CN118524849A

CN118524849A - Interleukin 5 binding protein dosing regimen for treatment of polyangiitis, eosinophilia syndrome, chronic sinusitis eosinophilia syndrome with nasal polyp (CRSWNP) or chronic sinusitis without nasal polyp (CRSSNP)

Info

Publication number: CN118524849A
Application number: CN202280079630.5A
Authority: CN
Inventors: D·J·奥斯汀; A·C·伯格斯; N·P·伯德; M·A·蒙克; I·J·普利奎; M·A·舒曼; C·泽克迟
Original assignee: GlaxoSmithKline Intellectual Property Development Ltd
Current assignee: GlaxoSmithKline Intellectual Property Development Ltd
Priority date: 2021-12-03
Filing date: 2022-12-01
Publication date: 2024-08-20

Abstract

The present invention relates to pharmaceutical compositions comprising from about 100mg to about 300mg of an antigen binding protein that binds to IL-5. The compositions and antigen binding proteins of the present disclosure are useful for treating IL-5 mediated diseases, such as EGPA, HES, CRSsNP and CRSwNP, and may be administered about once every 6 months.

Description

Interleukin 5 binding protein dosing regimen for treatment of polyangiitis, eosinophilia syndrome, chronic sinusitis eosinophilia syndrome with nasal polyp (CRSWNP) or chronic sinusitis without nasal polyp (CRSSNP)

Technical Field

The present invention relates to pharmaceutical compositions comprising antigen binding proteins, such as antibodies, that bind to IL-5 at novel dosages and dosing regimens. In particular, the invention relates to the use of antigen binding proteins (e.g., antibodies) that bind to IL-5 or pharmaceutical compositions comprising the antigen binding proteins to treat IL-5 mediated diseases at novel dosages and dosing schedules. The invention also relates to antigen binding proteins or pharmaceutical compositions comprising the antigen binding proteins for use in the treatment of IL-5 mediated diseases by the novel dosages or dosing regimens. The invention also relates to methods of treating IL-5 mediated diseases by administering an antigen binding protein (e.g., an antibody) that binds to IL-5 or a pharmaceutical composition comprising the antigen binding protein at novel doses and dosing regimens.

Background

Asthma is a chronic heterogeneous pulmonary disease characterized by inflammation, airway narrowing and reversible airway obstruction. Patients with uncontrolled asthma may suffer from persistent symptoms and acute episodes of the disease. Attacks in particular incapacitate, often forcing the patient to be treated with oral/systemic corticosteroids. The frequency of asthma attacks appears to be closely related to eosinophilic airway inflammation (FitzGerald & Gibson, pre. Thorax.2006; 61:992-999).

Persistent eosinophilic inflammation is a hallmark of more than 50% of patients with severe asthma (Chung et al Eur. Respir. J.2014; 43:343-73). Several monoclonal antibodies targeting eosinophilic inflammation have obtained marketing approval for asthma with eosinophilic phenotype, including 3 targeting interleukin 5 (IL-5) or its receptor (IL-5R): melizumab (Nucala), riluzumab (Cinqair) and present riluzumab (Fasenra). All three drugs used blood eosinophils as biomarkers to predict whether patients respond to treatment, and the results showed that they could reduce asthma attacks in eosinophilic-phenotype asthmatics and improve lung function and health-related quality of life.

IL-5 is a secreted protein. IL-5 plays a role in many different diseases, such as asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, subaeosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic polyangiitis (EGPA), eosinophilic syndrome (HES), nasal polyp disease (NP), vesicular pemphigus, eosinophilic esophagitis, atopic dermatitis, moderate and severe atopic dermatitis and chronic sinusitis (CRSwNP) with nasal polyps, inflammatory Bowel Disease (IBD), allergic bronchopulmonary aspergillosis (ABPA) and chronic sinusitis (CRSsNP) without nasal polyps. These serious diseases affect hundreds of millions of people worldwide.

In view of the foregoing, there is a clear need for more effective asthma treatments. In particular, for IL-5 mediated diseases, such as eosinophilic asthma, there is a need for effective therapies with reduced dose profiles.

Accordingly, the present invention provides novel doses, dosing regimens of such compositions and methods of treatment for IL-5 mediated diseases, such as asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, subaeosinophilic asthma and Inflammatory Bowel Disease (IBD), allergic bronchopulmonary aspergillosis (ABPA), eosinophilic polyangiitis (EGPA), eosinophilic syndrome (HES), nasal Polyposis (NP), chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps (CRSsNP) and dermatitis, the novel doses, dosing regimens of such compositions and methods of treatment being both effective and having a reduced dose profile.

Summary of The Invention

In a first aspect, the invention provides a pharmaceutical composition comprising from about 100mg to about 300mg of an antigen binding protein that binds IL-5 and a pharmaceutically acceptable excipient, wherein the antigen binding protein comprises a heavy chain variable region having the CDRH1 amino acid sequence set forth in SEQ ID No. 5, the CDRH2 amino acid sequence set forth in SEQ ID No. 6, and the CDRH3 amino acid sequence set forth 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, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region.

In a further aspect, the invention provides an antigen binding protein that binds to IL-5, comprising a heavy chain variable region having the amino acid sequence of CDRH1 shown in SEQ ID NO.5, the amino acid sequence of CDRH2 shown in SEQ ID NO. 6, and the amino acid sequence of CDRH3 shown in SEQ ID NO. 7; and a light chain variable region having the CDRL1 amino acid sequence set forth in SEQ ID No. 8, the CDRL2 amino acid sequence set forth in SEQ ID No. 9, and the CDRL3 amino acid sequence set forth in SEQ ID No.10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region for use in treating IL-5 mediated diseases by administration to a subject at a dose of about 100mg to about 300mg at a frequency of about once every 6 months.

In a further aspect, the invention provides a pharmaceutical composition for use in treating an IL-5 mediated disease, wherein the composition comprises from about 100mg to about 300mg of an antigen binding protein that binds to IL-5, wherein the antigen binding protein comprises a heavy chain variable region having a CDRH1 amino acid sequence as set forth in SEQ ID No. 5, a CDRH2 amino acid sequence as set forth in SEQ ID No. 6, and a CDRH3 amino acid sequence as set forth in SEQ ID No. 7; and a light chain variable region having the CDRL1 amino acid sequence set forth in SEQ ID No. 8, the CDRL2 amino acid sequence set forth in SEQ ID No. 9, and the CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region, and wherein the pharmaceutical composition is for administration to a subject about once every 6 months.

In a further aspect, the invention provides a method of treating an IL-5 mediated disease comprising administering to a subject in need thereof an IL-5 binding antigen binding protein comprising a heavy chain variable region having the amino acid sequence of CDRH1 shown in SEQ ID NO. 5, the amino acid sequence of CDRH2 shown in SEQ ID NO. 6 and the amino acid sequence of CDRH3 shown in SEQ ID NO. 7 in an amount of about 100mg to about 300mg, about once every 6 months; 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, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region.

In a further aspect, the invention provides a method of treating an IL-5 mediated disease in a subject comprising the steps of:

a) Identifying a subject having a disease selected from the group consisting of: asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, subaeosinophilic asthma; and

B) About 100mg to about 300mg of an antigen binding protein that binds to IL-5 comprising a heavy chain variable region having the amino acid sequence CDRH1 shown in SEQ ID No. 5, the amino acid sequence CDRH2 shown in SEQ ID No. 6, and the amino acid sequence CDRH3 shown in SEQ ID No. 7, administered to a subject about once every 6 months; and a light chain variable region having a CDRL1 amino acid sequence shown in SEQ ID No. 8, a CDRL2 amino acid sequence shown in SEQ ID No. 9, and a CDRL3 amino acid sequence shown in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region;

Thereby treating the disease in the subject.

In a further aspect, the invention provides a method of reducing absolute blood eosinophil count in a subject comprising the steps of:

a) Identifying a subject having a condition selected from the group consisting of: asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, subaeosinophilic asthma; and

B) Administering to the subject an antigen binding protein that binds to IL-5 comprising a heavy chain variable region having a CDRH1 amino acid sequence as set forth in SEQ ID No. 5, a CDRH2 amino acid sequence as set forth in SEQ ID No. 6, and a CDRH3 amino acid sequence as set forth in SEQ ID No. 7, in an amount of about 100mg to about 300mg, about once every 6 months; and a light chain variable region having a CDRL1 amino acid sequence shown in SEQ ID No. 8, a CDRL2 amino acid sequence shown in SEQ ID No. 9, and a CDRL3 amino acid sequence shown in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region;

Thereby reducing the absolute blood eosinophil count of the subject.

In a further aspect, the present invention provides a prefilled syringe comprising:

a) About 100mg to about 300mg of an antigen binding protein that binds to IL-5, the antigen binding protein comprising a heavy chain variable region having a CDRH1 amino acid sequence as set forth in SEQ ID No. 5, a CDRH2 amino acid sequence as set forth in SEQ ID No. 6, and a CDRH3 amino acid sequence as set forth in SEQ ID No. 7; and a light chain variable region having a CDRL1 amino acid sequence shown in SEQ ID No. 8, a CDRL2 amino acid sequence shown in SEQ ID No. 9, and a CDRL3 amino acid sequence shown in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region; and

B) Pharmaceutically acceptable excipients.

In some embodiments, disclosed herein are compositions comprising about 100mg of an antigen binding protein disclosed herein. In some embodiments, the method comprises administering about 100mg of the antigen binding protein.

In some embodiments, the heavy chain variable region of the antigen binding protein further comprises a heavy chain FR4 amino acid sequence shown as SEQ ID NO. 19.

In some embodiments, the heavy chain Fc domain is an IgG1 Fc domain. In a further embodiment, the heavy chain Fc domain is a human IgG1 Fc domain.

In some embodiments, 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.

In some embodiments, the antigen binding protein is an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO. 1 and a light chain having the amino acid sequence set forth in SEQ ID NO. 2.

In some embodiments, the composition is for subcutaneous administration.

In some embodiments, the composition is administered once every 6 months. In some embodiments, the composition is administered once every 26 weeks (Q26W).

In some embodiments, the composition is administered to a human subject.

In some embodiments, the absolute blood eosinophil count of the subject (prior to treatment) is greater than or equal to 150 cells per μl. In further embodiments, the absolute blood eosinophil count of the subject (prior to treatment) is greater than or equal to 200 cells per μl.

In further embodiments, the subject may also have a high sensitivity C-reactive protein (hsCRP) <10mg L ^-1.

In some embodiments, the composition comprises an aqueous liquid formulation having a pH of about 6.0, comprising an antigen binding protein and histidine, trehalose, arginine, EDTA, and/or polysorbate 80. In some embodiments, the composition comprises an aqueous liquid formulation having a pH of about 6.0, comprising an antigen binding protein and histidine, trehalose, arginine, EDTA, and polysorbate 80. In a further embodiment, the composition comprises an aqueous liquid formulation having a pH of about 6.0, comprising an antigen binding protein and about 20mM histidine, about 180mM trehalose, about 40mM arginine, about 0.05mM EDTA and about 0.02% polysorbate 80 by weight volume.

In some embodiments, the IL-5 mediated disease is asthma. In a further embodiment, the asthma is selected from the group consisting of: mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, eosinophilic asthma and subaeosinophilic asthma. Preferably, the asthma is asthma having an eosinophilic phenotype (i.e. mild eosinophilic asthma, moderate eosinophilic asthma or severe eosinophilic asthma, in particular severe eosinophilic asthma). In a further embodiment, the asthma is severe asthma.

In some embodiments, the IL-5 mediated disease is selected from the group consisting of: inflammatory Bowel Disease (IBD), allergic bronchopulmonary aspergillosis (ABPA), eosinophilic polyangiitis (EGPA), eosinophilic syndrome (HES), nasal Polyposis (NP), chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps (CRSsNP), and dermatitis.

Drawings

Fig. 1: graphical summary of study design. The planned single increment Subcutaneous (SC) doses of 28Y042-7F11-1 were 2, 10, 30, 100 and 300mg. The actual dose level exceeding the 2mg starting dose was confirmed from the emerging data. The planned queue size is displayed; if necessary, additional participants will be added to the cohort to characterize the pharmacokinetics or pharmacodynamics of 28Y042-7F 11-1. In each cohort, participants were randomly assigned to receive 28Y042-7F11-1 or placebo at a 3:1 ratio. If deemed necessary, an additional cohort of up to 12 participants will be added to test additional dose levels or repeat the dose levels that have been tested; but the dose must not exceed 300mg. The planned sample size was 48 participants; the maximum sample size allowed is n=72 participants (not including substitutes for the participants who withdraw ahead).

Fig. 2: geometric mean (and 95% CI) of Blood Eosinophil Count (BEC) data (GI/L). Annotation: only when at least 3 participants participated in the statistical analysis will 95% Confidence Intervals (CIs) be displayed.

Fig. 3: the geometric mean (and 95% ci) of the ratio to baseline blood eosinophil data was adjusted. The log-transformed data was analyzed using MMRM model, where treatment, planning time points, and classification effects of treatment interactions with planning time points were fixed, and log baseline blood eosinophil count and continuous covariates of log baseline blood eosinophil count interactions with planning time points were fixed. The Toeplitz covariance structure was used. Annotation: the reference line with ratio = 0.22 shows a 78% reduction from baseline, as observed in the topolimab MUSCA trial at stage 3 b. The reference line with ratio = 0.16 indicates a 84% reduction from baseline, as observed in the meperiab MENSA critical phase 3 trial.

Fig. 4: geometric mean (and 95% CI) of serum total IL-5 data (ng/L). Values below the lower limit of quantitation (llq=16.38 ng/L) are attributed to LLQ/2.LLQ is shown by a horizontal reference line. Annotation: only when at least 3 participants participated in the statistics and at least one value was not below the lower limit of quantification will 95% ci be displayed.

Detailed Description

Definition of the definition

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.

The term "antigen binding polypeptide" as used herein refers to antibodies, antibody fragments, and other protein constructs capable of binding an antigen.

The term "antibody" is used herein in the broadest sense to refer to molecules having an immunoglobulin-like domain (e.g., igG, igM, igA, igD or IgE), including monoclonal, recombinant, polyclonal, chimeric, human, humanized, multispecific antibodies, including bispecific antibodies and heteroconjugate antibodies; single variable domains (e.g., domain Antibodies (DABs)), antigen-binding antibody fragments, fab, F (ab') ₂, fv, disulfide-linked Fv, single chain Fv, disulfide-linked scFv, diabodies, TANDABS, and the like, as well as modified versions of any of the foregoing (see Holliger and Hudson, nature Biotechnology,2005,Vol 23,No.9,1126-1136 for a summary of alternative "antibody" forms). Alternative antibody formats are also contemplated and include alternative scaffolds, wherein one or more CDRs of an antigen binding protein may be arranged onto a suitable non-immunoglobulin scaffold or scaffold, such as an affibody, spA scaffold, LDL receptor class a domain, avimer or EGF domain.

Antibodies can be derived from rat, mouse, primate (e.g., cynomolgus monkey, old world monkey, or large ape), human, or other sources, such as nucleic acids encoding antibody molecules generated using molecular biology techniques.

Antibodies may comprise constant regions, which may be of any isotype or subclass. The constant region may be an IgG isotype, e.g., igG ₁、IgG₂、IgG₃、IgG₄ or a variant thereof. The antigen binding protein constant region may be IgG ₁.

The antigen binding protein may comprise one or more modifications selected from mutated constant domains such that the antibody has enhanced effector function/ADCC and/or complement activation.

The term "antibody variant" as used herein refers to an antibody that differs from a parent antibody for the following reasons: at least one amino acid modification (e.g., due to having different amino acid side chains), post-translational modification, or other modification on at least one heavy chain, light chain, or combination of these, which results in a structural change (e.g., different amino acid side chains, different post-translational modification, or other modification) relative to the parent antibody. Structural changes may be determined directly by a variety of methods well known in the art, such as LC-MS, direct sequencing, or indirectly via isoelectric focusing, among others. Such methods are well known to those of ordinary skill in the art.

In particular, references herein to "antigen binding proteins of the invention" refer to antigen binding proteins that bind to IL-5, and any variant or particular embodiment of such antigen binding proteins described herein, comprising a heavy chain variable region having a CDRH1 amino acid sequence as set forth in SEQ ID No. 5, a CDRH2 amino acid sequence as set forth in SEQ ID No. 6, and a CDRH3 amino acid sequence as set forth 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, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region. Amino acid numbering in the heavy chain Fc domain (i.e., tyrosine residue at position 252, threonine residue at position 254, and glutamic acid residue at position 256) is derived using EU numbering as follows: EDELMAN ET al (1969) Proc.Natl.Acad.USA,63:78-85[ PMID:5257969].

