced by about 0.95. In one embodiment, the nasal polyps score is reduced by about 1.0. In one embodiment, the nasal polyps score is reduced by about 1.1.

[0097] In one embodiment, the nasal obstruction score is reduced by about 10% to about 50%, by about 20% to about 40%, or by about 25% to about 30%. In one embodiment, the nasal obstruction score is reduced by about 10% to about 30%. In one embodiment, the nasal obstruction score is reduced by about 10% to about 20%. In one embodiment, the nasal obstruction score is reduced by at least about 10%. In one embodiment, the nasal obstruction score is reduced by at least about 15%. In one embodiment, the nasal 70542W001 obstruction score is reduced by at least about 20%. In one embodiment, the nasal obstruction score is reduced by at least about 25%. In one embodiment, the nasal obstruction score is reduced by at least about 30%. In one embodiment, the nasal obstruction score is reduced by at least about 35%. In one embodiment, the nasal obstruction score is reduced by at least about 40%. In one embodiment, the nasal obstruction score is reduced by at least about 45%. In one embodiment, the nasal obstruction score is reduced by at least about 50%. In one embodiment, the nasal obstruction score is reduced by about 10%. In one embodiment, the nasal obstruction score is reduced by about 20%.

[0098] In one embodiment, the nasal obstruction score is reduced by at least about 0.1, at least about 0.15, at least about 0.2, at least about 0.25, at least about 0.3, at least about 0.35, at least about 0.4, at least about 0.45, or at least about 0.5. In one embodiment, the nasal obstruction score is reduced by at least about 0.1. In one embodiment, the nasal obstruction score is reduced by at least about 0.15. In one embodiment, the nasal obstruction score is reduced by at least about 0.2. In one embodiment, the nasal obstruction score is reduced by at least about 0.23. In one embodiment, the nasal obstruction score is reduced by at least about 0.25. In one embodiment, the nasal obstruction score is reduced by at least about 0.27. In one embodiment, the nasal obstruction score is reduced by at least about 0.29. In one embodiment, the nasal obstruction score is reduced by at least about 0.3. In one embodiment, the nasal obstruction score is reduced by at least about 0.31. In one embodiment, the nasal obstruction score is reduced by at least about 0.35. In one embodiment, the nasal obstruction score is reduced by at least about 0.36. In one embodiment, the nasal obstruction score is reduced by at least about 0.38. In one embodiment, the nasal obstruction score is reduced by at least about 0.4. In one embodiment, the nasal obstruction score is reduced by at least about 0.41. In one embodiment, the nasal obstruction score is reduced by at least about 0.43. In one embodiment, the nasal obstruction score is reduced by at least about 0.45. In one embodiment, the nasal obstruction score is reduced by at least about 0.49. In one embodiment, the nasal obstruction score is reduced by at least about 0.5.

[0099] In one embodiment, the nasal obstruction score is reduced by about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, or about 0.5. In one embodiment, the nasal obstruction score is reduced by about 0.1. In one embodiment, the nasal obstruction score is reduced by about 0.15. In one embodiment, the nasal obstruction score is reduced by about 0.2. In one embodiment, the nasal obstruction score is reduced by about 0.23. In one embodiment, the nasal obstruction 70542W001 score is reduced by about 0.25. In one embodiment, the nasal obstruction score is reduced by about 0.27. In one embodiment, the nasal obstruction score is reduced by about 0.29. In one embodiment, the nasal obstruction score is reduced by about 0.3. In one embodiment, the nasal obstruction score is reduced by about 0.31. In one embodiment, the nasal obstruction score is reduced by about 0.35. In one embodiment, the nasal obstruction score is reduced by about 0.36. In one embodiment, the nasal obstruction score is reduced by about 0.38. In one embodiment, the nasal obstruction score is reduced by about 0.4. In one embodiment, the nasal obstruction score is reduced by about 0.41. In one embodiment, the nasal obstruction score is reduced by about 0.43. In one embodiment, the nasal obstruction score is reduced by about 0.45. In one embodiment, the nasal obstruction score is reduced by about 0.49. In one embodiment, the nasal obstruction score is reduced by about 0.5.

[0100] In one embodiment, the antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 is for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s total endoscopic nasal polyps score is reduced by at least about 0.55, optionally reduced by at least about 0.6, and wherein the antigen binding protein is to be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

[0101] In one embodiment, the antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 is for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s total endoscopic nasal polyps score is reduced by at least about 0.55 compared to baseline or untreated control levels, optionally reduced by at least about 0.6, and wherein the antigen binding protein is to be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

[0102] In one embodiment, the antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown 70542W001 in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 is for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s total endoscopic nasal polyps score is reduced by at least about 0.65, optionally reduced by at least about 0.7, and wherein the antigen binding protein is to be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

[0103] In one embodiment, the antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 is for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s total endoscopic nasal polyps score is reduced by at least about 0.65 compared to baseline or untreated control levels, optionally reduced by at least about 0.7, and wherein the antigen binding protein is to be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

[0104] In one embodiment, the antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 is for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s mean nasal obstruction score is reduced by at least about 0.2, optionally reduced by at least about 0.24, and wherein the antigen binding protein is to be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

[0105] In one embodiment, the antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid 70542W001 sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 is for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s mean nasal obstruction score is reduced by at least about 0.2 compared to baseline or untreated control levels, optionally reduced by at least about 0.24, and wherein the antigen binding protein is to be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

[0106] In one embodiment, the antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 is for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s mean nasal obstruction score is reduced by at least about 0.2, optionally reduced by at least about 0.25, and wherein the antigen binding protein is to be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

[0107] In one embodiment, the antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 is for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s mean nasal obstruction score is reduced by at least about 0.2 compared to baseline or untreated control levels, optionally reduced by at least about 0.25, and wherein the antigen binding protein is to be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

[0108] In one embodiment, the antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 is for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s mean nasal obstruction score is reduced by at least 70542W001 about 0.2, optionally reduced by at least about 0.23, and wherein the antigen binding protein is to be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

[0109] In one embodiment, the antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 is for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s mean nasal obstruction score is reduced by at least about 0.2 compared to baseline or untreated control levels, optionally reduced by at least about 0.23, and wherein the antigen binding protein is to be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

[0110] In one embodiment, the antigen binding protein comprises a heavy chain variable region sequence having at least about 90% identity for example about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity to the amino acid sequence shown in SEQ ID NO: 3; and / or a light chain variable region sequence having at least about 90% identity for example about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity the amino acid sequence shown in SEQ ID NO: 4. In one embodiment, the antigen binding protein comprises a heavy chain variable region sequence having at least about 90% identity for example about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity to the amino acid sequence shown in SEQ ID NO: 3; and / or a light chain variable region sequence having at least about 90% identity for example about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity the amino acid sequence shown in SEQ ID NO: 4, wherein the heavy chain variable region has the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and the light chain variable region has the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10. In one embodiment, the antigen binding protein comprises a heavy chain variable region sequence having the amino acid sequence shown in SEQ ID NO: 3; and a light chain variable region sequence having the amino acid sequence shown in SEQ ID NO: 4. 70542W001

[0111] The antigen binding protein may comprise an Fc domain. The antigen binding protein may comprise a heavy chain Fc domain. The antigen binding protein may comprise an lgG1 , lgG2, lgG3 or lgG4 Fc domain. The antigen binding protein may comprise a human lgG1 , lgG2, lgG3 or lgG4 Fc domain. The antigen binding protein may comprise an lgG1 Fc domain. The antigen binding protein may comprise a human IgG 1 Fc domain. The antigen binding protein may also comprise a heavy chain Fc domain (e.g., an IgG 1 Fc) comprising a tyrosine residue at position 252, a threonine residue at position 254 and a glutamic acid residue at position 256. The antigen binding protein may comprise a human IgG 1 Fc domain comprising a tyrosine residue at position 252, a threonine residue at position 254 and a glutamic acid residue at position 256. The numbering of the amino acids in the heavy chain Fc domain (i.e., a tyrosine residue at position 252, a threonine residue at position 254 and a glutamic acid residue at position 256) was derived using Ell numbering, as described in: Edelman et al. (1969) Proc. Natl. Acad. USA, 63: 78-85 [PMID: 5257969], The antigen binding protein may comprise a human IgG 1 Fc domain comprising a tyrosine residue at position 252 (EU numbering), a threonine residue at position 254 (EU numbering) and a glutamic acid residue at position 256 (EU numbering).