The antigen binding proteins of the invention may be used in any pharmaceutical composition, dosing regimen or method of treatment of the invention. The antigen binding proteins of the invention may be antibodies, such as IgG ₁ antibodies.

The term "about" or "approximately" may mean within an acceptable error range for a particular value as determined by one of skill in the art, which will depend in part on how the value is measured or determined, e.g., limitations of the measurement system.

For example, "about" may mean plus or minus 10%, according to practice in the art. Or "about" may refer to a range of plus or minus 20%, plus or minus 10%, plus or minus 5%, or plus or minus 1% of a given value. Or in particular for biological systems or processes, the term may mean within an order of magnitude, within a factor of 5, or within a factor of 2. When a particular value is described in the application and claims, unless otherwise indicated, the term "about" shall be assumed to mean within an acceptable error range for the particular value. Further, when numerical ranges and/or subranges are provided, the ranges and/or subranges can include the endpoints of the ranges and/or subranges. 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. The term "interleukin-5 receptor" or "IL-5R" as used herein includes human IL-5 receptor subunit alpha isoform 1, which comprises the amino acid sequence shown in SEQ ID NO. 12.

The term "specifically binds" as used herein in relation to an antigen binding protein refers to binding of the antigen binding protein to a target antigen and to discrete domains or discrete amino acid sequences within the target antigen, while not binding or binding is not significant to other (e.g., unrelated) proteins. However, the term does not exclude the fact that antigen binding proteins may also cross-react with closely related molecules (e.g. molecules having a high degree of sequence identity or from another genus or species). The antigen binding proteins described herein have a binding affinity for human IL-5 that is at least 2, 5, 10, 50, 100, or 1000-fold higher than the binding affinity for a closely related molecule.

The binding affinity (K _D) for the antigen binding protein-target antigen interaction may be 1mM or less, 100nM or less, 10nM or less, 2nM or less or 1nM or less. Or K _D may be between 5 and 10 nM; or between 1 and 2 nM. K _D can be between 1pM and 500 pM; or between 500pM and 1 nM. The binding affinity of antigen binding proteins is determined by the binding constant (K _a) and the dissociation constant (K _d) (K _D＝K_d/K_a). Binding affinity can be measured by BIACORE ^TM, for example, by capturing the test antibody to the protein a coated sensor surface and allowing the target antigen to flow over the surface. Alternatively, binding affinity can be measured by FORTEBIO, for example, capturing the test antibody receptor onto a protein a coated needle and flowing the target antigen over the surface.

K _d can be 1x10 ^-3 Ms^-1 or less, 1x10 ^-4 Ms^-1 or less, or 1x10 ^-5 Ms^-1 or less. K _d can be between 1x10 ^-5 Ms^-1 and 1x10 ^-4 Ms^-1; or between 1x10 ^-4 Ms^- and 1x10 ^-3Ms^-1. Slower K _d may result in slower dissociation of the antigen binding protein-target antigen complex and improved neutralization of the target antigen.

The term "specific antigen binding activity" as used herein refers to antigen binding activity as measured by Surface Plasmon Resonance (SPR). IL-5 specific binding activity can be determined by SPR using a BIACORE ^TM instrument, e.g., in binding mode. Which is the binding activity divided by the total protein (e.g., 28Y042-7F 11-1) content in the sample.

The term "FcRn binding activity" as used herein refers to neonatal Fc (FcRn) receptor binding activity as measured by Surface Plasmon Resonance (SPR). FcRn binding can be measured using the BIACORE ^TM instrument. Which is the binding activity to the FcRn receptor divided by the total protein concentration in the sample.

The SPR method of specific antigen binding and FcRn binding uses a reference standard of 28Y042-7F 11-1. The 28Y042-7F11-1 reference standard may be used for assays to obtain system suitability and sample comparability data to ensure proper performance of the method. The reference standard may allow a calibration curve to be established and the concentration of the sample to be interpolated from the curve.

By "isolated" is meant that a molecule (e.g., an antigen binding protein) is removed from its environment in which it may exist in nature. For example, the molecule may be purified from substances with which it normally co-exists in nature. For example, the mass of the molecules in the sample may be 95% of the total mass.

The terms "VH" and "VL" as used herein refer to the heavy chain variable region and the light chain variable region, respectively, of an antigen binding protein.

"CDR" is defined as the complementarity determining region amino acid sequence of an antigen binding protein. These are hypervariable regions of immunoglobulin heavy and light chains. The variable portion of an immunoglobulin has three heavy chain CDRs (or CDR regions) and three light chain CDRs (or CDR regions). Thus, as used herein, "CDR" 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 at least one CDR is CDRH3. The framework regions follow each of these CDR regions. One of ordinary skill in the art can readily identify acceptable heavy and light chain variable region framework 1, framework 2, and framework 3 regions. One of ordinary skill in the art can also readily identify acceptable heavy chain constant regions (including hinge regions) and light chain constant regions. Those of ordinary skill in the art can likewise readily recognize acceptable antibody isoforms.

Throughout this specification, amino acid residues in the variable domain sequence and the full-length antibody sequence are numbered according to the Kabat numbering convention. Similarly, the terms "CDR", "CDRL1", "CDRL2", "CDRL3", "CDRH1", "CDRH2", "CDRH3" as used in this specification follow the Kabat numbering convention.

It will be apparent to those skilled in the art that alternative numbering rules exist for amino acid residues in variable domain sequences and full length antibody sequences. CDR sequences also have alternative numbering rules, such as those listed according to Chothia numbering rules. The structure and protein folding of an antibody may mean that other residues are considered part of the CDR sequence, and will be understood by those skilled in the art.

Other CDR sequence numbering rules available to those skilled in the art include "AbM" (university of bas) and "contact" (university of london) methods. The minimum overlap region may be determined using at least two of the Kabat, chothia, abM and contact methods to provide a "minimum binding unit". The minimal binding unit may be a sub-portion of a CDR.

The term "asthma" as used herein refers to inflammatory diseases of the respiratory tract characterized by reversible airflow obstruction and bronchospasm. Common symptoms include wheezing, coughing, chest distress, and dyspnea. Asthma is a heterogeneous disease, often characterized by chronic airway inflammation. It is defined as a history of respiratory symptoms such as wheezing, dyspnea, chest distress, and cough, which vary in time and intensity, with variable expiratory airflow limitation.

In the method of the present invention, the diagnosis of asthma in a subject may be made according to the guidelines provided by the global asthma initiative (GINA) global asthma management and prevention strategy (2016 update) file. Those of ordinary skill in the art will be familiar with the GINA diagnostic flow chart for clinical practice shown below and diagnostic criteria for adult, adolescent and 6-11 year old childhood asthma (table 1) as well as other aspects of the guidance (e.g., for pregnant women, etc.). See also tables 2 and 3.

Table 1.

Table 2.

Table 3.

In the methods of the invention, "asthma" may be "mild asthma", "moderate asthma" or "severe asthma". In the method of the present invention, the severity of asthma may be assessed according to GINA guidelines. In particular, asthma severity can be assessed retrospectively from the level of treatment required to control symptoms and exacerbations. For example, an assessment may be made several months after the patient receives the control therapy and, where appropriate, attempt to stop the therapy to find the patient's lowest effective therapeutic level. The severity of asthma is not static and may vary over months or years.

When patients receive routine control treatments for months, the severity of asthma can be assessed:

"mild asthma" means asthma which can be well controlled by treatment at step 1 or step 2 (see figure 9 of WO 2018215964), i.e. by on-demand alleviation of drugs alone or by low intensity control treatments, such as low doses of ICS, leukotriene receptor antagonists or chromones.

"Moderate asthma" means asthma which can be well controlled by a 3 rd step treatment (see figure 9 of WO 2018215964), e.g. low dose ICS/LABA.

"Severe asthma" refers to asthma requiring treatment at step 4 or step 5 (see figure 9 of WO 2018215964), e.g. high dose ICS/LABA, to prevent it from becoming "uncontrolled", or asthma which is "uncontrolled" despite such treatment. While many patients with uncontrolled asthma may be refractory to inadequate or inadequate treatment, continued compliance problems or complications (e.g., chronic sinusitis or obesity), the european respiratory society/the american thoracic society's severe asthma monograph deems that the definition of "severe asthma" should be retained for refractory asthma patients and patients with incomplete response to treatment with complications. Table 4 may also be referenced during the evaluation of asthma severity.

Table 4.

In the methods of the invention, "asthma" may be "mild eosinophilic asthma", "moderate eosinophilic asthma" or "severe eosinophilic asthma".

"Mild eosinophilic asthma" is mild asthma with eosinophilic phenotype. For example, a subject with mild eosinophilic asthma may have mild asthma, and blood eosinophils greater than or equal to 150 eosinophils per μl of blood in the past 12 months, blood eosinophils greater than or equal to 200 eosinophils per μl of blood in the past 12 months, blood eosinophils greater than or equal to 300 eosinophils per μl of blood in the past 12 months, or blood eosinophils greater than or equal to 350 eosinophils per μl of blood in the past 12 months.

"Moderate eosinophilic asthma" is moderate asthma with eosinophilic phenotype. For example, a subject with moderate eosinophilic asthma may have moderate asthma, and blood eosinophils greater than or equal to 150 eosinophils per μl of blood in the past 12 months, greater than or equal to 200 eosinophils per μl of blood in the past 12 months, greater than or equal to 300 eosinophils per μl of blood in the past 12 months, or greater than or equal to 350 eosinophils per μl of blood in the past 12 months.

"Severe eosinophilic asthma" is severe asthma with eosinophilic phenotype. For example, a subject with severe eosinophilic asthma may have severe asthma, and blood eosinophils greater than or equal to 150 eosinophils per μl of blood over the past 12 months, greater than or equal to 200 eosinophils per μl of blood over the past 12 months, greater than or equal to 300 eosinophils per μl of blood over the past 12 months (preferred) or greater than or equal to 350 eosinophils per μl of blood over the past 12 months.

Subjects with severe eosinophilic asthma may also meet one or more of the criteria described in table 5.

Table 5.

Importantly, according to these criteria, subjects with severe eosinophilic asthma may have less than 150 eosinophils per μl of blood at the beginning of treatment.

The term "pharmaceutical composition" as used herein refers to a composition suitable for administration to a patient.

The term "therapeutically effective amount" as used herein refers to an amount of an agent (e.g., an antigen binding protein or pharmaceutical composition) that provides a therapeutic benefit in treating or managing one or more symptoms of a condition to be treated (e.g., asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, and subaeosinophilic asthma). Examples of such treatment or management of one or more symptoms of asthma (including asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, and subaeosinophilic asthma) include 1) reducing the frequency of asthma attacks; 2) Reducing the time to first clinically significant episodes requiring oral or systemic corticosteroids, hospitalization, and/or Emergency Department (ED) visits; 3) Reducing the frequency of episodes requiring hospitalization (including intubation and entry into an intensive care unit) or ED visits; 4) Reducing the time to first episode in need of hospitalization or ED visit; 5) Changes from baseline in pre-clinical bronchodilator FEV 1; 6) Changes from baseline in FEV1 following clinical bronchodilators; 7) Changes in Asthma Control Questionnaire (ACQ) score from baseline; 8) Improvement in lung function assessed by spirometry (e.g., lung capacity (VC), forced lung capacity (FVC), 0.5, 1.0 (FEV 1), forced lung capacity (FEV) at 2.0 and 3.0 second intervals, forced expiratory flow 25-75% (FEF 25-75) and maximum spontaneous ventilation (MVV) lung volume, idal, residual capacity, expiratory reserve, inspiratory lung volume, functional residual capacity, residual capacity expressed as a percentage of total lung volume, alveolar gas volume, actual lung volume including conductive airway volume, forced lung volume, etc.); and 9) reducing asthma attacks requiring steroid control (e.g., oral steroids or steroids administered by any route, such as prednisone, prednisolone, etc.). The reduction in asthma attacks requiring steroid control may be about 50% less in asthma attacks requiring steroid (e.g., oral steroid) use.

The therapeutically effective amount and treatment regimen will typically be determined empirically and may depend on the age, weight and health of the patient, as well as on the disease or condition to be treated, among other factors. These factors are within the authority of the attending physician.

The term "treating" as used herein refers to ameliorating or stabilizing a particular condition, reducing or eliminating symptoms of a condition, slowing or eliminating the progression of a condition, and preventing or delaying the recurrence of a condition in a previously afflicted patient or subject.

The methods, antigen binding proteins, and compositions of the present disclosure need not affect complete cure, or eliminate each symptom or manifestation of the disease to constitute a viable therapeutic approach. As recognized in the art, drugs used as therapeutic agents in therapeutic methods may reduce the severity of a particular disease state, but need not eliminate every manifestation of the disease to be considered a useful therapeutic agent. It may be sufficient to reduce the impact of the disease (e.g., by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or to reduce the likelihood of the disease developing or worsening in the subject (e.g., by delaying the onset of the disease).

The term "subject" as used herein refers to a human or animal body. The terms "individual," "subject," and "patient" are used interchangeably herein. The subject is typically a human. The subject may also be a mammal, such as a mouse, rat, or primate (e.g., marmoset or monkey). The subject may be a non-human animal. The antigen binding proteins, compositions and methods of the present disclosure also have veterinary uses. The subject to be treated may be a farm animal, such as a cow or bull, sheep, pig, steer, goat or horse, or may be a domestic animal, such as a dog or cat. The animal may be of any age or mature adult. The subject may be an adult (. Gtoreq.18 years) or adolescent (. Gtoreq.12 years but less than 18 years) or pediatric (. Gtoreq.12 years) subject. The subject may be 6 to 18 years old.

In some embodiments, the subject described herein is a subject that has been converted from a treatment comprising an agent that targets IL-5 or IL-5R to a treatment comprising an antigen binding protein described herein. In some embodiments, the subject described herein is a subject that has been converted from a treatment comprising meperiab, rayleigh bead mab, or the subject rayleigh bead mab to a treatment comprising an antigen binding protein described herein. In some embodiments, the subject described herein is a subject being treated with an abiotic therapy comprising an agent that targets IL-5 or IL-5R. In some embodiments, the subject described herein is a subject being treated for asthma with an abiotic therapy, e.g., a corticosteroid and/or other controlling agent, such as a long-acting beta-2-agonist (LABA) and/or a long-acting muscarinic antagonist (LAMA). The corticosteroid may be a daily inhaled corticosteroid. In embodiments, a subject described herein may receive daily corticosteroid, e.g., by inhalation, e.g., fluticasone, e.g., the subject may receive corticosteroid, i.e., TRELEGY or RELVAR. In one embodiment, the subject may receive ≡440 micrograms of fluticasone propionate or another such agent in amounts clinically comparable according to GINA 2020 guidelines. In some embodiments, the subject described herein is a subject that has been converted from a treatment comprising an agent that targets IL-5 or IL-5R to a treatment comprising an antigen binding protein described herein and wherein the subject is receiving an abiotic treatment of asthma. In some embodiments, the subject described herein is a subject that has been converted from a treatment comprising an agent that targets IL-5 or IL-5R (e.g., meperiab, rayleigh zumab, or present rayleigh zumab) to a treatment comprising an antigen-binding protein described herein, and wherein the subject is receiving an abiotic treatment of asthma, e.g., a corticosteroid and/or other control agent, such as a long-acting β -2-agonist (LABA) and/or a long-acting muscarinic antagonist (LAMA). In some embodiments, the antigen binding protein is 28Y042-7F11-1.

In one embodiment, the subject receiving treatment receives a maximum daily dose (μg) of corticosteroid of beclomethasone dipropionate (chlorofluorocarbonate-CFC) =about 1000, beclomethasone dipropionate (hydrofluoroalkane propellant-HFA) =about 400, budesonide (DPI) =about 800, ciclesonide (HFA) =about 320, fluticasone propionate (dry powder inhaler-DPI) =about 500, fluticasone furoate (DPI) =about 100, mometasone furoate=about 440, triamcinolone acetonide=about 2000.

As used herein, the phrase "once every 6 months" refers to a dose of an antigen binding protein of the invention administered to a subject only on one day and not on other days during a 6 month period, typically about 183 days. Once every 6 months may also be referred to as "Q26W" (meaning once every 26 weeks). Reference herein to "about once every 6 months" refers to an intended dosing regimen once every 6 months, but allows for patient compliance, thus allowing for up to four week variation to be scheduled according to the patient's schedule.

Any type of range provided herein includes all values within the specified range as well as the values of the endpoints of the specified range.

If desired, an effective dose of an antibody or antigen binding protein of the present disclosure (e.g., as a pharmaceutical composition) may be administered as a unit dosage form. The administration of the dose may be by slow continuous infusion over a period of 2 to 24 hours, for example 2 to 12 hours, or 2 to 6 hours. Such a mode of administration may result in reduced side effects.

Antigen binding proteins

The extended Pharmacokinetic (PK) and pharmacological profile of the antigen binding proteins described herein (28Y 042-7F 11-1) are achieved by decreasing clearance and increasing affinity for IL-5 and are believed to be able to be administered once every 26 weeks, in contrast to current dosing regimens in which mellimab and rayleigh bead are administered once every 4 weeks or in which the present rayleigh beads are administered once every 8 weeks (the first 3 doses are administered once every 4 weeks).

Disclosure of Invention

In one aspect, the invention provides an antigen binding protein that binds IL-5 comprising a heavy chain variable region having a CDRH1 amino acid sequence as set forth in SEQ ID NO. 5, a CDRH2 amino acid sequence as set forth in SEQ ID NO. 6, and a CDRH3 amino acid sequence as set forth in SEQ ID NO. 7; and a light chain variable region having the CDRL1 amino acid sequence set forth in SEQ ID No. 8, the CDRL2 amino acid sequence set forth in SEQ ID No. 9, and the CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain (e.g., igG1 Fc) having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region, for use in treating an IL-5 mediated disease, such as asthma (e.g., mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, eosinophilic asthma) by administration to a subject in an amount of about 100mg to about 300mg at a frequency of about once every 6 months. In one embodiment, the heavy chain variable region of the antigen binding protein further comprises the heavy chain FR4 amino acid sequence shown as SEQ ID NO. 19.

An antigen binding protein that binds to IL-5 and comprises 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, and further comprising a heavy chain Fc domain (e.g., igG1 Fc) having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region, and which is a compound of the invention and is disclosed in international patent application publication No. WO 2018215964.

In one embodiment, the antigen binding proteins of the invention comprise a heavy chain variable region having the amino acid sequence of CDRH1 shown in SEQ ID NO. 5, the amino acid sequence of CDRH2 shown in SEQ ID NO. 6, and the amino acid sequence of CDRH3 shown in SEQ ID NO. 7; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain (e.g., igG1 Fc) having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region, and further comprising a heavy chain FR4 amino acid sequence set forth in SEQ ID No. 19.

In another embodiment, the antigen binding proteins of the invention comprise: 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, and a heavy chain Fc domain (e.g., igG1 Fc) having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region, and further optionally comprising a heavy chain FR4 amino acid sequence shown in SEQ ID NO. 19.

In one embodiment, the antigen binding protein of the invention is an antibody comprising a heavy chain and a light chain, wherein:

a) The heavy chain comprises a heavy chain variable region with a CDRH1 amino acid sequence shown in SEQ ID NO. 5, a CDRH2 amino acid sequence shown in SEQ ID NO. 6 and a CDRH3 amino acid sequence shown in SEQ ID NO. 7; and is also provided with

B) The light chain comprises a light chain variable region having a CDRL1 amino acid sequence as shown in SEQ ID NO. 8, a CDRL2 amino acid sequence as shown in SEQ ID NO. 9, and a CDRL3 amino acid sequence as shown in SEQ ID NO. 10. The antibody may also comprise a heavy chain FR4 amino acid sequence as shown in SEQ ID NO. 19 and/or a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254 and a glutamic acid residue at position 256. The heavy chain Fc domain may be an IgG1 Fc domain, such as a human IgG1 Fc domain.

In another embodiment, the antigen binding protein of the invention is an antibody comprising a heavy chain and a light chain, wherein:

a) The heavy chain comprises a heavy chain variable region sequence with an amino acid sequence shown in SEQ ID NO. 3; and is also provided with

B) The light chain comprises a light chain variable region sequence having the amino acid sequence shown in SEQ ID NO. 4. The antibody may also comprise a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256. The heavy chain Fc domain may be an IgG1 Fc domain, such as a human IgG1 Fc domain.

In another embodiment, the antigen binding protein of the invention is an antibody comprising 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.

The antigen binding proteins of the invention may be variants that retain the ability to bind IL-5 as described above, e.g., useful variants may be those that bind human IL-5 with a binding affinity of about at least 10pM as determined by KINEXA phase affinity assay at about 25℃or with a binding affinity of about at least 30pM (e.g., about 39 pM) as determined using BIACORE T200 at about 37 ℃. Useful variants may also have a binding affinity for human FcRn of about at least 150nM at pH 6.0 (determined by BIACORET200,200 at 37 ℃), and a binding affinity of about at least 16100nM at pH 7.4 (determined by BIACORE T200 at 37 ℃). Useful variants may also have an improved half-life (PK) of about at least 20 days, for example about 24 days, as determined in cynomolgus monkey serum. For example, useful variants may include antibodies having at least about 90% identity to any of the sequences described herein, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity to any of the sequences described herein. For example, the variant may be an antibody comprising a heavy chain variable region sequence having at least about 90% identity to the amino acid sequence set forth in SEQ ID NO. 3, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity to the amino acid sequence set forth in SEQ ID NO. 3; and/or a light chain variable region sequence having at least about 90% identity to the amino acid sequence set forth in SEQ ID NO. 4, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity to the amino acid sequence set forth in SEQ ID NO. 4; the variant may further comprise a heavy chain FR4 amino acid sequence as shown in SEQ ID NO. 19, and may further comprise a heavy chain Fc domain (e.g., igG1 Fc) having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region.

A variant may also be an antibody comprising a heavy chain having at least about 90% identity (e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity) to the amino acid sequence set forth in SEQ ID NO. 1 and a light chain having at least about 90% identity (e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 100% identity) to the amino acid sequence set forth in SEQ ID NO. 2.

In embodiments, the invention provides an antibody that binds IL-5, comprising a heavy chain having the amino acid sequence set forth in SEQ ID No. 1 and a light chain having the amino acid sequence set forth in SEQ ID No. 2, for use in treating asthma, such as eosinophilic asthma (e.g., moderate or severe eosinophilic asthma), by administration to a human subject in an amount of about 100mg to about 300mg, at a frequency of about once every 6 months.

28Y042-7F11-1 comprising the heavy chain amino acid sequence shown in SEQ ID NO. 1 and the light chain amino acid sequence shown in SEQ ID NO. 2 is an example of an antibody of the present invention. 28Y042-7F11-1 or an antigen binding protein of the present disclosure binds human IL-5 and antagonizes its activity.

28Y042-7F11-1 is a recombinant humanized monoclonal antibody (IgG 1,. Kappa.). 28Y042-7F11-1 has two light chains and two heavy chains.

28Y042-7F11-1 heavy chain variable region is encoded by the nucleic acid sequence shown in SEQ ID NO. 15. 28Y042-7F11-1 light chain variable region is encoded by the nucleic acid sequence shown in SEQ ID NO. 16.

28Y042-7F11-1 full length heavy chain is encoded by the nucleic acid sequence shown in SEQ ID NO. 17. 28Y042-7F11-1 full length light chain is encoded by the nucleic acid sequence shown in SEQ ID NO. 18. During manufacture, the nucleic acid sequence may comprise a leader sequence, so that the 28Y042-7F11-1 full length heavy chain may be encoded by the nucleic acid sequence set forth in SEQ ID NO. 13, while the 28Y042-7F11-1 full length light chain may be encoded by the nucleic acid sequence set forth in SEQ ID NO. 14.

The heavy and light chains of 28Y042-7F11-1 are covalently linked by a disulfide bond, and the heavy chains are linked to each other by two disulfide bonds, thus forming a typical IgG molecule.

The antigen binding proteins described herein can be produced by a variety of conventional techniques. For example, the antigen binding proteins may be expressed in and purified from a recombinant expression system. In one embodiment, the antigen binding protein is produced by a method of culturing a host cell under conditions suitable for expression of a polypeptide comprising SEQ ID NO. 1 and SEQ ID NO. 2, wherein the composition is expressed, and optionally purified, and optionally formulated within a pharmaceutical composition.

The composition may be produced using a variety of different expression systems and purification schemes. Typically, host cells are transformed with recombinant expression vectors encoding antibodies. A variety of host cells may be used, including eukaryotic cell lines of mammalian origin (e.g., CHO, perc6, HEK293, heLa, NS 0). Suitable host cells include mammalian cells such as CHO (e.g., CHOK1 and CHO-DG 44).

The host cell may be an isolated host cell. The host cell is typically not part of a multicellular organism (e.g., a plant or animal). The host cell may be a non-human host cell.

Cloning and expression vectors and cloning methods suitable for eukaryotic or mammalian cell hosts are known in the art.

The cells may be cultured under conditions that promote expression of the antigen binding protein. For example, bioreactors are produced for culturing cells. The volume of the production bioreactor may be: (i) about 20,000 liters, about 10,000 liters; about 5,000 liters; about 2,000 liters; about 1,000 liters; or about 500 liters; or (ii) between 500 and 20,000 liters; between 500 and 10,000 litres; between 500 and 5,000 litres; between 1,000 and 10,000 liters or between 2,000 and 10,000 liters. For example, the cells may be cultured in a production bioreactor at a pH of about 6.75 to pH 7.00. Alternatively, the cells may be cultured in the bioreactor for about 12 to about 18 days. Alternatively, the cells may be cultured in the bioreactor at a pH of about 6.75 to pH 7.00 for about 12 to about 18 days. This incubation step may help to control the level of deamidated antibody variant, e.g., reduce the level of deamidated antibody variant.

The antigen binding proteins may be recovered and purified by conventional protein purification procedures. For example, the antigen binding protein may be harvested directly from the culture medium. Harvesting of the cell culture medium may be achieved via clarification, for example, by centrifugation and/or depth filtration. The antigen binding proteins are recovered and then purified to ensure adequate purity.

One or more chromatographic steps, such as one or more chromatographic resins, may be used in the purification; and/or one or more filtration steps. For example, the composition may be purified using affinity chromatography on a resin (e.g., protein A, G or L). Alternatively or additionally, ion exchange resins (e.g., cation exchange) may also be used to purify antigen binding proteins. Alternatively or additionally, hydrophobic interaction chromatography resins may also be used to purify antigen binding proteins. Alternatively, the purification step comprises: an affinity chromatography resin step, followed by a cation exchange resin step, followed by a hydrophobic interaction chromatography resin step.

For example, the harvest is placed in contact with protein a resin. The solution comprising the composition may be eluted from the protein a resin and treated at a pH of 3.3 to 3.7 for 15 to 240 minutes. This protein a resin step may help to control the level of aggregated antibody variants, e.g. reduce the level of aggregated antibody variants.

The solution comprising the antigen binding protein may then be further clarified by depth filtration and/or double filtration.

Alternatively or additionally, anion exchange resins may also be used. The solution comprising the antigen binding protein may be placed in contact with an anion exchange resin (e.g., Q-SEPHAROSE ^TM rapid flow anion exchange chromatography) loaded at a pH of 8.3 to 8.7. The solution containing the composition may be eluted from the anion exchange resin and held for 96 hours or less. This anion exchange resin step may help to control the level of deamidated antibody variant, e.g. reduce the level of deamidated antibody variant.

Optionally, guanidine and/or ammonium sulfate may be added to the solution comprising the composition and held for 15 to 240 minutes.

Alternatively or additionally, hydrophobic interaction chromatography resins may also be used. The solution comprising the antigen binding protein may be placed in contact with a hydrophobic interaction chromatography resin (e.g., phenyl SEPHAROSE ^TM flash flow chromatography) at a loading rate of 12 to 27g protein/L resin. For example, a gradient elution volume (bed volume; BV) of about 9 to about 11 may be used to elute a solution comprising the antigen binding protein. During elution from the hydrophobic interaction chromatography resin, an elution peak cut-off value (% of maximum peak height) of about 17 to about 23 may be used. This hydrophobic interaction chromatography resin step may help to control the level of aggregated antibody variants, e.g. reduce the level of aggregated antibody variants.

Medical use and method of treatment

The administration of an antigen binding protein that binds to IL-5 according to the invention in an amount of about 100mg to about 300mg (e.g., 100 mg) at a frequency of about once every 6 months can provide a safe and effective therapy for the treatment of IL-5 mediated diseases such as asthma (e.g., mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, subaeosinophilic asthma). This administration strategy may also improve efficacy due to increased patient compliance, as patients need to take the drug only once every 6 months, thus being a less burdensome treatment regimen.

In one aspect, the invention provides a method of treating an IL-5 mediated disorder such as asthma (e.g., mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, eosinophilic asthma), the method comprising administering to a subject in need thereof an antigen binding protein that binds IL-5 comprising a heavy chain variable region having a CDRH1 amino acid sequence set forth in SEQ ID NO:5, a CDRH2 amino acid sequence set forth in SEQ ID NO:6, and a CDRH3 amino acid sequence set forth in SEQ ID NO:7 in an amount of about 100mg to about 300mg, about once every 6 months; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain (e.g., igG1 Fc) having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region.

In one embodiment, the IL-5 mediated disease is asthma. Asthma may be selected from the group consisting of: mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, eosinophilic asthma and subaeosinophilic asthma. In further embodiments, the asthma has an eosinophilic phenotype, e.g., selected from mild eosinophilic asthma, moderate eosinophilic asthma, or severe eosinophilic asthma. In one embodiment, the asthma is severe asthma.

The invention also provides a method of treating asthma (e.g., mild, moderate or severe asthma, such as mild, moderate or severe eosinophilic asthma), comprising administering to a subject in need thereof an IL-5-binding antigen binding protein comprising a heavy chain variable region sequence having the amino acid sequence set forth in SEQ ID NO 3 and a light chain variable region sequence having the amino acid sequence set forth in SEQ ID NO 4 in an amount of about 100mg to about 300mg, about once every 6 months.

The invention also provides a method of treating asthma (e.g., mild, moderate or severe asthma, such as mild, moderate or severe eosinophilic asthma) comprising administering to a subject in need thereof an antibody that binds IL-5, the antigen binding protein comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO:1 and a light chain having the amino acid sequence set forth in SEQ ID NO:2, in an amount of about 100mg to about 300mg, about once every 6 months.

In one aspect, the invention provides a method of treating an IL-5 mediated disease in a subject, the method comprising: a) Identifying a subject having a disease selected from the group consisting of: asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, eosinophilic asthma and subaeosinophilic asthma; and b) administering from about 100mg to about 300mg of an antigen binding protein that binds to IL-5, said antigen binding protein comprising a heavy chain variable region having the amino acid sequence of CDRH1 shown in SEQ ID NO. 5, the amino acid sequence of CDRH2 shown in SEQ ID NO. 6, and the amino acid sequence of CDRH3 shown in SEQ ID NO. 7; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region, administered to a subject about once every 6 months; thereby treating the disease in the subject.

In one embodiment, the IL-5 mediated disease is selected from the group consisting of: inflammatory Bowel Disease (IBD), allergic bronchopulmonary aspergillosis (ABPA), eosinophilic polyangiitis (EGPA), eosinophilic syndrome (HES), nasal Polyposis (NP), chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps (CRSsNP), and dermatitis. The disease may be characterized by an eosinophil phenotype. The inflammatory bowel disease may be Crohn's disease or ulcerative colitis.

In embodiments, there is provided use of an antigen binding protein described herein for treating chronic sinusitis (CRSwNP) with nasal polyps by administering to a subject about once every 6 months, wherein the amount of antigen binding protein is about 100mg.

In embodiments, there is provided use of an antigen binding protein described herein for treating chronic sinusitis (CRSsNP) that is not accompanied by nasal polyps by administration to a subject about once every 6 months, wherein the amount of antigen binding protein is about 100mg.

The subject to be treated with CRSwNP may have severe CRSwNP and/or be receiving SOC treatment, e.g. treatment with nasal endothelin steroids. Corticosteroid treatment and/or surgery may not provide adequate disease control.

The subject to be treated for chronic sinusitis (CRSsNP) without nasal polyps may have severe CRSsNP and/or be undergoing standard of care (SOC) treatment, such as with oral corticosteroids. Corticosteroid treatment and/or surgery may not provide adequate disease control. Chronic sinusitis (CRSsNP), which is free of nasal polyps, is an inflammatory disease of the paranasal sinuses characterized by fibrosis, basement membrane thickening, and goblet cell proliferation. In the united states, up to 50% of the participants of subtype CRSsNP have type 2 inflammatory endotypes, with pain being a significant factor in the decline in quality of life for CRSsNP patients. Although fewer eosinophils were found in the mucosal tissue of CRSsNP compared to CRSwNP, it appears to be eosinophil ("type 2") type. Since activated eosinophils secrete a large number of inflammatory mediators (including granulin, lipid mediators, cytokines, chemokines and growth factors such as TGF- β), their presence may lead to the pathological features present in CRSsNP. Thus, patients suffering from CRSsNP treated in accordance with the present invention may have such a type 2 or eosinophil endotype, with elevated eosinophil levels in the nasal mucosa, e.g., they may have a blood eosinophil count of ≡150 cells/. Mu.L, e.g., a blood eosinophil count of ≡300 cells/. Mu.L.