[0112] The antigen binding protein may further comprise a heavy chain FR4 amino acid sequence as shown in SEQ ID NO: 13.

[0113] In one embodiment, the antigen binding protein comprises a heavy chain having at least about 90% identity for example about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain having at least about 90% identity for example about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity the amino acid sequence shown in SEQ ID NO: 2. In one embodiment, the antigen binding protein comprises a heavy chain having at least about 90% identity for example about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity to the amino acid sequence shown in SEQ ID NO: 1 and a light chain having at least about 90% identity for example about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity the amino acid sequence shown in SEQ ID NO: 2, wherein the heavy chain has the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and the light chain has the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10. In one embodiment, the antigen binding protein of the invention is an antibody comprising a heavy chain having the amino acid sequence shown 70542W001 in SEQ ID NO: 1 and a light chain having the amino acid sequence shown in SEQ ID NO: 2.

[0114] In one embodiment, the antigen binding protein is depemokimab.

[0115] In one embodiment, the antigen binding protein may be formulated within a pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises the antigen binding protein and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition comprises the antigen binding protein and an aqueous liquid formulation at about pH 6.0 comprising about 20 mM histidine, about 180 mM trehalose, about 40 mM arginine, about 0.05 mM EDTA and about 0.02% weight of polysorbate 80 to volume.

[0116] In one embodiment, the CRSwNP is inadequately controlled CRSwNP. The CRSwNP may be inadequately controlled despite standard of care. The standard of care may be nasal corticosteroids. The standard of care may be intranasal corticosteroids. The CRSwNP may be inadequately controlled despite use of nasal corticosteroids. The CRSwNP may be inadequately controlled despite use of intranasal corticosteroids. In one embodiment, the antigen binding protein is for use as add-on maintenance treatment in patients with inadequately controlled CRSwNP. In one embodiment, the antigen binding protein is a second line therapy on top of standard of care, optionally intranasal corticosteroids plus as needed oral corticosteroids.

[0117] Further improvements in reducing the nasal polyps score and / or nasal obstruction score can be achieved in patients according to their baseline peripheral blood eosinophil levels. The patient may have a baseline peripheral blood eosinophil count selected from the group consisting of at least 150 cel Is / microl iter, at least 200 cells / microliter, at least 250 cells / microliter, at least 300 cells / microliter, and at least 500 cells / microliter. The patient may have a baseline peripheral blood eosinophil count of at least 150 cells / microliter. The patient may have a baseline peripheral blood eosinophil count of at least 200 cells / microliter. The patient may have a baseline peripheral blood eosinophil count of at least 250 cells / microliter. The patient may have a baseline peripheral blood eosinophil count of at least 300 cells / microliter. The patient may have a baseline peripheral blood eosinophil count of at least 500 cells / microliter, optionally at least 560 cells / microliter. In one embodiment, the patient has a baseline peripheral blood eosinophil count of at least 300 cells / microliter and the nasal polyps score is reduced by at least about 0.65, optionally reduced by at least about 0.7. In one embodiment, the patient has a baseline peripheral blood eosinophil count of at least 500 cells / microliter, optionally at least 560 cells / microliter, and the nasal polyps score is reduced by at least about 1.0, optionally reduced by at least about 1.1. The nasal polyps score may be the total 70542W001 endoscopic nasal polyps score. The reduction in total endoscopic nasal polyps score may be measured by a change from baseline in total endoscopic nasal polyps score at week 52 following treatment with the antigen binding protein. The reduction in total endoscopic nasal polyps score may be measured by a change from baseline in total endoscopic nasal polyps score at week 52 following treatment with the antigen binding protein versus placebo. In one embodiment, the patient has a baseline peripheral blood eosinophil count of at least 300 cells / microliter and the nasal obstruction score is reduced by at least about 0.25, optionally reduced by at least about 0.29. In one embodiment, the patient has a baseline peripheral blood eosinophil count of at least 300 cells / microliter and the nasal obstruction score is reduced by at least about 0.3, optionally reduced by at least about 0.31. In one embodiment, the patient has a baseline peripheral blood eosinophil count of at least 500 cells / microliter, optionally at least 560 cells / microliter, and the nasal obstruction score is reduced by at least about 0.4, optionally reduced by at least about 0.41. The nasal obstruction score may be the mean nasal obstruction score. The reduction in mean nasal obstruction score may be measured by a change from baseline in mean nasal obstruction score from week 49 through to week 52 following treatment with the antigen binding protein. The reduction in mean nasal obstruction score may be measured by a change from baseline in mean nasal obstruction score from week 49 through to week 52 following treatment with the antigen binding protein versus placebo.

[0118] In one embodiment, the antigen binding protein is for use in a method of reducing the nasal polyps score in a patient with CRSwNP, wherein the method comprises: a) determining the blood eosinophil count of the patient, b) where if the patient has blood eosinophil count of at least 300 cells / microliter, administering to the patient an effective amount of the antigen binding protein.

[0119] In one embodiment, the antigen binding protein is for use in a method of reducing the nasal obstruction score in a patient with CRSwNP, wherein the method comprises: a) determining the blood eosinophil count of the patient, b) where if the patient has blood eosinophil count of at least 300 cells / microliter, administering to the patient an effective amount of the antigen binding protein.

[0120] Further improvements in reducing the nasal polyps score can be achieved according to the presence of comorbid asthma. Further improvements in reducing the nasal obstruction score can be achieved according to the presence of comorbid asthma. In one embodiment, the patient has CRSwNP and asthma, and the nasal polyps score is reduced by at least about 0.65, optionally reduced by at least about 0.7. In one 70542W001 embodiment, the patient has CRSwNP and asthma, and the nasal polyps score is reduced by at least about 0.75, optionally reduced by at least about 0.8. The nasal polyps score may be the total endoscopic nasal polyps score. The reduction in total endoscopic nasal polyps score may be measured by a change from baseline in total endoscopic nasal polyps score at week 52 following treatment with the antigen binding protein. The reduction in total endoscopic nasal polyps score may be measured by a change from baseline in total endoscopic nasal polyps score at week 52 following treatment with the antigen binding protein versus placebo. In one embodiment, the patient has CRSwNP and asthma, and the nasal obstruction score is reduced by at least about 0.35, optionally reduced by at least about 0.36. In one embodiment, the patient has CRSwNP and asthma, and the nasal obstruction score is reduced by at least about 0.45, optionally reduced by at least about 0.5. The nasal obstruction score may be the mean nasal obstruction score. The reduction in mean nasal obstruction score may be measured by a change from baseline in mean nasal obstruction score from week 49 through to week 52 following treatment with the antigen binding protein. The reduction in mean nasal obstruction score may be measured by a change from baseline in mean nasal obstruction score from week 49 through to week 52 following treatment with the antigen binding protein versus placebo.

[0121] In one embodiment, the antigen binding protein is for use in a method of reducing the nasal polyps score in a patient with CRSwNP, wherein the method comprises: a) determining whether the patient has comorbid asthma, b) where if the patient has comorbid asthma, administering to the patient an effective amount of the antigen binding protein.

[0122] In one embodiment, the antigen binding protein is for use in a method of reducing the nasal obstruction score in a patient with CRSwNP, wherein the method comprises: a) determining whether the patient has comorbid asthma, b) where if the patient has comorbid asthma, administering to the patient an effective amount of the antigen binding protein.

[0123] Further improvements in reducing the nasal polyps score can be achieved in patients according to the number of previous nasal polyp surgeries. Further improvements in reducing the nasal obstruction score can be achieved in patients according to the number of previous nasal polyp surgeries. In one embodiment, the patient has had one, two, or more than two previous nasal polyp surgeries. In one embodiment, the patient has had one previous nasal polyp surgery. In one embodiment, the patient has had two previous nasal polyp surgeries. In one embodiment, the patient 70542W001 has had more than two previous nasal polyp surgeries. In one embodiment, the patient has had more than two previous nasal polyp surgeries, including three, four, five or more than five previous nasal polyp surgeries. The CRSwNP may be recurrent CRSwNP. The CRSwNP may be persistent CRSwNP. In one embodiment, the patient has had more than two previous nasal polyps surgeries and the nasal polyps score is reduced by at least about 0.85, optionally reduced by at least about 0.9. The nasal polyps score may be the total endoscopic nasal polyps score. The reduction in total endoscopic nasal polyps score may be measured by a change from baseline in total endoscopic nasal polyps score at week 52 following treatment with the antigen binding protein. The reduction in total endoscopic nasal polyps score may be measured by a change from baseline in total endoscopic nasal polyps score at week 52 following treatment with the antigen binding protein versus placebo. In one embodiment, the patient has had one, two, or more than two previous nasal polyps surgeries and the nasal obstruction score is reduced by at least about 0.25. In one embodiment, the patient has recurrent CRSwNP or persistent CRSwNP and the nasal obstruction score is reduced by at least about 0.25. In one embodiment, the patient has had one previous nasal polyps surgery and the nasal obstruction score is reduced by at least about 0.35, optionally reduced by at least about 0.4. In one embodiment, the patient has had one previous nasal polyps surgery and the nasal obstruction score is reduced by at least about 0.4, optionally reduced by at least about 0.43. In one embodiment, the patient has had two previous nasal polyps surgeries and the nasal obstruction score is reduced by at least about 0.25, optionally reduced by at least about 0.27. In one embodiment, the patient has had more than two previous nasal polyps surgeries and the nasal obstruction score is reduced by at least about 0.35, optionally reduced by at least about 0.38. In one embodiment, the patient has had more than two previous nasal polyps surgeries and the nasal obstruction score is reduced by at least about 0.45, optionally reduced by at least about 0.49. The nasal obstruction score may be the mean nasal obstruction score. The reduction in mean nasal obstruction score may be measured by a change from baseline in mean nasal obstruction score from week 49 through to week 52 following treatment with the antigen binding protein. The reduction in mean nasal obstruction score may be measured by a change from baseline in mean nasal obstruction score from week 49 through to week 52 following treatment with the antigen binding protein versus placebo.

[0124] Further improvements in reducing the nasal polyps score can be achieved in patients from the United States of America. In one embodiment, the patient is from the United States of America and the nasal polyps score is reduced by at least about 1.0. The nasal polyps score may be the total endoscopic nasal polyps score. The reduction in total 70542W001 endoscopic nasal polyps score may be measured by a change from baseline in total endoscopic nasal polyps score at week 52 following treatment with the antigen binding protein. The reduction in total endoscopic nasal polyps score may be measured by a change from baseline in total endoscopic nasal polyps score at week 52 following treatment with the antigen binding protein versus placebo.

[0125] In one embodiment, an effective amount of antigen binding protein is to be administered to the patient. The effective amount of antigen binding protein may be a dose of 100 mg. The antigen binding protein may be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

[0126] In one embodiment, the antigen binding protein further improves one or more of the following measures of disease: a) rhinorrhea score, optionally mean rhinorrhea score (VRS) during weeks 49-52, b) loss of smell score, optionally mean loss of smell score (VRS) during weeks 49-52, c) Lund Mackay CT score, optionally Lund Mackay CT score at week 52, d) SNOT-22 total score, optionally SNOT-22 total score at week 52, and / or e) nasal obstruction score, optionally mean nasal obstruction score (VRS) from weeks 21 through to week 24.

[0127] In one embodiment, the antigen binding protein improves one or more symptoms of chronic rhinosinusitis selected from the group consisting of nasal blockage, nasal congestion, runny nose, post-nasal drip, mucus drainage down the throat, prominent nasal obstruction, nasal discharge, loss of smell, asthma symptoms, headache, facial pain, facial pressure, difficulty with sense of smell, difficulty with sleeping due to nasal symptoms, difficulty with daily activities due to nasal symptoms.

[0128] In one embodiment, the antigen binding protein is in a pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises the antigen binding protein in an amount of 100 mg, and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition comprises the antigen binding protein in an amount of 100 mg, and an aqueous liquid formulation at about pH 6.0 comprising about 20 mM histidine, about 180 mM trehalose, about 40 mM arginine, about 0.05 mM EDTA and about 0.02% weight of polysorbate 80 to volume.

[0129] In one embodiment, the patient is human.

[0130] In one embodiment, the patient is greater than or equal to (>)18 years of age. In one embodiment, the patient has a total endoscopic nasal polyps score of at least 5 prior to treatment. In one embodiment the patient has a total endoscopic nasal polyps score of 70542W001 at least 5 out of a maximum score of 8 prior to treatment, with a minimum score of two in each nasal cavity. In one embodiment, the patient has at least one of the following prior to treatment: previous nasal surgery for the removal of nasal polyps, have used at least three consecutive days of systemic corticosteroids in the previous 2 years for the treatment of nasal polyps, and / or medically unsuitable or intolerant to systemic corticosteroid. In one embodiment, the patient is on daily treatment with intranasal corticosteroid (INCS). In one embodiment, the patient is on daily treatment with intranasal corticosteroid (INCS), expect for wherein the patient is from Japan. In one embodiment, the patient is on daily treatment with intranasal corticosteroid (INCS) for at least 8 weeks prior to treatment. The INCS may include intranasal liquid steroid wash / douching. In one embodiment, the patient has severe nasal polyps symptoms. Severe nasal polyps symptoms may be defined as symptoms of nasal congestion / blockade / obstruction with moderate or severe severity and loss of smell or rhinorrhea. In one embodiment, the patient has symptoms of chronic rhinosinusitis. Chronic rhinosinusitis may be defined by at least 2 different symptoms prior to treatment, wherein one of the symptoms is either nasal blockage / obstruction / congestion or nasal discharge plus facial pain / pressure and / or reduction or loss of smell.

[0131] Clauses

[0132] 1. An antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s nasal polyps score is reduced.

[0133] 2. The antigen binding protein for use according to clause 1 , wherein the patient’s nasal polyps score is reduced by at least about 0.4, at least about 0.5, at least about 0.55, at least about 0.6, at least about 0.65, at least about 0.7, at least about 0.75, at least about 0.8, at least about 0.85, at least about 0.9, at least about 0.95, or at least about 1.0.

[0134] 3. The antigen binding protein for use according to clause 1 or 2, wherein the patient’s nasal polyps score is reduced by at least about 0.5.

[0135] 4. The antigen binding protein for use according to any one of clauses 1-3, wherein the patient’s nasal polyps score is reduced by at least about 0.6. 70542W001

[0136] 5. The antigen binding protein for use according to any one of clauses 1-4, wherein the patient’s nasal polyps score is reduced by at least about 0.7.

[0137] 6. The antigen binding protein for use according to any one of clauses 1-4, wherein the patient’s nasal polyps score is reduced by at least about 0.8.

[0138] 7. The antigen binding protein for use according to any one of clauses 1-5, wherein the patient’s nasal polyps score is reduced by at least about 0.9.

[0139] 8. The antigen binding protein for use according to any one of clauses 1-4, wherein the patient’s nasal polyps score is reduced by at least about 1.0.

[0140] 9. The antigen binding protein for use according to any one of clauses 1-4, wherein the patient’s nasal polyps score is reduced by at least about 1.1.

[0141] 10. A method of treating CRSwNP comprising administering to a patient an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10, wherein the patient’s nasal polyps score is reduced.

[0142] 11. The method according to clause 10, wherein the patient’s total endoscopic nasal polyps score is reduced by at least about 0.4, at least about 0.5, at least about 0.55, at least about 0.6, at least about 0.65, at least about 0.7, at least about 0.75, at least about 0.8, at least about 0.85, at least about 0.9, at least about 0.95, or at least about 1.0.

[0143] 12. An antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 for use in a method of reducing nasal polyps score in a patient with CRSwNP.

[0144] 13. A method of reducing nasal polyps score in patient with CRSwNP comprising administering to a patient a therapeutic amount of an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 70542W001 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0145] 14. An antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s nasal obstruction score is reduced.

[0146] 15. The antigen binding protein for use according to clause 14, wherein the patient’s nasal obstruction score is reduced by at least about 0.2, at least about 0.25, at least about 0.3, at least about 0.35, at least about 0.4, at least about 0.45, or at least about 0.5.

[0147] 16. The antigen binding protein for use according to clause 14 or 15, wherein the patient’s nasal obstruction score is reduced by at least about 0.2.