In embodiments, there is provided use of an antigen binding protein described herein for treating Eosinophilic Granulomatosis (EGPA) with polyangiitis by administering to a subject about once every 6 months, wherein the amount of antigen binding protein is about 200mg.

The subject to be treated with EGPA may have relapsing remitting or refractory eosinophilic granulomatosis with polyangiitis. The treatment of the invention may be supplemented with other SOC treatments, such as Oral Corticosteroid (OCS) therapies, e.g. with prednisolone/prednisone.

In embodiments, there is provided use of an antigen binding protein described herein for treating eosinophilia (HES) by administering to a subject about once every 6 months, wherein the amount of antigen binding protein is about 200mg.

The subject to be treated with HES may have poorly controlled eosinophilia and no identifiable non-hematologic secondary cause. The treatment of the invention may be supplemented with other SOC treatments, such as Oral Corticosteroid (OCS) therapies, e.g. with prednisolone/prednisone.

The current definition and diagnosis of HES employs the following criteria:

1. blood eosinophils >1500 eosinophils/. Mu.L (interval in two examinations

1 Month or more)

2. Tissue eosinophils cause organ damage and/or dysfunction;

3. Exclusion of other diseases or conditions as a major cause of organ damage

The screening blood eosinophil count of subjects with HES to be treated may be >1500 eosinophils/μl (as defined above) or they may be patients who have been diagnosed with HES and have been treated with standard HES but still have ≡1000 cells/μl.

When the dose administered is 200mg (e.g., for HES or EGPA therapy), it may be contained in one unit or multiple units (e.g., 2 units, each containing 100mg of active ingredient), and each unit dose may be administered separately, sequentially or simultaneously.

The subject treated as described herein may be an adult subject (. Gtoreq.18 years) or adolescent (. Gtoreq.12 years but less than 18 years) or pediatric subject (. <12 years). The subject may be 6 to 18 years old. In embodiments, the doses detailed herein are administered to adult subjects as well as subjects <18 years of age but weighing 40 kg or more (e.g., pediatric/adolescent). For subjects less than 18 years of age but weighing less than 40 kg, a fixed dose regimen will be employed to approximate the target adult exposure as closely as possible, depending on the particular weight range.

In one aspect, the invention provides a method of treating an IL-5 mediated disease in a subject, the method comprising administering to the subject about once every 6 months about 100mg to about 300mg of an IL-5 binding antigen binding protein comprising a heavy chain variable region having the amino acid sequence of CDRH1 shown in SEQ ID NO. 5, the amino acid sequence of CDRH2 shown in SEQ ID NO. 6, and the amino acid sequence of CDRH3 shown in SEQ ID NO. 7; and a light chain variable region having a CDRL1 amino acid sequence shown in SEQ ID No. 8, a CDRL2 amino acid sequence shown in SEQ ID No. 9, and a CDRL3 amino acid sequence shown in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region; thereby treating the disease in the subject.

The heavy chain variable region of the antigen binding protein may also comprise the heavy chain FR4 amino acid sequence shown as SEQ ID NO. 19, as described herein. In one embodiment, the heavy chain Fc domain is an IgG1 Fc domain. In a further embodiment, the heavy chain Fc domain is a human IgG1 Fc domain.

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. In a further embodiment, the antigen binding protein is an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO. 1 and a light chain having the amino acid sequence set forth in SEQ ID NO. 2.

In one embodiment, the method comprises administering about 100mg of the antigen binding protein.

In one embodiment, the method comprises subcutaneously administering the antigen binding protein.

In one embodiment, the subject is a human subject.

Preferably, the subject (prior to treatment, e.g., at any time point within 12 months prior to treatment) has an absolute blood eosinophil count selected from the group consisting of: greater than or equal to 100 cells per μL, such as greater than or equal to 150 cells per μL, or greater than or equal to 200 cells per μL, or greater than or equal to 250 cells per μL, or greater than or equal to 300 cells per μL, or greater than or equal to 350 cells per μL.

In one embodiment, there is provided the use of an antigen binding protein as described herein in the manufacture of a medicament for the treatment of an IL-5 mediated disease, the medicament being administered about once every 6 months, wherein the medicament comprises an antigen binding protein in an amount of about 100mg to about 300 mg.

In another aspect, the invention provides a method of reducing absolute blood eosinophil count in a subject, the method comprising: a) Identifying a subject having a disease selected from the group consisting of: asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, subaeosinophilic asthma; and b) administering to the subject an IL-5 binding antigen binding protein comprising a heavy chain variable region having the amino acid sequence of CDRH1 shown in SEQ ID NO. 5, the amino acid sequence of CDRH2 shown in SEQ ID NO. 6, and the amino acid sequence of CDRH3 shown in SEQ ID NO. 7 in an amount of about 100mg to about 300mg, about once every 6 months; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain (e.g., igG1 Fc) having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region, thereby reducing absolute blood eosinophil count in the subject.

The invention also provides a method of reducing absolute blood eosinophil count in a subject, the method comprising: a) Identifying a subject having asthma (e.g., mild, moderate or severe asthma, such as mild, moderate or severe eosinophilic asthma), and b) administering to the subject in need thereof an IL-5-binding antigen binding protein comprising a heavy chain variable region sequence having the amino acid sequence set forth in SEQ ID NO 3 and a light chain variable region sequence having the amino acid sequence set forth in SEQ ID NO 4 in an amount of about 100mg to about 300mg, about once every 6 months, thereby reducing the absolute blood eosinophil count of the subject.

The invention also provides a method of reducing absolute blood eosinophil count in a subject, the method comprising: a) Identifying a subject having asthma (e.g., mild, moderate or severe asthma, such as mild, moderate or severe eosinophilic asthma), and b) administering to said subject an antibody that binds IL-5 comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO:1 and a light chain having the amino acid sequence set forth in SEQ ID NO:2 in an amount of about 100mg to about 300mg, about once every 6 months, thereby reducing the absolute blood eosinophil count in the subject.

One embodiment of the method of the present disclosure further comprises: a) Performing a first measurement of absolute blood eosinophil count of the subject; b) A second measurement of the absolute blood eosinophil count of the subject following administration of the therapeutically effective amount of the antigen binding protein to the subject; and c) comparing the first measurement with the second measurement to determine the effectiveness of the treatment.

One embodiment of the method of the present disclosure further comprises: a) Performing a first measurement of absolute blood eosinophil count of the subject; b) A second measurement of the absolute blood eosinophil count of the subject following administration of the therapeutically effective amount of the antigen binding protein to the subject; and c) comparing the first measurement with the second measurement; wherein the subject has an absolute blood eosinophil count selected from the group consisting of: greater than or equal to 150 cells per μL, greater than or equal to 200 cells per μL, and greater than or equal to 350 cells per μL.

In one embodiment, the subject (prior to treatment) has an absolute blood eosinophil count selected from the group consisting of: greater than or equal to 150 cells per μL, e.g., greater than or equal to 200 cells per μL.

In some embodiments, described herein are methods of reducing absolute blood eosinophil count, comprising administering to a subject an antigen binding protein that binds to IL-5, wherein absolute blood eosinophil count is maintained or reduced as compared to a baseline prior to treatment. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, described herein are methods of treating asthma, comprising administering to a subject an antigen binding protein that binds to IL-5, wherein absolute blood eosinophil count is maintained or reduced as compared to baseline prior to treatment. in some embodiments, blood eosinophil count is reduced by ≡50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% compared to baseline prior to administration at least about 1,2,3,4, 5,8, 10, 12, 15, 18, 20, 24, 26, 30, 32, 36, 40 or 50 weeks after a single administration of an antigen binding protein that binds IL-5 to a subject. In some embodiments, absolute blood eosinophil count is reduced by ≡50%, 55%, 60%, 65%, 70%, 75%, 80% from baseline prior to administration at least about 26 weeks after a single administration of the antigen binding protein to the subject. In some embodiments, absolute blood eosinophil count is reduced by ≡50%, 55%, 60%, 65%, 70%, 75%, 80% from baseline prior to administration at least about 32 weeks after a single administration of the antigen binding protein to the subject. In some embodiments, absolute blood eosinophil count is reduced by ≡50%, 55%, 60%, 65%, 70%, 75%, 80% from baseline prior to administration at least about 36 weeks after a single administration of the antigen binding protein to the subject. In some embodiments, absolute blood eosinophil count is reduced by ≡50%, 55%, 60%, 65%, 70%, 75%, 80% from baseline prior to administration at least about 40 weeks after a single administration of the antigen binding protein to the subject. In some embodiments, 100mg of the antigen binding protein that binds to IL-5 is administered to the subject, and the absolute blood eosinophil count is reduced by at least about 80% from baseline prior to administration 24 weeks after a single administration of the antigen binding protein to the subject. In some embodiments, 100mg of the antigen binding protein that binds to IL-5 is administered to the subject, and the absolute blood eosinophil count is reduced by at least about 82% from baseline prior to administration 26 weeks after a single administration of the antigen binding protein to the subject. In some embodiments, 300mg of the antigen binding protein that binds to IL-5 is administered to the subject, and the absolute blood eosinophil count is reduced by at least about 83% as compared to baseline prior to administration 26 weeks after a single administration of the antigen binding protein to the subject. In some embodiments, 300mg of the antigen binding protein that binds to IL-5 is administered to the subject, and the absolute blood eosinophil count is reduced by at least about 80% from baseline prior to administration 24 weeks after a single administration of the antigen binding protein to the subject. In some embodiments, the antigen binding protein that binds IL-5 comprises a heavy chain variable region having the amino acid sequence of CDRH1 shown in SEQ ID NO. 5, the amino acid sequence of CDRH shown in SEQ ID NO.6, and the amino acid sequence of CDRH3 shown in SEQ ID NO. 7. In some embodiments, the antigen binding protein that binds IL-5 comprises a light chain variable region having the amino acid sequence of CDRL1 shown in SEQ ID NO. 8, the amino acid sequence of CDRL2 shown in SEQ ID NO. 9, and the amino acid sequence of CDRL3 shown in SEQ ID NO. 10. In some embodiments, an antigen binding protein that binds to IL-5 comprises a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256. In some embodiments, the antigen binding protein that binds to IL-5 comprises the amino terminus of a heavy chain Fc domain, which is linked to the carboxy terminus of a heavy chain variable region. In some embodiments, the antigen binding protein that binds IL-5 comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO. 1 and a light chain having the amino acid sequence set forth in SEQ ID NO. 2. In some embodiments, the asthma includes mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, and subaeosinophilic asthma. In some embodiments, the asthma comprises severe asthma, e.g., severe eosinophilic asthma.

The dosing regimen described herein is useful for treating IL-5 mediated diseases, particularly asthma, in a human or animal subject. In one embodiment, the subject is a human.

Asthma may be selected from: mild asthma, moderate asthma, severe asthma, eosinophilic asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, eosinophilic asthma and subaeosinophilic asthma. In one embodiment, the asthma is mild or moderate asthma. In one embodiment, the asthma is severe asthma. The invention is particularly useful in asthmatic patients suffering from eosinophilic phenotypes. Thus, in a further embodiment, the asthma is mild, moderate or severe eosinophilic asthma.

Pharmaceutical composition

Antigen binding proteins are typically presented as pharmaceutical compositions. In one embodiment, the pharmaceutical composition comprising the antigen binding protein of the invention further comprises a pharmaceutically acceptable excipient. In a further embodiment, the pharmaceutical composition comprises an antigen binding protein of the invention and one or more pharmaceutically acceptable excipients.

In one aspect, the invention provides a pharmaceutical composition comprising about 100mg to about 300mg of an antigen binding protein that binds to IL-5 and a pharmaceutically acceptable excipient, wherein the antigen binding protein comprises a heavy chain variable region having a CDRH1 amino acid sequence set forth in SEQ ID No. 5, a CDRH2 amino acid sequence set forth in SEQ ID No. 6, and a CDRH3 amino acid sequence set forth 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, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region.

In one embodiment, the pharmaceutical composition comprises about 100mg of the antigen binding protein of the invention and a pharmaceutically acceptable excipient.

In one embodiment, the pharmaceutical composition comprises an antigen binding protein of the invention, wherein the heavy chain variable region of the antigen binding protein further comprises the heavy chain FR4 amino acid sequence shown in SEQ ID NO. 19.

In one embodiment, the pharmaceutical composition comprises an antigen binding protein of the invention, wherein the heavy chain Fc domain is an IgG1 Fc domain. The heavy chain Fc domain may be a human IgG1 Fc domain.

In one embodiment, the pharmaceutical composition comprises an antigen binding protein of the invention, wherein 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.

The invention also provides a pharmaceutical composition comprising an antigen binding protein that binds to IL-5 in an amount of about 100mg, said antigen binding protein comprising a heavy chain variable region sequence having the amino acid sequence set forth in SEQ ID No. 3 and a light chain variable region sequence having the amino acid sequence set forth in SEQ ID No. 4, and a pharmaceutically acceptable excipient.

In one embodiment, the pharmaceutical composition comprises an antigen binding protein of the invention, wherein the antigen binding protein is an antibody comprising 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.

The invention also provides a pharmaceutical composition comprising an antibody that binds to IL-5 in an amount of about 100mg and a pharmaceutically acceptable excipient, the antigen binding protein comprising 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.

In one embodiment, the pharmaceutical composition is formulated for subcutaneous administration. In particular, the pharmaceutical composition may be formulated for administration to a human subject. The subject (prior to treatment) may have an absolute blood eosinophil count selected from the group consisting of: greater than or equal to 150 cells per μL, e.g., greater than or equal to 200 cells per μL.

In one embodiment, the pharmaceutical composition is for administration to a subject about once every 3 months, once every 4 months, once every 5 months, or once every 6 months. In a further embodiment, the pharmaceutical composition is administered to the subject about once every 6 months.

In one embodiment, the pharmaceutical composition is administered at an interval (or treatment cycle) of administration of about once every 13 weeks (Q13W), once every 17 weeks (Q17W), once every 22 weeks (Q22W), or once every 26 weeks (Q26W). In a further embodiment, the pharmaceutical composition is administered to the subject about once every 26 weeks (Q26W).

In another aspect, the invention provides a pharmaceutical composition for treating an IL-5 mediated disease such as asthma (e.g., mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, subacidic asthma), wherein the composition comprises from about 100mg to about 300mg of an antigen binding protein that binds IL-5 comprising a heavy chain variable region having the CDRH1 amino acid sequence set forth in SEQ ID NO:5, the CDRH2 amino acid sequence set forth in SEQ ID NO:6, and the CDRH3 amino acid sequence set forth in SEQ ID NO: 7; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain (e.g., igG1 Fc) having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region, wherein the pharmaceutical composition is for administration to a subject about once every 6 months. In one embodiment, the heavy chain variable region of the antigen binding protein further comprises a heavy chain FR4 amino acid sequence shown as SEQ ID NO. 19.

The invention also provides a pharmaceutical composition for treating asthma (e.g., mild, moderate or severe asthma, such as mild, moderate or severe eosinophilic asthma), wherein the composition comprises from about 100mg to about 300mg of an antigen binding protein that binds IL-5, the antigen binding protein comprising: a heavy chain variable region sequence having the amino acid sequence set forth in SEQ ID No. 3 and a light chain variable region sequence having the amino acid sequence set forth in SEQ ID No. 4, wherein the pharmaceutical composition is for administration to a human subject about once every 6 months.

The invention also provides a pharmaceutical composition for use in treating asthma (e.g., mild, moderate or severe asthma, such as mild, moderate or severe eosinophilic asthma), wherein the composition comprises from about 100mg to about 300mg of an antibody that binds IL-5, the antigen binding protein comprising a heavy chain having the amino acid sequence set forth in SEQ ID No. 1 and a light chain having the amino acid sequence set forth in SEQ ID No. 2, wherein the pharmaceutical composition is for administration to a human subject about once every 6 months.

28Y042-7F11-1 or antigen binding proteins of the disclosure may be provided as a lyophilized powder comprising the antibody and excipients, which may be reconstituted with a pharmaceutically acceptable carrier (e.g., sterile water). The reconstituted pharmaceutical composition may then be administered subcutaneously or intravenously (e.g., further diluted). 28Y042-7F11-1 or antigen binding proteins of the present disclosure may also be provided as a liquid formulation comprising an antibody, excipient, and a pharmaceutically acceptable carrier. The liquid pharmaceutical composition may then be administered subcutaneously or intravenously (e.g., further diluted).