[0148] 17. The antigen binding protein for use according to any one of clauses 14-16, wherein the patient’s nasal obstruction score is reduced by at least about 0.23.

[0149] 18. The antigen binding protein for use according to any one of clauses 14-17, wherein the patient’s nasal obstruction score is reduced by at least about 0.25.

[0150] 19. The antigen binding protein for use according to any one of clauses 14-18, wherein the patient’s nasal obstruction score is reduced by at least about 0.27.

[0151] 20. The antigen binding protein for use according to any one of clauses 14-19, wherein the patient’s nasal obstruction score is reduced by at least about 0.29.

[0152] 21 . The antigen binding protein for use according to any one of clauses 14-20, wherein the patient’s nasal obstruction score is reduced by at least about 0.3.

[0153] 22. The antigen binding protein for use according to any one of clauses 14-21 , wherein the patient’s nasal obstruction score is reduced by at least about 0.31.

[0154] 23. The antigen binding protein for use according to any one of clauses 14-22, wherein the patient’s nasal obstruction score is reduced by at least about 0.36.

[0155] 24. antigen binding protein for use according to any one of clauses 14-23, wherein the patient’s nasal obstruction score is reduced by at least about 0.38. 1 70542W001

[0156] 25. The antigen binding protein for use according to any one of clauses 14-24, wherein the patient’s nasal obstruction score is reduced by at least about 0.4.

[0157] 26. The antigen binding protein for use according to any one of clauses 14-25, wherein the patient’s nasal obstruction score is reduced by at least about 0.41.

[0158] 27. The antigen binding protein for use according to any one of clauses 14-26, wherein the patient’s nasal obstruction score is reduced by at least about 0.43.

[0159] 28. The antigen binding protein for use according to any one of clauses 14-27, wherein the patient’s nasal obstruction score is reduced by at least about 0.45.

[0160] 29. The antigen binding protein for use according to any one of clauses 14-28, wherein the patient’s nasal obstruction score is reduced by at least about 0.49.

[0161] 30. The antigen binding protein for use according to any one of clauses 14-29, wherein the patient’s nasal obstruction score is reduced by at least about 0.5.

[0162] 31. A method of treating CRSwNP comprising administering to a patient an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10, wherein the patient’s nasal obstruction score is reduced.

[0163] 32. The method according to clause 31 , wherein the patient’s nasal obstruction score is reduced by at least about 0.2, at least about 0.25, at least about 0.3, at least about 0.35, at least about 0.4, at least about 0.45, or at least about 0.5.

[0164] 33. An antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 for use in a method of reducing nasal obstruction score in a patient with CRSwNP.

[0165] 34. A method of reducing nasal obstruction score in patient with CRSwNP comprising administering to a patient a therapeutic amount of an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 70542W001 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0166] 35. The antigen binding protein for use or the method according to any one of clauses 1- 13, wherein the nasal polyps score is the total endoscopic nasal polyps score.

[0167] 36. The antigen binding protein for use or the method according to clause 35, wherein the reduction in total endoscopic nasal polyps score is measured by a change from baseline in total endoscopic nasal polyps score at week 52 following treatment with the antigen binding protein.

[0168] 37. The antigen binding protein for use or the method according to clause 36, wherein the reduction in total endoscopic nasal polyps score is measured by a change from baseline in total endoscopic nasal polyps score at week 52 following treatment with the antigen binding protein versus placebo.

[0169] 38. The antigen binding protein for use or the method according to any one of clauses 14- 34, wherein the nasal obstruction score is the mean nasal obstruction score.

[0170] 39. The antigen binding protein for use or the method according to clause 38, wherein the reduction in mean nasal obstruction score is measured by a change from baseline in mean nasal obstruction score from week 49 through to week 52 following treatment with the antigen binding protein.

[0171] 40. The antigen binding protein for use or the method according to of clause 39, wherein the reduction in mean nasal obstruction score is measured by a change from baseline in mean nasal obstruction score from week 49 through to week 52 following treatment with the antigen binding protein versus placebo.

[0172] 41. The antigen binding protein for use or the method according to any one of clauses 1-

[0173] 40, wherein the heavy chain variable region sequence comprises the amino acid sequence shown in SEQ ID NO: 3; and the light chain variable region sequence comprises the amino acid sequence shown in SEQ ID NO: 4.

[0174] 42. The antigen binding protein for use or the method according to any one of clauses 1-

[0175] 41 , wherein the antigen binding protein is an antibody.

[0176] 43. The antigen binding protein for use or the method according to clause 42, wherein the antibody comprises an IgG 1 Fc domain. 70542W001

[0177] 44. The antigen binding protein for use or the method according to clause 43, wherein the IgG 1 Fc domain comprises a tyrosine residue at position 252, a threonine residue at position 254 and a glutamic acid residue at position 256.

[0178] 45. The antigen binding protein for use or the method according to any one of clauses 1-

[0179] 44, wherein the antigen binding protein comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a light chain having the amino acid sequence shown in SEQ ID NO: 2.

[0180] 46. The antigen binding protein for use or the method according to any one of clauses 1-

[0181] 45, wherein the antigen binding protein is depemokimab.

[0182] 47. The antigen binding protein for use or the method according to any one of clauses 1-

[0183] 46, wherein the patient has inadequately controlled CRSwNP.

[0184] 48. The antigen binding protein for use or the method according to any one of clauses 1-

[0185] 47, wherein the CRSwNP is inadequately controlled by standard of care.

[0186] 49. The antigen binding protein for use or the method according to any one of clauses 1-

[0187] 48, wherein the CRSwNP is inadequately controlled by intranasal corticosteroids.

[0188] 50. The antigen binding protein for use or method according to any one of clauses 1-49, wherein the patient has an endoscopic bilateral nasal polyps score of at least 5 out of a maximum score of 8 (at least 2 in each nasal cavity) prior to treatment.

[0189] 51. The antigen binding protein for use or method according to any one of clauses 1-50, wherein the patient has severe nasal polyps symptoms, optionally nasal congestion / blockade / obstruction with moderate or severe severity and loss of smell or rhinorrhea.

[0190] 52. The antigen binding protein for use or method according to any one of clauses 1-51, wherein the patient has symptoms of chronic rhinosinusitis, optionally nasal blockage / obstruction / congestion or nasal discharge, facial pain / pressure and / or reduction or loss of smell.

[0191] 53. The antigen binding protein for use or method according to any one of clauses 1-52, wherein the patient has had prior treatment with systemic corticosteroid in the past 2 years and / or has medical contraindication / intolerance to systemic corticosteroid, and / or has had a documented history of prior surgery of nasal polyp.

[0192] 54. The antigen binding protein for use or the method according to any one of clauses 1- 53, wherein the patient has a baseline peripheral blood eosinophil count of at least 150 cells / microliter. 70542W001

[0193] 55. The antigen binding protein for use or the method according to any one of clauses 1-

[0194] 54, wherein the patient has a baseline peripheral blood eosinophil count of at least 200 cells / microliter.

[0195] 56. The antigen binding protein for use or the method according to any one of clauses 1-

[0196] 55, wherein the patient has a baseline peripheral blood eosinophil count of at least 300 cells / microliter.

[0197] 57. The antigen binding protein for use or the method according to any one of clauses 1-

[0198] 56, wherein the patient has a baseline peripheral blood eosinophil count of at least 500 cells / microliter, optionally at least 560 cells / microliter.

[0199] 58. The antigen binding protein for use or the method according to any one of clauses 1- 53, wherein the number of previous nasal polyp surgeries for the patient is 1 , 2, or more than 2.

[0200] 59. The antigen binding protein for use or the method according to clause 58, wherein the number of previous nasal polyp surgeries for the patient is more than 2.

[0201] 60. The antigen binding protein for use or the method according to any one of clauses 1- 53, wherein the patient has comorbid asthma.

[0202] 61. The antigen binding protein for use or method according to any one of clauses 1-60, wherein an effective amount of antigen binding protein is to be administered to the patient.

[0203] 62. The antigen binding protein for use or the method according to clause 61, wherein the antigen binding protein is to be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

[0204] 63. The antigen binding protein for use or the method according to clause 61 or 62, wherein the antigen binding protein is to be administered to the patient subcutaneously.

[0205] 64. The antigen binding protein for use or the method of treatment according to any one of clauses 1-63, wherein the patient is human.

[0206] 65. The antigen binding protein for use or the method according to any one of clauses 1-

[0207] 64, wherein the patient is an adult (>18 years).

[0208] 66. The antigen binding protein for use or the method according to any one of clauses 1-

[0209] 65, wherein the antigen binding protein further improves one or more of the following measures: i) rhinorrhea score, ii) loss of smell score, 70542W001 iii) Lund Mackay CT score, iv) SNOT-22 total score, and / or v) mean nasal obstruction score (VRS) from week 21 through to week 24.

[0210] Example 1 - Study Design (ANCHOR-1 / 2)

[0211] ANCHOR-1 / 2 were randomized, double-blind, placebo-controlled, parallel-group, replicate Phase III trials.

[0212] Participants

[0213] Key eligibility criteria were: adult participants (>18 years of age at time of consent) with inadequately controlled CRSwNP defined as endoscopic bilateral NP score >5 out of a maximum score of 8 (>2 in each nasal cavity) assessed by the investigator; severe NP symptoms defined as symptoms of moderate or severe nasal congestion / blockade / obstruction, and loss of smell or rhinorrhea; symptoms of chronic rhinosinusitis (CRS) defined as presence of >2 different symptoms for >12 weeks prior to Visit 1 , one of which must have been either nasal blockage / obstruction / congestion or nasal discharge (anterior / posterior nasal drip), with facial pain / pressure and / or reduction or loss of smell; had received at least three days of prior treatment with SCS anytime within the past 2 years (and / or have a medical contraindication / intolerance to SCS), and / or had a documented history of prior surgery for NP at the Screening Visit.

[0214] Full inclusion and exclusion criteria are provided below:

[0215] Participants were eligible to be included in the studies if they met all of the following criteria:

[0216] 1. 18 years of age and older inclusive, at the time of signing the informed consent

[0217] 2. Endoscopic bilateral nasal polyp (NP) score of at least 5 out of a maximum score of 8 (with a minimum score of 2 in each nasal cavity) assessed by the investigator

[0218] 3. Participants who have had at least one of the following at Visit 1 : a. previous nasal surgery for the removal of NP, b. have used at least three consecutive days of systemic corticosteroids in the previous 2 years for the treatment of NP, c. medically unsuitable or intolerant to systemic corticosteroid. 70542W001

[0219] 4. Daily treatment with intranasal corticosteroid (including intranasal liquid steroid wash / douching) for at least the 8 weeks immediately prior to screening (except for those in Japan).

[0220] 5. Severe NP symptoms defined as symptoms of nasal congestion / blockade / obstruction with moderate or severe severity and loss of smell or rhinorrhoea (runny nose) based on clinical assessment by the investigator.

[0221] 6. Symptoms of chronic rhinosinusitis as described by at least two different symptoms for >12 weeks prior to Visit 1, one of which should be either nasal blockage / obstruction / congestion or nasal discharge (anterior / posterior nasal drip), plus facial pain / pressure and / or reduction or loss of smell

[0222] 7. Female participants were eligible if they met the following criteria: a. Were not pregnant or breastfeeding, and was a woman of non-childbearing potential (WONCBP), or a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective, with a failure rate of <1%, from >14 days prior to the first dose of depemokimab until >30 weeks after the last administered dose of depemokimab b. WOCBP must have had a negative highly sensitive serum pregnancy test at Screening Visit 1 and a negative highly sensitive urine pregnancy test within 24 hours before the first dose of depemokimab. c. Contraceptive use by WOCBP must have been consistent with local regulations regarding the methods of contraception for those participating in clinical studies. d. The investigator must have evaluated the potential for contraceptive method failure (e.g., noncompliance, recently initiated in relationship to the first dose of depemokimab). e. The investigator was responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of women with an early undetected pregnancy.

[0223] 8. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this study protocol.

[0224] Participants were excluded from the studies if they met any of the following criteria:

[0225] 1. As a result of medical interview, physical examination, or screening investigation the physician responsible considered the participant unfit for the studies

[0226] 2. Presence of the following concurrent conditions / medical history: 70542W001 a. Cystic fibrosis b. Antrochoanal polyps c. Nasal cavity tumor (malignant or benign) d. Fungal rhinosinusitis e. Severe nasal septal deviation occluding one nostril preventing full assessment of nasal polyps in both nostrils f. A sino-nasal or sinus surgery that has changed the lateral wall structure of the nose making the evaluation of NP score impossible g. Acute sinusitis or upper respiratory tract infection at screening or in two weeks prior to Screening h. Ongoing rhinitis medicamentosa (rebound or chemical induced rhinitis) i. Have had an asthma exacerbation requiring admission to hospital within four weeks of Screening j. Have undergone any intranasal and / or sinus surgery (for example polypectomy, balloon dilatation or nasal stent insertion) within six months prior to Visit 1; nasal biopsy prior to Visit 1 for diagnostic purposes only is excepted k. NP surgery is contraindicated in the opinion of the Investigator l. Eosinophilic Diseases: other conditions that could lead to elevated eosinophils such as hyper-eosinophilic syndromes including (but not limited to) eosinophilic granulomatosis with polyangiitis or eosinophilic esophagitis m. A known, pre-existing parasitic infestation within six months prior to Visit 1 n. A known immunodeficiency (e.g., human immunodeficiency virus), other than that explained by the use of corticosteroids taken as therapy for asthma o. A current malignancy or previous history of cancer in remission for less than 12 months prior to screening (participants that had localised carcinoma of the skin which was resected for cure will not be excluded) p. Liver disease defined as: alanine aminotransferase >2x upper limit of normal (ULN); total bilirubin >1.5x ULN (isolated bilirubin >1.5xllLN was acceptable if bilirubin was fractionated and direct bilirubin <35%); cirrhosis or current unstable liver or biliary disease per investigator assessment (presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, persistent jaundice). Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome, asymptomatic 70542W001 gallstones, and chronic stable hepatitis B or C) were acceptable if participant otherwise met entry criteria. q. Known, pre-existing, clinically significant cardiac, endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment. r. Current diagnosis of vasculitis. Participants with high clinical suspicion of vasculitis at Screening were evaluated and current vasculitis must have been excluded prior to enrolment. s. Hypersensitivity: Participants with allergy / intolerance to the excipients of depemokimab, a monoclonal antibody, or biologic. t. Participants that, according to the investigator's medical judgment, are likely to have had active COVID-19 infection. Participants with known COVID-19 positive contacts within the past 14 days must be excluded for at least 14 days following the exposure during which the participant should remain symptom-free. Reported smell / taste complications from COVID-19 were used as exclusion. u. Exposed to ionising radiation in excess of 10mSv above background over the previous three year period as a result of occupational exposure or previous participation in research studies. Clinically justified therapeutic or diagnostic exposures are not included in this cumulative calculation.

[0227] 3. Previous participation in any study with mepolizumab, reslizumab, or benralizumab and received study intervention (including placebo) within 12 months prior to Visit 1.

[0228] 4. Were enrolled in another clinical study OR had received treatment with an investigational drug within the specified washout periods prior to Visit 1 (this also included investigational formulations of marketed products).

[0229] 5. Had received monoclonal antibodies targeting IL- 5 / 5 receptor (mepolizumab, reslizumab, or benralizumab) within 12 months prior to Visit 1.

[0230] 6. Had received other monoclonal antibodies in the treatment of asthma or CRSwNP (omalizumab or dupilumab) within 130 days prior to Visit 1.

[0231] 7. Had received any other monoclonal antibodies not used for the treatment of asthma or CRSwNP within five half-lives of Visit 1. (with the exception of monoclonal antibodies for the treatment of COVID-19, which are permitted, unless experimental). 70542W001

[0232] 8. Women who are pregnant or lactating or are planning on becoming pregnant during the studies.

[0233] 9. Considered unlikely to survive the duration of the study period or has any rapidly progressing disease or immediate life-threatening illness (e.g., cancer). In addition, any participant who has any other condition (e.g., neurological condition) that is likely to affect respiratory function was not be included in the study.

[0234] 10. ECG Assessment: QTcF >450 msec or QTcF >480 msec for participants with Bundle Branch Block in the 12-lead ECG central over-read from Screening Visit 1.