The pharmaceutical compositions described herein may comprise a purified preparation of the antigen binding proteins described herein. For example, a pharmaceutical formulation may include a purified formulation of an antigen binding protein described herein in combination with a pharmaceutically acceptable carrier.

Typically, such pharmaceutical compositions comprise a pharmaceutically acceptable carrier that is known and required by acceptable pharmaceutical practice. Examples of such carriers include sterile carriers, such as saline, ringer's solution or dextrose solution, optionally buffered with a suitable buffer to a pH in the range of 5 to 8.

The pharmaceutical composition may be administered by injection or infusion (e.g. intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular or intravenous, in particular subcutaneous). Such compositions are suitably free of visible particulate matter.

The formulations described herein are stable pharmaceutical compositions.

Preferably, the pharmaceutical composition comprises an aqueous liquid formulation. The pharmaceutical composition may be in the pH range of 5 to 8. For example, the pH of the pharmaceutical composition may range between 5.5 and 7.5, such as between 5.8 and 7.2, 5.9 and 6.7, or 6.0 and 6.5. In particular, the pharmaceutical composition has a pH of about 6.0. In some embodiments, the pH of the pharmaceutical composition is about 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, or 6.6.

Methods of preparing such pharmaceutical compositions are well known to those skilled in the art. The pharmaceutical composition may comprise the antigen binding protein in unit dosage form, optionally together with instructions for use. The pharmaceutical composition may be lyophilized (freeze-dried) for reconstitution prior to administration according to methods well known or apparent to those skilled in the art. When the antibody has an IgG1 isotype, a chelating agent for copper, such as citrate (e.g., sodium citrate) or EDTA or histidine, may be added to the pharmaceutical composition to reduce the extent of copper-mediated degradation of the isotype antibody. The pharmaceutical composition may also contain a solubilizing agent (e.g., arginine), a surfactant/anti-aggregation agent (e.g., polysorbate 80), and an inert gas (e.g., nitrogen) to replace oxygen in the headspace of the vial.

The compositions of the present disclosure may further comprise a buffer selected from the group consisting of: histidine, disodium hydrogen phosphate heptahydrate, phosphate, citric acid, citrate, sodium phosphate, potassium phosphate and sodium citrate, providing a pH between 5.8 and 7.2 or a pH from pH 6.0 to pH 6.6, with a pH of 6.0 being preferred. The buffer in the compositions of the present disclosure may be present in a range of about 10-30mM, about 10-20mM, about 20mM, or about 15.5 mM. In one embodiment, the composition comprises histidine in the range of about 5-50mM, for example about 10-50mM, about 10-30mM, or about 10-20mM. For example, the buffer in the compositions of the present disclosure is present at about 20mM histidine.

In some embodiments, the composition comprises a surfactant. The surfactant is a surfactant which can act on solid-solid, solid-liquid, liquid-liquid and liquid-gas interface surfaces because the chemical composition of the surfactant contains hydrophilic groups and hydrophobic groups. Surfactants can reduce the concentration of proteins in dilute solutions at gas-water and/or water-solid interfaces where proteins can be adsorbed and possibly aggregate. The surfactant may be bound to a hydrophobic interface in the protein formulation. Some of the parental-acceptable nonionic surfactants contain polysorbate or polyether groups. Polysorbate 20 and 80, particularly polysorbate 80 (PS 80), are suitable surfactant stabilizers in the compositions of the present invention. Thus, the compositions of the present disclosure may further comprise polysorbate 80. Polysorbate 80 may be present in a weight to volume ratio in the range of about 0.01% to 0.1%, for example about 0.01% to about 0.05% or about 0.01 to about 0.03% w/v. For example, polysorbate 80 may be present in the compositions of the present disclosure at about 0.02% weight to volume ratio (0.02% w/v).

The compositions of the present disclosure may also include EDTA, which may aid in the stability of the formulation. EDTA may be present in a range of about 0.01 to 0.1mM, for example about 0.02 to 0.08mM or about 0.03 to 0.06 mM. For example, EDTA may be present at about 0.05 mM. The compositions of the present disclosure may comprise 20-60mM histidine. The compositions of the present disclosure may comprise 30-110mM arginine. The compositions of the present disclosure may comprise 0-30mM methionine. The compositions of the present disclosure may comprise 0-110mM glycine. The compositions of the present disclosure may comprise 0-350mM trehalose.

The compositions of the present disclosure may also comprise a sugar. In some embodiments, the composition comprises a polyol. In some embodiments, the polyol is a sugar, and preferably is a non-reducing sugar. In some embodiments, the non-reducing sugar is trehalose. Thus, the compositions of the present disclosure may further comprise trehalose. In some embodiments, the composition comprises trehalose in the range of about 100mM to about 250mM, for example about 150mM to about 200mM, particularly about 160mM to about 190mM. For example, trehalose may be present at about 180 mM.

The composition may also comprise a solubilising agent such as arginine, for example L-arginine-HCl. In some embodiments, the composition comprises arginine in a range of about 10mM to about 120mM, such as about 20mM to about 100mM, particularly about 30mM to about 50mM. In some embodiments, the composition comprises about 40mM arginine.

In one embodiment, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients selected from the group consisting of: histidine, trehalose, arginine, EDTA and polysorbate 80. In a further embodiment, the pharmaceutical composition comprises histidine, trehalose, arginine, EDTA and polysorbate 80. In some embodiments, the pharmaceutical composition comprises glycine.

In one embodiment, the pharmaceutical composition comprises about 20mM histidine, about 180mM trehalose, about 40mM arginine, about 0.05mM EDTA, and about 0.02% polysorbate 80 by weight volume.

As expected, any excipient used is pharmaceutically acceptable and compatible with the other components of the composition (other excipients and active ingredients). According to another aspect of the invention, there is also provided a method of preparing a pharmaceutical composition comprising admixing an antigen binding protein of the invention in an amount of about 100mg to about 300mg (preferably 100 mg) with a pharmaceutically acceptable excipient.

The pharmaceutical composition for treating IL-5 mediated diseases according to the present invention may be administered subcutaneously. Such compositions may be prepared by any method known in the pharmaceutical arts, for example by combining the active ingredient with an excipient.

In one embodiment, the invention provides an antigen binding protein disclosed herein for use in treating an IL-5 mediated disease, such as asthma, in a human or animal subject by subcutaneous administration in an amount of about 100mg to about 300mg, at a frequency of about once every six months.

In another aspect, the invention provides an antigen binding protein disclosed herein for use in treating an IL-5 mediated disease, such as asthma, in a human or animal subject by subcutaneous administration in an amount of about 30mg to about 300mg, or in an amount of about 30mg to about 200mg, at a frequency of about once every six months, e.g., an amount of about 30mg to about 100mg, such as 40mg or more, 50mg or more, 60mg or more, 70mg or more, 80mg or more, 90mg or more, once every 6 months.

The pharmaceutical compositions may be presented in unit dosage form containing a predetermined amount of the active ingredient per unit dose. Preferred unit dose compositions are those containing an all day dose or sub-dose of the active ingredient, or an appropriate fraction thereof. Thus, unit doses containing a sub-dose of a recommended dose of a day may be administered multiple times to complement the total dose of a day. For example, if the dose for a day is 100mg, it may be contained in one unit or in a plurality of units (e.g., 2 units, each containing 50mg of active ingredient). In one embodiment, the pharmaceutical composition is in unit dosage form.

Prefilled syringe

The present invention provides a prefilled syringe comprising from about 100mg to about 300mg of an antigen binding protein of the invention. In one embodiment, a pre-filled syringe comprising a pharmaceutical composition as disclosed herein is provided.

In one aspect, the present invention provides a prefilled syringe comprising: a) About 100mg to about 300mg (e.g., 100 mg) of an antigen binding protein that binds to IL-5, the antigen binding protein comprising a heavy chain variable region having the amino acid sequence CDRH1 shown in SEQ ID No. 5, the amino acid sequence CDRH2 shown in SEQ ID No. 6, and the amino acid sequence CDRH3 shown in SEQ ID No. 7; and a light chain variable region having a CDRL1 amino acid sequence shown in SEQ ID No. 8, a CDRL2 amino acid sequence shown in SEQ ID No. 9, and a CDRL3 amino acid sequence shown in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region; and b) a pharmaceutically acceptable excipient.

In another aspect, the invention provides a prefilled syringe comprising from about 30mg to about 300mg of an antigen binding protein of the invention, or from about 30mg to about 200mg, e.g., the prefilled syringe may comprise from about 30mg to about 100mg of an antigen binding protein, e.g., 40mg or more, 50mg or more, 60mg or more, 70mg or more, 80mg or more, 90mg or more.

In one embodiment, a pre-filled syringe comprising a pharmaceutical composition as disclosed herein is provided.

In one embodiment, the heavy chain variable region of the antigen binding protein further comprises the heavy chain FR4 amino acid sequence shown as SEQ ID NO. 19. In another embodiment, the heavy chain Fc domain is an IgG1 Fc domain. In a further embodiment, the heavy chain Fc domain is a human IgG1 Fc domain.

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. Accordingly, the present invention also provides a prefilled syringe comprising about 100mg of an antigen binding protein that binds to IL-5, the antigen binding protein comprising: 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.

In one embodiment, the antigen binding protein is an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO. 1 and a light chain having the amino acid sequence set forth in SEQ ID NO. 2. Accordingly, the present invention also provides a prefilled syringe comprising about 100mg of an antibody that binds to IL-5 and a pharmaceutically acceptable excipient, the antigen binding protein comprising 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.

In one embodiment, the prefilled syringe is for subcutaneous administration. In a further embodiment, the prefilled syringe is administered to a human subject. The subject (prior to treatment) may have an absolute blood eosinophil count selected from the group consisting of: greater than or equal to 150 cells per μL, e.g., greater than or equal to 200 cells per μL.

In one embodiment, the prefilled syringe is administered about once every 6 months. In one embodiment, the prefilled syringe is administered about once every 26 weeks (Q26W).

In one embodiment, the prefilled syringe comprises an aqueous liquid formulation. The formulation may also comprise a solubilizing agent (e.g., arginine), a surfactant/anti-aggregation agent (e.g., polysorbate 80), a polyol (e.g., sugar), and/or a buffer as described herein.

The prefilled syringe may comprise a buffer selected from the group consisting of: histidine, disodium hydrogen phosphate heptahydrate, phosphate, citric acid, citrate, sodium phosphate, potassium phosphate and sodium citrate, providing a pH between 5.8 and 7.2 or a pH from pH 6.0 to pH 6.6, with a pH value of 6.0 being preferred. The buffer may be present in a range of about 10-30mM, about 10-20mM, about 20mM, or about 15.5 mM. In one embodiment, the formulation present in the prefilled syringe comprises histidine in the range of about 5-50mM, for example about 10-50mM, about 10-30mM, or about 10-20mM. For example, the buffer is present at about 20mM histidine.

In some embodiments, the prefilled syringe comprises a surfactant. Polysorbate 20 and 80, particularly polysorbate 80 (PS 80), are suitable surfactant stabilizers in the compositions of the present invention. Thus, the formulation in the prefilled syringe may further comprise polysorbate 80. Polysorbate 80 may be present in a weight to volume ratio in the range of about 0.01% to 0.1%, for example about 0.01% to about 0.05% or about 0.01% to about 0.03% w/v. For example, polysorbate 80 may be present in the formulation at a weight to volume ratio of about 0.02% (0.02% w/v).

The prefilled syringe may also contain EDTA. EDTA may be present in a range of about 0.01-0.1mM, for example about 0.02-0.08mM or about 0.03-0.06 mM. For example, EDTA may be present at about 0.05 mM.

The prefilled syringe may also contain sugar. In some embodiments, the formulation in the prefilled syringe comprises a polyol. In some embodiments, the polyol is a sugar, and preferably is a non-reducing sugar. In some embodiments, the non-reducing sugar is trehalose. Thus, the formulation in the prefilled syringe may also contain trehalose. In some embodiments, the formulation present in the prefilled syringe comprises trehalose in the range of about 100mM to about 250mM, for example about 150mM to about 200mM, particularly about 160mM to about 190mM. For example, trehalose may be present at about 180 mM.

The prefilled syringe may further comprise a solubilizing agent, such as arginine, e.g., L-arginine-HCl. In some embodiments, the formulation present in the prefilled syringe comprises arginine in the range of about 10mM to about 120mM, for example about 20mM to about 100mM, particularly about 30mM to about 50mM. In some embodiments, the composition comprises about 40mM arginine.

Specifically, the pH of the aqueous liquid formulation is about 6.0. Specifically, the pH of the liquid formulation is about 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, or 6.6. The formulation preferably contains an antigen binding protein and one or more pharmaceutically acceptable excipients. The excipient may be selected from one or more of the following groups: histidine, trehalose, arginine, EDTA and polysorbate 80. In a further embodiment, the excipient comprises histidine, trehalose, arginine, EDTA, and polysorbate 80. In a further embodiment, the prefilled syringe comprises an aqueous liquid formulation having a pH of about 6.0, containing an antigen binding protein and about 20mM histidine, about 180mM trehalose, about 40mM arginine, about 0.05mM EDTA and about 0.02% w/v polysorbate 80.

In some embodiments, the prefilled syringe may comprise EDTA present in the range of about 0.01-0.1mM, such as about 0.02-0.08mM or about 0.03-0.06mM. For example, EDTA may be present at about 0.05 mM. In some embodiments, the prefilled syringe may comprise 20-60mM histidine. In some embodiments, the prefilled syringe may comprise 30-110mM arginine. In some embodiments, the prefilled syringe may comprise 0-30mM methionine. In some embodiments, the prefilled syringe may comprise 0-110mM glycine. In some embodiments, the pre-filled syringe may comprise 0-350mM trehalose.

In one aspect, the invention provides a pre-filled syringe as disclosed herein for use in treating an IL-5 mediated disease. The IL-5 mediated disease may be asthma. Specifically, asthma is selected from the group consisting of: mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, eosinophilic asthma and subaeosinophilic asthma. Asthma may be mild or moderate asthma, for example mild or moderate eosinophilic asthma. Asthma may be severe asthma, such as severe eosinophilic asthma.

In one embodiment, the pre-filled syringe is provided in a Secure Syringe Device (SSD) or an auto-injector. Such devices are well known to those skilled in the art.

Combination therapy

In certain embodiments, the antigen binding proteins of the invention may be administered in combination with one or more (e.g., two) other therapeutic agents for the treatment of IL-5 mediated diseases (e.g., asthma).

These additional therapeutic agents may be administered via the same or different routes of administration. Furthermore, they may be administered in the same dose/dosing regimen as the antigen binding proteins or pharmaceutical compositions according to the invention.

If additional therapeutic agents are utilized, in one embodiment, the combined effect of the antigen binding protein and the additional therapeutic agent is greater than the sum of the individual effects. Thus, a combination of two or more therapeutic agents may provide a synergistic effect.

Combination therapy with one or more additional therapeutic agents includes co-administration (simultaneous administration) and sequential or serial administration. It is contemplated that the agents for combined use may be formulated as separate compositions, or may be formulated as a single pharmaceutical composition if all agents may be administered using the same dosing regimen.

Clause of (b)

In summary, the present disclosure includes:

1. A pharmaceutical composition comprising about 100mg to about 300mg of an antigen binding protein that binds IL-5 and a pharmaceutically acceptable excipient, wherein the antigen binding protein comprises a heavy chain variable region having the CDRH1 amino acid sequence set forth in SEQ ID No. 5, the CDRH2 amino acid sequence set forth in SEQ ID No. 6, and the CDRH3 amino acid sequence set forth in SEQ ID No. 7; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region.

2. The pharmaceutical composition of clause 1, comprising about 200mg or 100mg of the antigen binding protein.

3. The pharmaceutical composition of clause 1 or clause 2, wherein the heavy chain variable region of the antigen binding protein further comprises the heavy chain FR4 amino acid sequence set forth in SEQ ID No. 19.

4. The pharmaceutical composition of any one of clauses 1-3, wherein the heavy chain Fc domain is an IgG1 Fc domain.

5. The pharmaceutical composition of any one of clauses 1-4, wherein the heavy chain Fc domain is a human IgG1 Fc domain.

6. The pharmaceutical composition of any one of clauses 1-5, wherein 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.

7. The pharmaceutical composition of any one of clauses 1-6, wherein the antigen binding protein is an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID No. 1 and a light chain having the amino acid sequence set forth in SEQ ID No. 2.

8. The pharmaceutical composition of any one of clauses 1-7, wherein the pharmaceutical composition is for subcutaneous administration.

9. The pharmaceutical composition of any one of clauses 1-8, wherein the pharmaceutical composition is administered about once every 6 months.