[0235] 11. A known or suspected history of alcohol or drug abuse within 2 years prior to Screening that in the opinion of the investigator would prevent the participant from completing the study procedures.

[0236] 12. Known evidence of lack of adherence to controller medications and / or ability to follow physician’s recommendations

[0237] 13. Was an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in these studies.

[0238] 14. Any subject who is unable to read and / or would not be able to complete a questionnaire in the opinion of the investigator.

[0239] Randomisation

[0240] Participants were enrolled by study investigators and randomised in a 1:1 ratio into one of the two treatment groups, depemokimab 100 mg SC or placebo (both to be administered with SoC).

[0241] Procedures

[0242] Participants received depemokimab 100 mg SC or placebo once every 26 weeks (at Weeks 0 and 26) via single-use prefilled syringe (assembled in a safety device) for 52 weeks, in addition to SoC. Participant demography was assessed at Screening, with details entered into an electronic case report form (eCRF). Endoscopic NP score was assessed at Screening and Weeks 0, 12, 20, 26, 32, 40, 48 and 52 by trained health care professionals at study sites. All endoscopy images were sent to a central vendor where independent reviewers provided blinded NP scoring, graded based on NP size and recorded as the sum scores for each nostril from 0-8 (higher scores indicate worse outcomes). The severity of individual NP symptoms (including nasal obstruction, rhinorrhoea and loss of smell) were measured by verbal response scale (VRS), administered by participants using an eDiary each morning from screening to the end of 70542W001 the treatment period. Computerised tomography (CT) scans were performed prior to randomisation and at Week 52 (or Week 26 if a participant withdrew early). All CT scans were independently assessed by a central vendor using the Lund Mackay scoring system (0-24). Using an eDiary, participants rated the severity of their condition at each study visit using the Sino-Nasal Outcome Test (SNOT-22) questionnaire on a scale of 0-5 (total score ranges from 0-110; higher scores indicate greater disease impact). Whether a participant was on a waiting list for NP surgery or had received documented surgery was recorded at each study visit. The dose and duration of courses of SCS were recorded in the eCRF. Participants with asthma completed the Asthma Control Questionnaire (ACQ-5) using an eDiary at Weeks 0, 8, 16, 24, 26, 32, 40, 48 and 52. Incidence of AEs and serious AEs (SAEs) were assessed at each study visit. Clinical (liver) chemistry was assessed at Weeks 0, 4, 8, 12, 20, 26, 28, 40 and 52. Pharmacodynamic samples were assessed from haematology samples collected at Weeks 0, 4, 8, 12, 20, 26, 28, 32, 40, 48 and 52. Immunogenicity was assessed from serum samples taken at Weeks 0, 4, 8, 12, 26, 40 and 52 (or the final visit for participants that withdrew early).

[0243] Outcomes

[0244] The coprimary endpoints were change from baseline in: total endoscopic NP score at Week 52, and mean nasal obstruction score (VRS) over Week 49-52. Secondary endpoints were change from baseline in: mean symptom score from rhinorrhoea, and loss of smell (both VRS) over Week 49-52; Lund Mackay CT score, and SNOT-22 total score at Week 52; mean nasal obstructions score (VRS) over Week 21-24, and total endoscopic NP score at Week 26. Pre-specified secondary endpoints for pooled analyses across studies were time to first nasal surgery (actual or on entry onto waiting list)_or disease-modulating medication for CRSwNP up to Week 52; proportion of participants requiring >1 course of SCS or disease-modulating medication for CRSwNP or nasal surgery (actual) during the 52-week treatment period; and change from baseline in ACQ-5 at Week 52 among participants with partially controlled or uncontrolled asthma at baseline (ACQ-5 score >0.75).

[0245] Safety was assessed by monitoring the incidence of adverse events (AEs) and serious AEs (SAEs). Incidence of immunogenicity was measured by the presence of antidrug and neutralising antibodies.

[0246] Statistical analysis

[0247] The sample size for the studies was calculated to achieve sufficient power to observe statistical significance between treatment groups for the coprimary endpoints 70542W001

[0248] (>99% power), and the pooled secondary endpoint of time to first nasal actual surgery or added to waitlist (>90% power). Following testing of coprimary endpoints, statistical analyses of secondary endpoints for each trial were conducted in a closed-testing manner to account for multiplicity using the following pre-defined hierarchy: rhinorrhoea VRS score, loss of smell VRS score, Lund Mackay CT score, SNOT-22 total score, nasal obstructions VRS score (over Week 21-24), and total endoscopic score (at Week 26). A similar multiplicity adjustment was conducted for the pooled analysis, with the pre-defined hierarchy: time to first nasal surgery (actual or added to waitlist), time to first nasal surgery (actual), proportion of participants requiring at least one course of SCS, and change from baseline in ACQ-5 score.

[0249] The coprimary and secondary endpoints for each study, as well as the pooled analysis of ACQ-5, were expressed as the treatment difference between groups in mean change from baseline and analysed using a mixed model repeated measures (MMRM) analysis (except for Lund Mackay CT score). Lund Mackay CT score was analysed using analysis of covariance (ANCOVA). Data for participants who withdrew early was included and assumed to be missing at random (MAR). Subgroup analyses for each of the coprimary endpoints were performed for age, sex, race, region and baseline blood eosinophil category. Subgroup analyses of integrated data from ANCHOR-1 and ANCHOR-2 for each of the coprimary endpoints were conducted for age, sex, baseline body mass index, race, region, number of previous surgeries, baseline blood eosinophil category, patients with asthma, aspirin-exacerbated respiratory disease (AERD), and baseline IgE. The pooled analysis of time to first nasal surgery endpoints were analysed using Cox’s proportional hazards model; missing values were considered censored at random and data are expressed with hazard ratios (HR) and Kaplan-Meier estimates of the proportion of participants requiring surgery over time. The proportion of participants requiring >1 course of SCS was analysed using a logistic regression model; data are expressed as summaries with odds ratios (OR).

[0250] An intercurrent events strategy was employed for all efficacy endpoints, under which the intercurrent events of surgery or initiation of a disease-modulating medication for CRSwNP were incorporated into the definition of the endpoint.

[0251] For participants who underwent nasal polyps surgery or received a diseasemodulating medication, data collected for assessments following the start of surgery or initiating a disease-modulating medication were set to the worst-possible score of the relevant assessment for all continuous endpoints. For time to first nasal surgery, the initiation of a disease-modulating medication was assigned as requiring nasal surgery at the start of the medication. For the proportion of participants requiring >1 course of SCS, 70542W001 nasal surgery or initiation of a disease-modulating medication was assigned as requiring a course of SCS.

[0252] Efficacy endpoints (coprimary and all secondary) were analysed among the full analysis set (FAS) population. All safety analyses were performed on the safety analysis set. Both populations include all randomised participants who took >1 dose of study treatment.

[0253] These trials were registered with ClinicalTrials.gov (ANCHOR-1 : NCT05274750; ANCHOR-2: NCT05281523) Example 2 - Patient characteristics (ANCHOR-2)

[0254] A summary of the patient’s (ANCHOR-2) demographic characteristics, CRSwNP disease history and characteristics, baselines scores, asthma status is provided in Tables 1 , 2, 3 and 4 below.

[0255] Table 1. Summary of demographic characteristics (ANCHOR-2) 70542W001 70542W001 70542W001

[0256] 1] Age is imputed when full date of birth is not provided.

[0257] Table 2. Summary of CRSwNP disease history and characteristics (ANCHOR-2) 70542W001 70542W001 70542W001 70542W001 70542W001

[0258] Note: Percentages are calculated based on small n.

[0259] Note: Baseline eosinophil values of OGI / L are imputed with a value of 0.005GI / L.