10. The pharmaceutical composition of any one of clauses 1-8, wherein the pharmaceutical composition is administered about once every 26 weeks (Q26W).

11. The pharmaceutical composition of any one of clauses 1-10, wherein the pharmaceutical composition is administered to a human subject.

12. The pharmaceutical composition of clause 11, wherein the human subject has an absolute Blood Eosinophil Count (BEC) of greater than or equal to 300 or 200 cells per μl.

13. The pharmaceutical composition of any one of clauses 1-12, comprising an aqueous liquid formulation having a pH of about 6.0, the aqueous liquid formulation containing the antigen binding protein and histidine, trehalose, arginine, EDTA, and/or polysorbate 80.

14. The pharmaceutical composition of any one of clauses 1-13, comprising an aqueous liquid formulation having a pH of about 6.0, the aqueous liquid formulation containing the antigen binding protein and about 20mM histidine, about 180mM trehalose, about 40mM arginine, about 0.05mM EDTA, and about 0.02% by weight to volume polysorbate 80.

15. The pharmaceutical composition according to any one of clauses 1 to 14, for use in the treatment of IL-5 mediated diseases.

16. The pharmaceutical composition of clause 15, wherein the IL-5 mediated disease is asthma, inflammatory Bowel Disease (IBD), allergic bronchopulmonary aspergillosis (ABPA), eosinophilic polyangiitis (EGPA), eosinophilic syndrome (HES), nasal polyp disease (NP), chronic sinusitis with nasal polyp (CRSwNP), chronic sinusitis without nasal polyp (CRSsNP), or dermatitis.

17. The pharmaceutical composition of clause 16, wherein the disease is HES, EGPA CRSSNP, or CRSwNP.

18. The pharmaceutical composition of clause 16 or clause 17, wherein the EGPA is a relapsing-remitting or refractory eosinophilic granulomatosis with polyangiitis.

19. An antigen binding protein that binds to IL-5, said antigen binding protein comprising a heavy chain variable region having a CDRH1 amino acid sequence as set forth in SEQ ID No. 5, a CDRH2 amino acid sequence as set forth in SEQ ID No. 6, and a CDRH3 amino acid sequence as set forth in SEQ ID No. 7; and a light chain variable region having the CDRL1 amino acid sequence set forth in SEQ ID No. 8, the CDRL2 amino acid sequence set forth in SEQ ID No. 9, and the CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region for use in treating IL-5 mediated diseases by administration to a subject at a dose of about 100mg to about 300mg at a frequency of about once every 6 months.

20. The antigen binding protein for use according to clause 19, wherein the dose is about 100mg.

21. The antigen binding protein used according to clause 19 or clause 20, wherein the heavy chain variable region of the antigen binding protein further comprises the heavy chain FR4 amino acid sequence shown as SEQ ID NO. 19.

22. The antigen binding protein for use according to any one of clauses 19 to 21, wherein the heavy chain Fc domain is an IgG1 Fc domain.

23. The antigen binding protein for use according to any one of clauses 19 to 22, wherein the heavy chain Fc domain is a human IgG1 Fc domain.

24. The antigen binding protein for use according to any one of clauses 19 to 23, wherein 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.

25. The antigen binding protein for use according to any one of clauses 19 to 24, wherein the antigen binding protein is an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID No.1 and a light chain having the amino acid sequence set forth in SEQ ID No. 2.

26. The antigen binding protein for use according to any one of clauses 19 to 25, wherein the antigen binding protein is administered subcutaneously to the subject.

27. The antigen binding protein for use according to any one of clauses 19 to 26, wherein the antigen binding protein is administered to a human subject, e.g., an adult or pediatric human subject.

28. The antigen binding protein for use according to clause 27, wherein the human subject has an absolute blood eosinophil count of greater than or equal to 300 or 200 cells per μl.

29. The antigen binding protein for use according to any one of clauses 19 to 28, wherein the IL-5 mediated disease is selected from the group consisting of: asthma, inflammatory Bowel Disease (IBD), allergic bronchopulmonary aspergillosis (ABPA), eosinophilic polyangiitis (EGPA), eosinophilic syndrome (HES), nasal Polyposis (NP), chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps (CRSsNP), or dermatitis.

30. The antigen binding protein for use according to clause 29, wherein EGPA is relapsing remitting or refractory eosinophilic granulomatosis with polyangiitis.

31. An antigen binding protein for use according to clause 29, wherein the disease is: (i) CRSsNP and is of type 2 or eosinophil-type, have elevated eosinophil levels in the nasal mucosa, e.g., they may have blood eosinophils ≡150/. Mu.l, e.g., blood eosinophils ≡300/. Mu.l, or (ii) CRSwNP and the human subject has an endoscopic NP score of at least 5 points (top score 8 points), with the lowest score of 2 points per nasal cavity.

32. A pharmaceutical composition for use in treating an IL-5 mediated disease, wherein the composition comprises from about 100mg to about 300mg of an antigen binding protein that binds to IL-5, wherein the antigen binding protein comprises a heavy chain variable region having the CDRH1 amino acid sequence set forth in SEQ ID No. 5, the CDRH2 amino acid sequence set forth in SEQ ID No. 6, and the CDRH3 amino acid sequence set forth in SEQ ID No. 7; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region, and wherein the pharmaceutical composition is for administration to a subject about once every 6 months.

33. A pharmaceutical composition for use according to clause 32, comprising about 100mg of the antigen binding protein.

34. The pharmaceutical composition for use according to clause 32 or clause 33, wherein the heavy chain variable region of the antigen binding protein further comprises the heavy chain FR4 amino acid sequence as set forth in SEQ ID No. 19.

35. The pharmaceutical composition for use according to any one of clauses 32 to 34, wherein the heavy chain Fc domain is an IgG1 Fc domain.

36. The pharmaceutical composition for use according to any one of clauses 32 to 35, wherein the heavy chain Fc domain is a human IgG1 Fc domain.

37. The pharmaceutical composition for use according to any one of clauses 32 to 36, wherein 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.

38. The pharmaceutical composition for use according to any one of clauses 32 to 37, wherein the antigen binding protein is an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID No. 1 and a light chain having the amino acid sequence set forth in SEQ ID No. 2.

39. The pharmaceutical composition for use according to any one of clauses 32 to 38, wherein the pharmaceutical composition is for subcutaneous administration.

40. The pharmaceutical composition for use according to any one of clauses 32 to 39, wherein the pharmaceutical composition is administered to a human subject.

41. The pharmaceutical composition for use according to clause 40, wherein the human subject has an absolute blood eosinophil count of greater than or equal to 300 or 200 cells per μl.

42. The pharmaceutical composition for use according to any one of clauses 32 to 41, wherein the IL-5 mediated disease is selected from the group consisting of: asthma, inflammatory Bowel Disease (IBD), allergic bronchopulmonary aspergillosis (ABPA), eosinophilic polyangiitis (EGPA), eosinophilic syndrome (HES), nasal Polyposis (NP), chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps (CRSsNP), or dermatitis.

43. The pharmaceutical composition for use according to any one of clauses 32 to 42, wherein the pharmaceutical composition comprises an aqueous liquid formulation having a pH of about 6.0, the aqueous liquid formulation containing the antigen binding protein and histidine, trehalose, arginine, EDTA and/or polysorbate 80.

44. The pharmaceutical composition for use according to any one of clauses 32 to 43, wherein the pharmaceutical composition comprises an aqueous liquid formulation having a pH of about 6.0, the aqueous liquid formulation containing the antigen binding protein and about 20mM histidine, about 180mM trehalose, about 40mM arginine, about 0.05mM EDTA and about 0.02% by weight to volume polysorbate 80.

45. A method of treating an IL-5 mediated disease comprising administering to a subject in need thereof an antigen binding protein that binds to 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, in an amount of about 100mg to about 300mg, about once every 6 months; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region.

46. The method of clause 45, wherein the IL-5 mediated disease is selected from the group consisting of: asthma, inflammatory Bowel Disease (IBD), allergic bronchopulmonary aspergillosis (ABPA), eosinophilic polyangiitis (EGPA), eosinophilic syndrome (HES), nasal Polyposis (NP), chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps (CRSsNP), or dermatitis.

47. The method of clause 48, wherein the asthma is selected from the group consisting of: eosinophilic Granulomatosis (EGPA) with polyangiitis, eosinophilia (HES), chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps (CRSsNP).

48. A method of treating an IL-5 mediated disease in a subject, the method comprising

A) Identifying a subject having a disease selected from the group consisting of: eosinophilic Granulomatosis (EGPA) with polyangiitis, eosinophilia (HES), chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps (CRSsNP); and

B) Administering to the subject about 100mg to about 300mg, once every 6 months, of an antigen binding protein that binds 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 a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region;

Thereby treating the disease in the subject.

49. The method of any one of clauses 47 to 48, comprising administering about 100mg or about 200mg of the antigen binding protein.

50. The method of clause 49, wherein the IL-5 mediated disease is Eosinophilic Granulomatosis (EGPA) or eosinophilia (HES) with polyangiitis, and the method comprises administering the antigen binding protein in an amount of about 200 mg.

51. The method of clause 49, wherein the IL-5 mediated disease is selected from the group consisting of: chronic sinusitis with nasal polyps (CRSwNP) and chronic sinusitis without nasal polyps (CRSsNP), and the method comprises administering the antigen binding protein in an amount of about 100 mg.

52. The method of any one of clauses 47 to 51, wherein the heavy chain variable region of the antigen binding protein further comprises a heavy chain FR4 amino acid sequence as set forth in SEQ ID No. 19.

53. The method of any one of clauses 47-52, wherein the heavy chain Fc domain is an IgG1 Fc domain.

54. The method of any one of clauses 47 to 53, wherein the heavy chain Fc domain is a human IgG1 Fc domain.

55. The method of any one of clauses 47 to 54, wherein 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.

56. The method of any one of clauses 47 to 55, wherein the antigen binding protein is an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID No. 1 and a light chain having the amino acid sequence set forth in SEQ ID No. 2.

57. The method of any one of clauses 47 to 56, wherein the antigen binding protein is administered subcutaneously.

58. The method of any one of clauses 47 to 57, wherein the subject is a human subject.

59. The method of any one of clauses 47-58, wherein the subject has (a) an absolute blood eosinophil count at the start of treatment of (i) greater than or equal to 300 or 200 eosinophils per μl blood or (ii) greater than or equal to 150 eosinophils per μl blood and/or (b) a blood eosinophil count of greater than or equal to 300 eosinophils per μl blood over the past 12 months.

60. A method of reducing absolute blood eosinophil count in a subject, said method comprising:

a) Identifying a subject having a condition selected from the group consisting of: eosinophilic Granulomatosis (EGPA) with polyangiitis, eosinophilia (HES), chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps (CRSsNP); and

B) Administering to the subject an antigen binding protein that binds IL-5 comprising a heavy chain variable region having a CDRH1 amino acid sequence as set forth in SEQ ID No. 5, a CDRH2 amino acid sequence as set forth in SEQ ID No. 6, and a CDRH3 amino acid sequence as set forth in SEQ ID No. 7, in an amount of about 100mg to about 300mg, about once every 6 months; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region, thereby reducing absolute blood eosinophil count in the subject.

61. The method of clause 63, comprising administering the antigen binding protein in an amount of about 100mg or about 200 mg.

62. The method of clause 60 or clause 61, wherein the heavy chain variable region of the antigen binding protein further comprises the heavy chain FR4 amino acid sequence set forth in SEQ ID No. 19.

63. The method of any one of clauses 60-62, wherein the heavy chain Fc domain is an IgG1 Fc domain.

64. The method of any one of clauses 60-63, wherein the heavy chain Fc domain is a human IgG1 Fc domain.

65. The method of any one of clauses 60 to 64, wherein 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.

66. The method of any one of clauses 60 to 65, wherein the antigen binding protein is an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID No. 1 and a light chain having the amino acid sequence set forth in SEQ ID No. 2.

67. The method of any one of clauses 60 to 66, wherein the antigen binding protein is administered subcutaneously.

68. The method of any one of clauses 60 to 67, wherein the subject is a human subject.

69. The method of any one of clauses 60-68, wherein the absolute blood eosinophil count of the subject is greater than or equal to 200 or 300 cells per μl.

70. A prefilled syringe, comprising: a) About 100mg to about 300mg (e.g., in a total volume of about 1 mL) of an antigen binding protein that binds IL-5, said antigen binding protein comprising a heavy chain variable region having a CDRH1 amino acid sequence as set forth in SEQ ID No. 5, a CDRH2 amino acid sequence as set forth in SEQ ID No. 6, and a CDRH3 amino acid sequence as set forth in SEQ ID No. 7; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region; and b) a pharmaceutically acceptable excipient.

71. The pre-filled syringe of clause 70, wherein the pre-filled syringe comprises about 100mg or about 200mg of the antigen binding protein.

72. The pre-filled syringe of clause 70 or clause 71, wherein the heavy chain variable region of the antigen binding protein further comprises the heavy chain FR4 amino acid sequence set forth in SEQ ID No. 19.

73. The pre-filled syringe of any one of clauses 70-72, wherein the heavy chain Fc domain is an IgG1 Fc domain.

74. The pre-filled syringe of any one of clauses 70-73, wherein the heavy chain Fc domain is a human IgG1 Fc domain.

75. The pre-filled syringe of any one of clauses 70-74, wherein 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.

76. The pre-filled syringe of any one of clauses 70 to 75, wherein the antigen binding protein is an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID No. 1 and a light chain having the amino acid sequence set forth in SEQ ID No. 2.

77. The pre-filled syringe of any one of clauses 70-76, wherein the pre-filled syringe is for subcutaneous administration.

78. The pre-filled syringe of any one of clauses 70-77, wherein the pre-filled syringe is administered to a subject about once every 6 months.

79. The pre-filled syringe of any one of clauses 70-77, wherein the pre-filled syringe is administered to the subject about once every 26 weeks (Q26W).

80. The pre-filled syringe of any one of clauses 70-79, wherein the pre-filled syringe is administered to a human subject.

81. The pre-filled syringe of clause 80, wherein the pre-filled syringe comprises an aqueous liquid formulation having a pH of about 6.0, the aqueous liquid formulation containing the antigen binding protein and histidine, trehalose, arginine, EDTA, and/or polysorbate 80.

82. The pre-filled syringe of any one of clauses 70-81, wherein the pre-filled syringe comprises an aqueous liquid formulation having a pH of about 6.0 containing the antigen binding protein and about 20mM histidine, about 180mM trehalose, about 40mM arginine, about 0.05mM EDTA, and about 0.02% polysorbate 80 by weight volume.

83. The pre-filled syringe of any one of clauses 70-82, for use in treating an IL-5 mediated disease.

84. The pre-filled syringe of clause 88, wherein the IL-5 mediated disorder is selected from the group consisting of: HES, EGPA, CRSsNP or CRSwNP.

85. The pre-filled syringe of any one of clauses 74-84, wherein the pre-filled syringe is provided in a Secure Syringe Device (SSD) or an automatic syringe.

Examples

The following examples illustrate various non-limiting aspects of the invention. These examples are not intended to limit the scope of the invention in any way.

Interleukin 5 (IL-5) mediates eosinophil growth and differentiation in bone marrow and recruitment and activation in tissues (Corren, discov. Med.2012;13 (71): 305-312). Eosinophils have a circulating half-life of about 8 to 18 hours, but they can persist in tissues for longer periods of time (days to weeks) (Kovalszki & Weller, eosinopilia. 2016;43 (4): 607-617). IL-5 inhibition will eliminate key eosinophil growth factors and, given the short circulating half-life of eosinophils, it will lead to a rapid decrease in the circulating population. Eosinophil reduction has been identified as a therapeutic strategy for a number of diseases in which IL-5-targeting monoclonal antibodies (mAbs), such as, for example, meperiab, have been currently approved for the treatment of severe eosinophil asthma and are being developed for other indications (Legrand & Klion, J.allergy Clin.immunol. Practice.2015; 3 (2): 167-174).

28Y042-7F11-1 is an extended pharmacological humanized monoclonal antibody (immunoglobulin G1[ IgG1], kappa). It inhibits IL-5 signaling by blocking binding of human IL-5 to the IL-5 receptor complex expressed on the surface of eosinophils. anti-IL-5 monoclonal antibody therapy administered once every 4 weeks is well tolerated and approved as an additional maintenance therapy for patients with severe eosinophilic asthma. 28Y042-7F11-1 is expected to have similar efficacy and benefits as other IL-5 targeting monoclonal antibodies: risk profile, while administered at longer dosing intervals.

EXAMPLE 1 dose Studies

This is a single escalation dose, first human (FTIH) study aimed at studying 28Y042-7F11-1 safety, tolerability, immunogenicity, PK and PD, subcutaneous administration of participants with mild to moderate asthma, maintenance of low-to-moderate daily doses of Inhaled Corticosteroids (ICS) or ICS/long acting beta-agonists (LABA) and short acting beta-agonists (SABA).

Method of

Study design

28Y042-7F11-1 the first human study design is summarized in FIG. 1. Each participant received a single dose of 28Y042-7F11-1 or placebo as shown in figure 1.

Participants (participants)

Eligible participants were required to have a blood eosinophil count of 200 cells/. Gtoreq.200 cells/. Mu.L at the time of screening in order to study the decrease in blood eosinophil count after a single increment of 28Y042-7F11-1 dose and quantify the long-term blood eosinophil decrease expected in humans, given the expected prolonged half-life and higher IL-5 affinity of 28Y042-7F 11-1. Blood eosinophil pre-screening assessment was performed. If the participants had recorded blood measurements within 12 weeks prior to dosing showing blood eosinophil levels ∈200 cells/. Mu.L, they were eligible to skip the blood eosinophil pre-screening visit and go directly into the screening visit.

After successful completion of the screening, 48 participants with mild to moderate asthma, with blood eosinophils greater than or equal to 200 cells/μl at the time of screening, were randomly assigned and dosed. Participants were randomized according to the randomization plan generated Biostatistics using validated internal software prior to study initiation. The participants for each dose cohort were assigned a 3:1 ratio (active: placebo).

The follow-up period is up to 40 weeks post-administration and is dose dependent, based on the predicted blood eosinophil profile. Participants who received a queue of 2 and 10mg 28Y042-7F11-1 were at the clinic for a visit until week 32; participants who received 30 and 100mg of the 28Y042-7F11-1 cohort were at the clinic until week 36; participants who received a 300mg cohort were at the clinic and at the day 40.

Treatment of

The term "study treatment" as used herein may describe any combination of products that a participant has designed to accept according to a regimen.

TABLE 6 investigation of product Properties

Pharmacokinetic assessment

Blood samples were collected at pharmacokinetic sampling time points designed as part of the study for determination of 28Y042-7F11-1 plasma concentrations. Blood samples were collected via an indwelling cannula (or direct venipuncture) and collected into tripotassium ethylenediamine tetraacetic acid (K3 EDTA) tubes. Blood sample processing (i.e., centrifugation, then harvesting the resulting plasma and storing at-70 ℃) was completed within 2 hours after collection.

The concentration of 28Y042-7F11-1 in the plasma sample was determined using the bioanalytical method currently approved. Raw data is archived at a bioanalytical site.

Pharmacodynamic biomarkers

Serum samples were collected for this study to measure serum total IL-5 levels as a marker of target participation. Furthermore, blood eosinophil levels were measured as part of the hematology group as markers of pharmacological responses. As part of the study, samples were collected at designed time points.

Results

Plasma 28Y042-7F11-1 pharmacokinetic parameters

Table 7 summarizes the parameters of plasma 28Y042-7F11-1 PK obtained after a single subcutaneous administration of different doses (2 to 300 mg) of 28Y042-7F11-1 to participants with mild to moderate asthma.

TABLE 7 Single Subcutaneous (SC) administration of 28Y042-7F11-1 plasma pharmacokinetic parameters by participants after different doses of 28Y042-7F11-1

1. Geometric mean values of 95% Confidence Interval (CI) and variability (% CVb) are presented.

2. The median (min-max) is presented.

AUC (0- ≡) area under the concentration-time curve extrapolated from time zero (prior to dosing) to infinite time; AUC (0-t): area under the concentration-time curve for the participants from time zero (before dosing) to time of last quantifiable concentration in all treatments; AUC (0-week N): area under the concentration-time curve from time zero to week N (where n=4, 12 or 26); % AUCex: percentage AUC (0- ≡) obtained by extrapolation; CL/F: significant clearance (post-subcutaneous administration); cmax is as follows: maximum observed concentration; SC: subcutaneous administration; tlast, time to last quantifiable concentration; tmax: cmax time of occurrence; t1/2: end-stage half-life; vz/F: apparent distribution volume (after subcutaneous injection); λz: the rate constant is eliminated at the end stage.

Note that: in all cases, the number of observations (N) =n (number of participants).

In the SC dose range of 2 to 300mg, 28Y042-7F11-1 AUC (0- ≡), AUC (0-t) and Cmax increased with increasing 28Y042-7F11-1 dose. Within the dose range studied, the median tmax ranges from 8 to 14 days. The geometric mean 28Y042-7F11-1 t1/2 ranged from 38 to 53 days at different doses and was not dose dependent (range 38 to 44 days, excluding the 2mg dose, which% AUCex >20% and of the 4/6 participants, the calculated time period of t1/2 was less than twice the final t 1/2). There is no evidence that there is a tendency for target mediation. No significant change in CL/F was observed for 28Y042-7F11-1 over the 2mg to 300mg SC dose range studied (except for the 2mg dose), with a geometric mean ranging from 0.0807 to 0.160L/day (0.118 to 0.160L/day, excluding 2 mg). Similarly, the Vz/F of 28Y042-7F11-1 was consistent between doses studied, with a geometric mean ranging from 6 to 9L. The extrapolated part of the geometric mean of AUC (0- ≡) is smaller, ranging from 0.9% to 8% (excluding 2mg dose [24% ]).

Variability (% CVb) of 28Y042-7F11-1 systemic exposure (Cmax and AUC) is typically low to medium (7% -59%).

Blood eosinophil count

At baseline, the placebo group (0.359 GI/L) and the dose group (ranging from 0.288GI/L to 0.398 GI/L) had similar geometric mean blood eosinophil counts, with the baseline geometric mean blood eosinophil count measured for the 2mg group being lowest and the baseline geometric mean blood eosinophil count for the 30mg group being highest. From the evaluation after the first dose (24 hours), the blood eosinophil count was significantly reduced for all dose groups (compared to little change for placebo), and the reduction was highest for most dose groups at week 8. There was no significant difference in the magnitude of the decrease in blood eosinophil count between the dose groups until week 8. However, there was a dose-related difference in the duration of the decrease, where inhibition of blood eosinophils was maintained longer with increasing dose (fig. 2).

Fig. 3 presents the results of Mixed Model Repeat Measurement (MMRM) analysis of blood eosinophil data adjusted for baseline blood eosinophil count differences to baseline ratio.

At week 26 (6 months), the 100mg and 300mg groups had more than 80% decrease in blood eosinophils from baseline, adjusting the geometric mean ratio to 0.199 and 0.186 for baseline blood eosinophils, respectively (table 8). The ratio of the adjusted geometric mean values for these groups was 0.178 and 0.166, respectively (i.e., 82% and 83% reduction) compared to placebo. At the 26 week time point, the probability of the ratio of blood eosinophil count to baseline after placebo adjustment was less than 0.25 (i.e., blood eosinophil count decreased by more than 75%) for the 100mg group and 96% for the 300mg group (fig. 3 and table 8).

Table 8-statistical analysis of blood eosinophil data to baseline ratio at week 26

Annotation: the log-transformed data was analyzed using MMRM model, where treatment, planning time points, and classification effects of treatment interactions with planning time points were fixed, and log baseline blood eosinophil count and continuous covariates of log baseline blood eosinophil count interactions with planning time points were fixed. The Toeplitz covariance structure was used.

Note that: n is the number of participants with non-missing data at the relevant scheduled time point.

Since the magnitude of the decrease in blood eosinophils was similar for each group at the early time points, it was not appropriate to fit a 4-parameter dose response Emax bayesian model at each time point. Dose-response relationship analysis was performed using bayesian models only at the 26 th week time point, which was measured in all queues and was the time point of primary interest. The results of this analysis are presented in table 9.

Table 9-statistical analysis of blood eosinophil data to baseline ratio at week 26 (Bayes Emax sensitivity analysis)

Annotation: analysis was performed using a 4-parameter Emax bayesian dose response model fitted to log-transformed data, including a log baseline blood eosinophil count as a covariate. All parameters in the model use a non-information prior.

Bayesian analysis supported MMRM analysis, in which blood eosinophils in the 100mg and 300mg groups were reduced by 79% and 83% from baseline, respectively (table 9). The ratio of the adjusted geometric mean values for these groups was 0.206 and 0.167, respectively (i.e., 79% and 83% reduction) compared to placebo group. At the 26 week time point, the probability of the ratio of blood eosinophil count to baseline after placebo adjustment was less than 0.25 (i.e., blood eosinophil count decreased by more than 75%) for the 100mg group and 96% for the 300mg group (table 9).

A second sensitivity analysis was performed after application of the windowing to ensure evaluation within acceptable time ranges for the planned visit date and time. At week 26, 1 participant was excluded from all treatment groups due to time bias. Nevertheless, the results were similar to the primary analysis, with a placebo-adjusted blood eosinophil count to baseline ratio of less than 0.25 (i.e., blood eosinophil count reduced by more than 75%) for the 100mg group and 97% for the 300mg group at the 26 week point.

Serum Total IL-5

The geometric mean serum total IL-5 (i.e., free IL-5 plus IL-5 bound to 28Y042-7F 11-1) (9.206 ng/L) was slightly lower at baseline than in the dose group (10.376 to 15.109 ng/L). Overall, the baseline value for most participants was below the quantitative limit of the assay for each dose group. Starting from week 1 (day 8), all participants in the dose group had measurable serum total IL-5 concentrations. Serum total IL-5 was increased from baseline for all dose groups in all study visits. However, no clear dose response was observed. In contrast, the geometric mean of placebo-group serum total IL-5 remained similar to baseline during the study (fig. 4).

Exploratory biomarker results

The study evaluated exploratory asthma biomarkers. Eosinophil-derived neurotoxin (EDN), eosinophil chemokine, macrophage-derived chemokine (MDC), monocyte chemotactic protein 4 (MCP-4/CCL 13) and thymus and activation regulating chemokine (TARC/CCL 17) levels were measured on days-1, 29 and 127. The eosinophil-derived neurotoxin levels were reduced after 28Y042-7F11-1 treatment, while other markers were unchanged. These results were similar to those of the meperiab treatment using the same biomarker set.

Security results

The study assessed safety and tolerability of a single subcutaneous administration of 28Y042-7F11-1 2mg, 10mg, 30mg, 100mg and 300mg compared to placebo in adult participants with mild to moderate asthma. All 28Y042-7F11-1 doses were well tolerated by the participants. The incidence of adverse events during placebo treatment was 92% and the incidence of adverse events during all doses was 81%. Serious adverse events or adverse events leading to withdrawal from the study were not reported.

Conclusion(s)

Over the dose range studied, 28Y042-7F11-1 was slowly absorbed, and the observed median tmax was 8-14 days and distributed into an apparent distribution volume of 6-9L. This volume corresponds to the approximate plasma and interstitial spaces, consistent with the reported values for typical monoclonal antibodies targeting soluble ligands. After tmax, the plasma concentration of 28Y042-7F11-1 was reduced in a single exponential manner with a geometric mean t1/2 of 38-53 days and a significant clearance of 0.0807-0.160L/day. These values represent an increase in half-life and a reduction in significant clearance of about two-fold compared to the other anti-IL-5 monoclonal antibody, meperimab (Nucala PI). The geometric mean pharmacokinetic parameters (Vz/F, CL/F and t 1/2) were consistent over the dose range studied and therefore dose independent, suggesting that 28Y042-7F11-1 PK was linear with no evidence of target-mediated propensity. Furthermore, cmax and AUC (0- ≡) were not significantly deviated from dose ratio in the SC dose range of 10-300mg except for the 2mg dose.

Since the 28Y042-7F11-1 single SC dose range (2 to 300 mg) studied over an extended period of time (up to 40 weeks after dosing) was very broad, the dose response of blood eosinophil count could be assessed. A significant decrease in blood eosinophil count was observed from the first post-dosing evaluation on day 2 (24 hours), and the highest decrease was observed in most dose groups at week 8. Although the decrease was dose independent until week 8, there was a significant dose response to return to baseline. At week 26 (6 months), after adjustment relative to baseline blood eosinophil count, blood eosinophils were reduced by 82% and 83% in the 100mg and 300mg groups, respectively, as compared to placebo. These reductions were similar to those reported for meperimab at the approved therapeutic dose (product information PI). At the 26 th week time point, the probability of the ratio of blood eosinophil count to baseline after placebo adjustment <0.25 (i.e., blood eosinophil count decrease > 75%) was 95% for the 100mg group and 96% for the 300mg group (MMRM analysis). These probabilities exceeded a predefined 80% success criterion. These results reflect an increase in the affinity of 28Y042-7F11-1 for IL-5 and an increase in the half-life of the antibody.

To sum up:

28Y042-7F11-1 was well tolerated in adult participants with mild/moderate asthma who received single doses of 28Y042-7F11-1, up to 300mg.

Geometric mean end-stage half-life (38 to 53 days) was increased by about two-fold compared to traditional IgG1 monoclonal antibodies targeting soluble ligands.

28Y042-7F11-1 reduced blood eosinophil count and a clear dose response was observed for return to baseline. At week 26, the post-adjustment reductions were 82% and 83% for the 100mg group and 300mg group, respectively, compared to placebo. The ratio of placebo-adjusted to baseline blood eosinophil count at week 26 for both doses met the predetermined success criteria.

Using the results of this study and the model-guided drug development (MIDD) principle, the dose and dosing frequency of 28Y042-7F11-1 best conforms to the established phase 3 meperiab-like blood eosinophil pharmacology, with additional flexibility of 100mg once every 6 months (or-Q26W-once every 26 weeks-as the terms are used interchangeably once every 6 months and Q26W) if the patient delays their next dosing (e.g., provides 4 weeks of flexibility).

Example 2 phase III clinical protocol-asthma

This prophetic example describes an expected phase III clinical study. Each placebo-controlled seizure study will last 12 months, administered in duplicate doses of study 28Y042-7F11-1 100mg SC, and will study the effects of adult and juvenile (. Gtoreq.12 years) patients with asthma and eosinophil phenotypes, inhaled Corticosteroids (ICS) plus additional controlled therapies and a repeated seizure history (12 months ≡2 times before), who have been shown to obtain clinical benefit from anti-IL-5 therapy. The 12 month study allowed for two repeated administrations of 28Y042-7F11-1 and was long enough to assess the efficacy of 28Y042-7F11-1 100mg SC on clinically significant seizure frequency and other relevant outcomes every 26 weeks, as well as the safety profile of adequate exposure.

After a minimum 1 week (up to 6 weeks) of lead-in period, 375 eligible subjects will be randomly allocated in a 2:1 ratio to receive 28Y042-7F11-1 100mg SC (n=350) or matched placebo (n=175). The first injection will be administered randomly. Subjects will be visited at weeks 2,4, then every 4 weeks, and again at week 26 to administer a second injection. The last visit (study end visit) will be at week 52. The subject may choose to continue with an open label extension study for 12 months, where subjects who have received 28Y042-7F11-1 will receive up to 2 additional doses, while subjects who have previously received placebo will receive up to 2 doses of 28Y042-7F11-1.

Eligible subjects were adults and adolescents (. Gtoreq.12 years) diagnosed with asthma, receiving moderate to high doses of ICS and at least one other control. The subject should have uncontrolled asthma as evidenced by ≡2 attacks within the previous 12 months (even if treatment is present). In the screening, the subject is required to have a blood eosinophil level of 150 cells/. Mu.L or more, or 300 cells/. Mu.L or more in the first 12 months of screening.

The primary outcome measure will be the frequency of clinically significant episodes (i.e., episodes requiring systemic corticosteroid and/or ER visits and/or hospitalization) during 12 months of treatment. In addition to seizures, other efficacy endpoints include pulmonary function (FEV 1 before and after bronchodilator use), asthma control (asthma control questionnaire-ACQ-5), quality of life measured with the sheng-georgette respiratory questionnaire (SGRQ), and diary card parameters including peak flow, rescue use, daily symptoms, and nocturnal arousal from asthma. Other measures of asthma control and treatment response will also be evaluated during the study.

Blood eosinophils will be measured and sparse PK samples (pre-dose, week 2, week 12, week 26, week 28, week 40 and week 52) will be collected throughout the treatment period. The study will include comprehensive safety and immunogenicity assessments to robustly characterize safety results after repeated dosing. Immunogenicity will be assessed at weeks 0, 2,4, 8, 12, 26, 28, 30, 32, 36, 40 and 52 prior to dosing.