[0260] Table 3. Summary of baseline scores for co-primary and secondary endpoints (ANCHOR-2). 70542W001 70542W001

[0261] Table 4. Summary of asthma status, previous exacerbation history and asthma control (ACQ-5) status at baseline (ANCHOR-2). 70542W001 70542W001

[0262] Example 3 - Summary of Results (ANCHOR-2)

[0263] Coprimary endpoints

[0264] For the coprimary endpoints, significant improvements from baseline were observed with depemokimab versus placebo for total endoscopic NP score at Week 52 (treatment difference [95% confidence interval; Cl]: ANCHOR-2, -0.6 [-1.0, -0.2; p=0.004]) and mean nasal obstruction VRS score over Week 49-52 (treatment difference [95% Cl]: ANCHOR-2, -0.25 [-0.46, -0.03; p=0.025]). Secondary endpoints

[0265] The following was observed with depemokimab versus placebo in: mean rhinorrhoea VRS score (treatment difference [95% Cl]: ANCHOR-2, -0.18 [-0.40, 0.05]; p=0.125), and mean loss of smell VRS score (ANCHOR-2, -0.26 [-0.45, -0.07]) over Weeks 49-52; Lund Mackay CT score (ANCHOR-2, -3.2 [-4.4, -2.0]), and SNOT-22 total score (ANCHOR-2, -9.9 [-17.9, -2.0]) at Week 52. As with the coprimary endpoints, improvements were observed with depemokimab over Week 21-24 in mean nasal 70542W001 obstruction VRS score (ANCHOR-2, -0.24 [-0.43, -0.04]), and at Week 26 in total endoscopic NP score (ANCHOR-2, -0.3 [-0.7, 0.0]). Nominal significance (i.e., p<0.05 without multiplicity control) was achieved for mean loss of smell VRS score, Lund Mackay CT score, SNOT-22 total score and mean nasal obstruction VRS score over Week 21-24. Statistical significance was not achieved due to a break in the multiplicity-controlled testing hierarchy.

[0266] Safety

[0267] The proportion of participants reporting AEs during the on- and post-treatment periods was similar between depemokimab (ANCHOR-2: n=98 [76%]) and placebo groups (ANCHOR-2: n=102 [80%]). Incidence of SAEs was also similar between depemokimab (ANCHOR-2: n=6 [5%]) and placebo (ANCHOR-2: n=10 [8%]); No deaths were reported in the depemokimab or placebo groups.

[0268] Subgroups

[0269] This study also demonstrated that further improvements in reducing nasal polyps score and nasal obstruction score can be achieved in specific patient subgroups, for example, the patient may have a baseline peripheral blood eosinophil count of at least 300 cel Is / microl iter, the patient may have comorbid asthma or the patient may have more than two previous nasal polyp surgeries. A forest plot of subgroups for endoscopic nasal polyps score at week 52 is shown in Figure 1. A forest plot of subgroups for mean nasal obstruction score at weeks 49-52 is shown in Figure 2.

[0270] Example 4 - Summary of Results (ANCHOR-1)

[0271] Coprimary endpoints

[0272] For the coprimary endpoints, significant improvements from baseline were observed with depemokimab versus placebo for total endoscopic NP score at Week 52 (treatment difference [95% confidence interval; Cl]: ANCHOR-1, -0.7 [-1.1 , -0.3; p<0.001]) and mean nasal obstruction VRS score over Week 49-52 (treatment difference [95% Cl]: ANCHOR-1 , -0.23 [-0.46, -0.00; p=0.047]).

[0273] Secondary endpoints

[0274] The following was observed with depemokimab versus placebo in: mean rhinorrhoea VRS score (treatment difference [95% Cl]: ANCHOR-1 , -0.22 [(-0.46, 0.02]; p=0.074), and mean loss of smell VRS score (ANCHOR-1 , -0.19 [-0.39, 0.00]) over 70542W001

[0275] Weeks 49-52; Lund Mackay CT score (ANCHOR-1 , -2.0 [-3.3, -0.8]), and SNOT-22 total score (ANCHOR-1 , -6.8 [-15.2, 1.6]) at Week 52. As with the coprimary endpoints, improvements were observed with depemokimab over Week 21-24 in mean nasal obstruction VRS score (ANCHOR-1 , -0.17 [-0.37, 0.03]), and at Week 26 in total endoscopic NP score (ANCHOR-1 , -0.8 [-1.1 , -0.4]). Nominal significance (i.e., p<0.05 without multiplicity control) was achieved for Lund Mackay CT score and Week 26 total endoscopic NP score. Statistical significance was not achieved due to a break in the multiplicity-controlled testing hierarchy.

[0276] Safety

[0277] The proportion of patients who experienced AEs during the on- and post-treatment periods was similar between depemokimab (ANCHOR-1 : 74% [n=106]) and placebo groups (ANCHOR-1 : 79% [n=101]). SAE incidence was also similar between depemokimab (ANCHOR-1 : 3% [n=5]) and placebo (ANCHOR-1 : 5% [n=6]). No deaths were reported in the depemokimab or placebo groups.

[0278] Subgroups

[0279] This study also demonstrated that further improvements in reducing nasal polyps score and nasal obstruction score can be achieved in specific patient subgroups, for example, the patient may have a baseline peripheral blood eosinophil count of at least 300 cells / microliter or the patient may have comorbid asthma. A forest plot of subgroups for endoscopic nasal polyps score at week 52 is shown in Figure 3. A forest plot of subgroups for mean nasal obstruction score at weeks 49-52 is shown in Figure 4.

[0280] Example 5 - Patient characteristics (ANCHOR-1)

[0281] A summary of the patient’s (ANCHOR-1) demographic characteristics, CRSwNP disease history and characteristics, baselines scores, asthma status is provided in Tables 5, 6, 7 and 8 below.

[0282] Table 5. Summary of demographic characteristics (ANCHOR-1) 70542W001 70542W001 70542W001 70542W001

[0283] 1] Age is imputed when full date of birth is not provided.

[0284] Table 6. Summary of CRSwNP disease history and characteristics (ANCHOR-1) 70542W001 70542W001 70542W001 70542W001 70542W001

[0285] Note: Baseline eosinophil values of OGI / L are imputed with a value of 0.005GI / L. Table 7. Summary of baseline scores for co-primary and secondary endpoints

[0286] (ANCHOR-1) 70542W001 70542W001 70542W001

[0287] Table 8. Summary of asthma status, previous exacerbation history and asthma control (ACQ-5) status at baseline (ANCHOR-1). 70542W001 70542W001

[0288] Example 6 - Integrated and pooled analysis

[0289] Depemokimab treatment significantly improved total endoscopic NPS change from baseline at Week 52 (treatment difference [95% confidence interval; Cl]: integrated, -0.7 [- 0.9, -0.4; p<0.001]) and mean nasal obstruction VRS score change from baseline over

[0290] Weeks 49-52 (treatment difference [95% Cl]: integrated, -0.24 [-0.39, -0.08; p=0.003]), compared with placebo. Integrated p values are nominal.

[0291] The treatment difference (95% Cl) in mean rhinorrhoea VRS score for depemokimab versus placebo was -0.19 (-0.36, -0.03; p=0.021) for the integrated analysis. Treatment difference (depemokimab versus placebo) for mean loss of smell VRS score over Weeks 49-52 was -0.22 (-0.35, -0.08; p=0.002; integrated); for Lund Mackay CT score at Week 52, it was -2.5 (-3.4, -1.7; p<0.001 ; integrated); and for SNOT-22 total score at Week 52, treatment difference was -8.1 (-13.9, -2.3; p=0.007; integrated). The treatment difference in change from baseline in mean nasal obstruction VRS score over Weeks 21-24 was -0.20 (-0.34, -0.06; p=0.005; integrated). Treatment difference in total endoscopic NPS at Week 26 was -0.5 (-0.8, -0.3; p<0.001; integrated). Integrated p values are nominal.

[0292] For the pooled secondary endpoints, the proportion of patients meeting the CRSwNP surgery (actual or entry on waiting list, up to Week 52) endpoint was 16% 70542W001

[0293] (n=44) and 22% (n=56) for depemokimab and placebo groups, respectively, resulting in a percentage reduction in risk (depemokimab versus placebo) of 27% (hazard ratio; HR [95% Cl]: 0.735 [0.495, 1.092]; p=0.128). Since statistical significance was not achieved for this endpoint, the remaining pooled secondary efficacy endpoints were not multiplicity- adjusted. Depemokimab demonstrated a greater risk reduction versus placebo among patients with asthma compared with those without, and patients with blood eosinophil count >300 cells / pL versus <300 cells / pL (post hoc analyses). For risk of CRSwNP surgery (actual only), 12% (n=33) and 17% (n=43) of patients experienced the endpoint in the depemokimab and placebo groups, respectively, resulting in a percentage reduction in risk of 29% (HR: 0.713 [0.453, 1.124]). During the 52-week treatment period 26% (n=72) and 36% (n=92) of patients in the depemokimab and placebo groups, respectively, required >1 course of SCS for CRSwNP (depemokimab versus placebo odds ratio; OR [95% Cl]: 0.58 [0.40, 0.86]). Among patients with partially or not well controlled asthma at baseline (ACQ-5 score >0.75: depemokimab, n=104; placebo, n=102), the treatment difference (95% Cl; depemokimab versus placebo) in change from baseline in ACQ-5 score at Week 52 was -0.75 (-1.26, -0.25).

[0294] The proportion of patients no longer having a need for CRSwNP surgery at Week 52 in the pooled analysis was 24% (n=65) and 14% (n=35) in the depemokimab and placebo groups, respectively (OR [95% Cl]: 2.17 [1.33, 3.52]; p=0.002). The proportion of patients who remained SCS-free (regardless of indication) was 70% (n=190) in the depemokimab group and 59% (n=151) in the placebo group.

[0295] Integrated subgroup analyses are shown in Figures 5 and 6.

[0296] 70542W001

[0297] SEQUENCE LISTINGS

[0298] SEQ ID NO: 1 - Full length heavy chain

[0299] QVTLRESGPALVKPTQTLTLTCTVSGFSLTGSSVHWVRQPPGKGLEWLGVIWASGGTD

[0300] YNSALMSRLSISKDTSRNQWLTMTNMDPVDTATYYCARDPPSGLLRLDYWGRGTLVTV

[0301] SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL

[0302] QSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEL

[0303] LGGPSVFLFPPKPKDTLYITREPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPRE

[0304] EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

[0305] SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0306] SEQ ID NO: 2 - Full length light chain

[0307] DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGASTR

[0308] ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNVHSFPFTFGGGTKLEIKRTVAAPS

[0309] VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY

[0310] SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0311] SEQ ID NO: 3 - VH sequence

[0312] QVTLRESGPALVKPTQTLTLTCTVSGFSLTGSSVHWVRQPPGKGLEWLGVIWASGGTD

[0313] YNSALMSRLSISKDTSRNQVVLTMTNMDPVDTATYYCARDPPSGLLRLDYWGRGTLVTV SS

[0314] SEQ ID NO: 4 - VL sequence

[0315] DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGASTR

[0316] ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNVHSFPFTFGGGTKLEIKR

[0317] SEQ ID NO: 5 - CDRH1

[0318] GSSVH

[0319] SEQ ID NO: 6 - CDRH2

[0320] VIWASGGTDYNSALMS

[0321] SEQ ID NO: 7 - CDRH3

[0322] DPPSGLLRLDY

[0323] SEQ ID NO: 8 - CDRL1 70542W001

[0324] KSSQSLLNSGNQKNYLA

[0325] SEQ ID NO: 9 - CDRL2

[0326] GASTRES

[0327] SEQ ID NO: 10 - CDRL3

[0328] QNVHSFPFT

[0329] SEQ ID NO: 11 - Human IL-5 (mature protein)

[0330] IPTEIPTSALVKETLALLSTHRTLLIANETLRIPVPVHKNHQLCTEEIFQGIGTLESQTVQGG

[0331] TVERLFKN LSLI KKYI DGQKKKCGEERRRVNQFLDYLQEFLGVM NTEWI I ES

[0332] SEQ ID NO: 12 - Human IL-5 Receptor Subunit Alpha Isoform 1 (mature protein)

[0333] DLLPDEKISLLPPVNFTIKVTGLAQVLLQWKPNPDQEQRNVNLEYQVKINAPKEDDYETRI

[0334] TESKCVTILHKGFSASVRTILQNDHSLLASSWASAELHAPPGSPGTSIVNLTCTTNTTEDN

[0335] YSRLRSYQVSLHCTWLVGTDAPEDTQYFLYYRYGSWTEECQEYSKDTLGRNIACWFPR

[0336] TFILSKGRDWLAVLVNGSSKHSAIRPFDQLFALHAIDQINPPLNVTAEIEGTRLSIQWEKPV

[0337] SAFPIHCFDYEVKIHNTRNGYLQIEKLMTNAFISIIDDLSKYDVQVRAAVSSMCREAGLWS

[0338] EWSQPIYVGNDEHKPLREWFVIVIMATICFILLILSLICKICHLWIKLFPPIPAPKSNIKDLFVT

[0339] TNYEKAGSSETEIEVICYIEKPGVETLEDSVF

[0340] SEQ ID NO: 13 - Heavy chain FR4 sequence

[0341] WGRGTLVTVSS

Claims

70542WQ01CLAIMS1. An antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s nasal polyps score is reduced.

2. The antigen binding protein for use according to claim 1, wherein the patient’s nasal polyps score is reduced by at least about 0.4, at least about 0.5, at least about 0.55, at least about 0.6, at least about 0.65, at least about 0.7, at least about 0.75, at least about 0.8, at least about 0.85, at least about 0.9, at least about 0.95, or at least about 1.0.

3. An antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10 for use in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in a patient, wherein the patient’s nasal obstruction score is reduced.

4. The antigen binding protein for use according to claim 3, wherein the patient’s nasal obstruction score is reduced by at least about 0.2, at least about 0.25, at least about 0.3, at least about 0.35, at least about 0.4, at least about 0.45, or at least about 0.5.

5. The antigen binding protein for use according to any one of claims 1-4, wherein the heavy chain variable region sequence comprises the amino acid sequence shown in SEQ ID NO: 3; and the light chain variable region sequence comprises the amino acid sequence shown in SEQ ID NO: 4.

6. The antigen binding protein for use according to any one of claims 1-5, wherein the antigen binding protein is an antibody.70542WQ017. The antigen binding protein for use according to claim 6, wherein the antibody comprises an IgG 1 Fc domain.

8. The antigen binding protein for use according to claim 7, wherein the IgG 1 Fc domain comprises a tyrosine residue at position 252, a threonine residue at position 254 and a glutamic acid residue at position 256.

9. The antigen binding protein for use according to any one of claims 1-8, wherein the antigen binding protein comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a light chain having the amino acid sequence shown in SEQ ID NO: 2.

10. The antigen binding protein for use according to any one of claims 1-9, wherein the antigen binding protein is depemokimab.

11. The antigen binding protein for use according to any one of claims 1-10, wherein the patient has inadequately controlled CRSwNP.

12. The antigen binding protein for use according to any one of claims 1-11, wherein the patient has a baseline peripheral blood eosinophil count of at least 300 cells / microliter, optionally at least 560 cells / microliter.

13. The antigen binding protein for use according to any one of claims 1-11, wherein the number of previous nasal polyp surgeries for the patient is 1, 2, or more than 2.

14. The antigen binding protein for use according to claim 13, wherein the number of previous nasal polyp surgeries for the patient is more than 2.

15. The antigen binding protein for use according to any one of claims 1-11, wherein the patient has comorbid asthma.

16. The antigen binding protein for use according to any one of claims 1-15, wherein an effective amount of antigen binding protein is to be administered to the patient.

17. The antigen binding protein for use according to claim 16, wherein the antigen binding protein is to be administered to the patient at a dose of 100 mg once every 26 weeks or once every 6 months.

18. The antigen binding protein for use or the method according to claim 16 or 17, wherein the antigen binding protein is to be administered to the patient subcutaneously.70542WQ0119. A method of treating CRSwNP comprising administering to a patient an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10, wherein the patient’s nasal polyps score is reduced.

20. The method according to claim 19, wherein the patient’s nasal polyps score is reduced by at least about 0.4, at least about 0.5, at least about 0.55, at least about 0.6, at least about 0.65, at least about 0.7, at least about 0.75, at least about 0.8, at least about 0.85, at least about 0.9, at least about 0.95, or at least about 1.0.

21. A method of treating CRSwNP comprising administering to a patient an antigen binding protein which binds to human IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10, wherein the patient’s nasal obstruction score is reduced.

22. The method according to claim 21, wherein the patient’s nasal obstruction score is reduced by at least about 0.2, at least about 0.25, at least about 0.3, at least about 0.35, at least about 0.4, at least about 0.45, or at least about 0.5.

Images