28Y042-7F11-1 is expected to exhibit a clinical profile similar to that of meperimab. This is supported by the results of the study described in example 1, which collected pharmacokinetic, pharmacodynamic, safety and tolerability data. Single doses of up to 300mg SC (3-fold of the planned therapeutic dose) were evaluated in subjects with mild to moderate asthma but elevated blood eosinophils (200 cells/. Mu.L at screening). 28Y042-7F11-1 was well tolerated and no safety signal was detected. The effect on blood eosinophils was consistent with what was predicted from accumulated pharmacological knowledge of meperiab, with overall maximum blood eosinophil inhibition similar to that observed with 100mg SC/75mg IV of meperiab, although the inhibition period was prolonged compared to previously observed meperiab.

Thus, in addition to two seizure studies, a supportive study was proposed that recruited about 1,700 adult and adolescent subjects (. Gtoreq.12 years) currently undergoing treatment with either meperiab or present rituximab. The subjects will be randomized in a 1:1 ratio either to continue their existing treatment or to change to 28Y042-7F11-1 100mg SC every 26 weeks. The study was designed to take advantage of non-poor efficacy, indicating that 28Y042-7F11-1 100mg SC treatment every 26 weeks is not inferior to existing anti-IL-5 therapies in terms of clinically significant episode rate (i.e., episodes requiring systemic corticosteroid and/or ER visits and/or hospitalization) and other asthma control markers.

After a minimum 1 week (up to 6 weeks) of lead-in period, 1,600 subjects will be randomly allocated in a 1:1 ratio to receive 28Y042-7F11-1 100mg SC once every 26 weeks (n=800) or continue their existing treatment (n=800). At the time of randomization, subjects will receive two injections of active 28Y042-7F11-1 100mg and placebo matching meperiab/present rayleigh mab (depending on the subject's previous treatment), or placebo 28Y042-7F11-1 and active meperiab 100mg SC/present rayleigh mab 30mg SC (depending on their previous treatment), respectively. Thereafter, a clinical visit was made every 4 weeks, wherein subjects previously treated with meperiab received 100mg SC or matched placebo injections every 4 weeks. Subjects previously receiving the present rayleigh mab treatment will receive 30mg SC injections of the present rayleigh mab every 8 weeks or matched placebo injections. Further visits will be made at week 26 to administer 28Y042-7F11-1 100mg SC or matched placebo. The end of treatment visit will be at week 52 and the follow-up visit will be at week 56.

Eligible subjects were adults and adolescents (12 years or more) who were receiving treatment with either meperiab or present rituximab for at least 12 months prior to enrollment and have shown a confirmed response to anti-IL-5 therapy by assessing (1) a decrease in frequency of episodes by 50% or (2) a decrease in maintenance OCS usage by 50% or (3) no episodes in the last 6 months during anti-IL-5 treatment and an ACQ-5 score of 1.5 or less at screening. The subject must have obtained demonstrated clinical benefits from current anti-IL-5 therapies, whether a reduction in frequency of episodes and/or a reduction in maintenance oral corticosteroid therapy prior to initiation of anti-IL-5 therapy, as confirmed by the attending physician. In addition to anti-IL-5 treatment, subjects should also receive a medium or high dose of inhaled corticosteroid plus another controlling drug to treat asthma.

The primary outcome variable is the frequency of clinically significant episodes during 12 months of treatment. In addition, other efficacy measures include pulmonary function (FEV 1 before and after use of bronchodilators), asthma control assessed by the asthma control questionnaire (ACQ-5), quality of life using the sheng-georgette respiratory questionnaire (SGRQ), and diary card parameters (symptoms, peak flow, rescue use, and nocturnal arousal due to asthma). Other measures of asthma control and treatment response will also be evaluated throughout the course of the study.

Blood eosinophils will be measured throughout the treatment period. The study will include comprehensive safety and immunogenicity assessments to robustly characterize safety results after repeated dosing. Immunogenicity will be assessed at weeks 0, 4, 8, 12, 26, 40 and 52 prior to dosing.

Formulations

Previous studies have employed a 28Y042-7F11-1 injectable liquid formulation, 150mg/mL, provided in vials as a sterile, preservative-free, single use aqueous solution. The required dose level was prepared at the clinical site by dilution with saline and then injected as Subcutaneous (SC) doses (single injection up to 100mg dose, 3 injections 300mg dose).

Phase 3 studies were initiated with new formulations based on the previous formulations. The changes of the new preparation and the original preparation are as follows: 28Y042-7F11-1 concentration was reduced from 150mg/mL to 100mg/mL, methionine was removed, and the concentration of some excipients was reduced (Table 10).

TABLE 10 product Profile

During these studies, a 100mg/mL 28Y042-7F11-1 injection would be provided as a disposable sterile liquid Drug (DP) in a clear glass prefilled syringe (PFS) that could deliver 100mg of 28Y042-7F11-1 for subcutaneous administration. The DP primary container and closure consisted of a 1mL long type I glass siliconizing cylinder, a 29G thin wall x 12.7mm stainless steel needle, and a thermoplastic elastomer needle shield covered with a rigid plastic shield and sealed with a brominated butyl elastomer rubber stopper. The prefilled syringe will be assembled into a safety syringe device-BD UltraSafe Passive Plus safety devices.

The 28Y042-7F11-1 formulation detailed in Table 10 has particularly good stability and is found to remain stable after storage for up to 18 months at the recommended long-term storage temperatures of 2-8deg.C. In addition, the drug remains stable after storage for 1 month at-20 ℃, 0.5 month at 30 ℃/65% Relative Humidity (RH), and 3 freeze-thaw cycles. The injectable medicine (100 mg/mL) is stored at 2-8deg.C (36-46 deg.F) in the dark for 30 months.

Example 3 modeling to determine the dosage of chronic sinusitis with nasal polyps (CRSwNP) and chronic sinusitis without nasal polyps (CRSsNP)

The 28Y042-7F11-1 dose and dosing frequency of 100mg every 26 weeks suggested in the CRSwNP phase 3 study was determined using the model-guided drug development (MIDD) principle. The selected 28Y042-7F11-1 dosing regimen was very similar to the blood eosinophil pharmacology observed with meperimab in the critical phase 3 trial in CRSwNP population throughout the treatment period. Before the proposed phase 3 program in CRSwNP is started, a further 28Y042-7F11-1 dose range is considered unnecessary. Simulation analysis showed that there would be limited additional benefit in terms of blood eosinophilia, except for the recommended 28Y042-7F11-1 100mg SC dose administered every 26 weeks; while lower doses would not be in line with the desired blood eosinophil pharmacology and would therefore likely be ineffective. The doses in CRSsNP were chosen in a similar manner, assuming the desired pharmacological equivalence of blood eosinophils between CRSwNP and CRSsNP.

The desired blood eosinophil pharmacology was known from a critical phase 3 trial with meperimab. In the key phase 3 trial of CRSwNP, after 100mg of meperidine administered per 4 weeks of SC, steady state eosinophils were reduced by 84% from baseline. In a 100mg day queue receiving SC administration of meperidine at every 4 weeks, this reduction translates to a geometric mean (std log) of blood eosinophil count at 52 weeks equal to 0.06 (0.768) GI/L. The pharmacological level is associated with clinical efficacy. At the end of the 52-week treatment period, the proportion of participants in the mellimab group that showed a 1-point increase in total endoscopic NP score was higher than that in the placebo group (50% and 28%, respectively), and the proportion of participants in the contemporaneous mellimab group that had a deterioration in total endoscopic NP score was less than that in the placebo group (22% and 30%, respectively). For the common primary endpoint of change in endoscopic NP scores from baseline at week 52, the median change for the meperimab group was-1.0, while the placebo group was 0. There was a statistically significant improvement in this endpoint for meperimab. Furthermore, in severe eosinophilic asthma (a disease with many common features to CRSwNP), the use of approved doses of meperimab (100 mg administered every 4 weeks SC) resulted in 86% and 81% decrease in blood eosinophils, with a sustained decrease in annual rate of about 50% in phase 3 trials. Simulation analysis showed that there was limited additional benefit in terms of blood eosinophilia, except for the proposed 28Y042-7F11-1 dosing regimen of 100mg per 26 weeks SC administration. Furthermore, the simulation analysis showed that the lower dose did not match the desired eosinophil pharmacology and was therefore likely ineffective.

The selection based on targeting the previous 28Y042-7F11-1 dose and dosing frequency of the meperiab pharmacology is effective and rapid because:

28Y042-7F11-1 targets the same IL-5 epitope as the mepolimumab, thus, upon establishment of the same blood eosinophilia reduction as the mepolimumab, a similar clinical efficacy was expected to be generated in the CRSwNP and CRSsNP patient populations selected in these studies via the same IL-5 neutralization;

the previous safety profile for IL-5 neutralization was comparable to placebo.

The PK-blood eosinophil model used to support 28Y042-7F11-1 dose selection was a newer model based on an indirect exposure-eosinophil model developed from data of 16 meperiab studies that collected pharmacokinetic samples, blood eosinophil count measurements, and covariates during the clinical development of meperiab for various eosinophil conditions and healthy subjects. The model was parameterized by baseline blood eosinophils (KRO), elimination (KOUT), maximum inhibitory effect (Imax), concentration that resulted in 50% of maximum inhibitory drug effect (IC 50) and the hill coefficient (GAMA). Differences between subjects included baseline blood eosinophils and maximum drug effects using an exponential model. The baseline blood eosinophil count measured was a covariate of KRO and Imax. The disease is a covariate of KRO. The model has been updated to maintain the same model structure to reflect the longer half-life and enhanced efficacy of 28Y042-7F11-1 compared to meperiab. Model IC50 parameters, differences between subjects, and residual unexplained differences were estimated from PK and eosinophil data in a single escalation dose phase I study of 28Y042-7F11-1 in mild to severe asthma. The effect of baseline eosinophil levels on baseline blood eosinophils that maximally achieved drug-inhibition response and model predictions were considered to be identical between meperiab and 28Y042-7F 11-1.

The 28Y042-7F11-1 PK-blood eosinophil model was based on the 28Y042-7F11-1 PK model developed from the data of the 28Y042-7F11-1 1 phase study and the updated PK-blood eosinophil model. The baseline eosinophil level simulated in CRSwNP reflects the value observed for meperiab in the CRSwNP phase 3 key trial (0.39 GI/L). The CRSsNP baseline simulated eosinophil levels reflect the range of values reported in literature CRSsNP (0.2-0.4 GI/L; J Allergy Clin. Immunol.2020Aug;146 (2) pp 337-343).

Model parameter values for simulation are sampled from a multivariate normal distribution centered on the parameter estimate, where covariance reflects uncertainty in the parameter estimate. The remaining unexplained differences are included in the simulation. Simulation results are summarized in terms of logarithmic geometric mean and standard deviation and 95% prediction interval.

Example 4 modeling to determine the dose of Eosinophilic Granulomatosis (EGPA) with polycystic inflammation

The 28Y042-7F11-1 dose and dosing frequency of 200mg every 26 weeks suggested in the EGPA 3 phase study was determined using the model-guided drug development (MIDD) principle. The selected 28Y042-7F11-1 dosing regimen was very similar to the blood eosinophil pharmacology observed with meperimab in the critical phase 3 trial of the EGPA population throughout the treatment period. Before the proposed phase 3 program is started, a further 28Y042-7F11-1 dose range is considered unnecessary. Simulation analysis showed that there was limited additional benefit in terms of blood eosinophilia, except for the recommended 28Y042-7F11-1 200mg SC dose administered every 26 weeks; while lower doses would not be in line with the desired blood eosinophil pharmacology and would therefore likely be ineffective.

Through a critical phase 3 trial with melitumumab in EGPA, the desired blood eosinophil pharmacology was known, with 32% of the participants in the melitumumab group reaching remission at both week 36 and week 48 (whereas the placebo group was 3%). In the experiments, steady state eosinophils were reduced by 79% from baseline after 300mg of meperiab administered every 4 weeks SC. In the cohort receiving 300mg SC administration of meperiab every 4 weeks, this reduction translates into a geometric mean (std log) of blood eosinophil count at the end of the treatment period, equal to 0.038 (0.9398) GI/L. Simulation analysis showed that there was limited additional benefit in terms of blood eosinophilia, except for the proposed dosing regimen of 200mg of 28Y042-7F11-1 administered per 26 weeks of SC. Furthermore, the simulation analysis showed that the lower dose did not match the desired eosinophil pharmacology and was therefore likely ineffective.

28Y042-7F11-1 targets the same IL-5 epitope as the mepolimumab and therefore, after establishing the same blood eosinophilia reduction as the mepolimumab, via the same IL-5 neutralization, is expected to generate similar clinical efficacy in the EGPA patient population selected in this study;

the previous safety profile for IL-5 neutralization was comparable to placebo.

The 28Y042-7F11-1 PK-blood eosinophil model was based on the 28Y042-7F11-1 PK model developed from the data of the 28Y042-7F11-1 1 phase study and the updated PK-blood eosinophil model. Baseline simulated eosinophil levels reflect the values observed in the key phase 3 trial of meperiab in EGPA (i.e., 0.177 GI/L) and higher (i.e., 1.0 GI/L), and more reflect the disease burden in gradually decreasing oral corticosteroid doses during treatment, with target oral corticosteroid doses below 4 mg/day.

Example 5 modeling to determine dose for eosinophilia (HES)

The 28Y042-7F11-1 dose and dosing frequency of 200mg every 26 weeks suggested in the HES 3 phase study were determined using the model-guided drug development (MIDD) principle. The 28Y042-7F11-1 dosing regimen selected was very similar to the blood eosinophil pharmacology observed with meperimab in the critical phase 3 trial of the HES population throughout the treatment period. Before the proposed phase 3 program is started, a further 28Y042-7F11-1 dose range is considered unnecessary. Simulation analysis did show that there is limited additional benefit in terms of blood eosinophilia, except for the recommended 28Y042-7F11-1 200mg SC dose administered every 26 weeks; while lower doses would not be in line with the desired blood eosinophil pharmacology and would therefore likely be ineffective.

Through a critical phase 3 trial with meperiab in HES, the expected blood eosinophil pharmacology was known, with a 50% reduction in the number of participants undergoing HES episodes or exiting the study for meperiab treatment compared to placebo. In the experiments, steady state eosinophils were reduced by 95% from baseline after 300mg of meperiab administered every 4 weeks SC. In the cohort receiving 300mg SC administration of meperiab every 4 weeks, this reduction translates into a geometric mean (std log) of blood eosinophil count at the end of the treatment period, equal to 0.07 (1.299) GI/L. Simulation analysis showed that there was limited additional benefit in terms of blood eosinophilia, except for the proposed 28Y042-7F11-1 dosing regimen of 200mg per 26 weeks SC administration. Furthermore, the simulation analysis showed that the lower dose did not match the desired eosinophil pharmacology and was therefore likely ineffective.

28Y042-7F11-1 targets the same IL-5 epitope as the mepolimumab and therefore, after establishment of the same blood eosinophilia reduction as the mepolimumab, via the same IL-5 neutralization, is expected to generate similar clinical efficacy in the HES patient population selected in this study;

the previous safety profile for IL-5 neutralization was comparable to placebo.

The 28Y042-7F11-1 PK-blood eosinophil model was based on the 28Y042-7F11-1 PK model developed from the data of the 28Y042-7F11-1 1 phase study and the updated PK-blood eosinophil model. Baseline simulated eosinophil levels reflected the values observed for meperimab in the HES 3 phase key trial (i.e., 1.46 GI/L).

EXAMPLE 6 phase III clinical protocol-chronic sinusitis with nasal polyps (CRSwNP)

This prophetic example describes an expected phase III clinical study.

This is a phase III study of about 250 CRSwNP adults in a randomized, double-blind, placebo-controlled, parallel group, de Mo Jishan anti (depemokimab) 100mg+ standard therapy (SoC). The purpose of this study was to evaluate the effectiveness and safety of 100mg of De Mo Jishan antibody (28Y 042-7F 11-1), administered Subcutaneously (SC) by on-site personnel, via a pre-filled safety syringe device once every 6 months + SoC for 52 weeks. The efficacy of the Mo Jishan antibodies will be assessed using a common primary endpoint, namely the change in total endoscopic Nasal Polyp (NP) score from baseline at week 52 and the change in average nasal obstruction VRS score from baseline at weeks 49 to 52.

The study population will consist of adult participants (18 years) with CRSwNP. Furthermore, participants must have an endoscopic NP score of at least 5 points (8 points maximum score), with a minimum score of 2 points per nasal cavity. Participants must also receive Systemic Corticosteroid (SCS) treatment at any time during the past 2 years; and/or medical contraindications/intolerances to SCS; and/or a history of NP surgery at the screening visit.

The study will include a 4 week lead-in period followed by a random 52 week treatment period as a double blind, placebo-controlled period. The total study time was about 56 weeks. Randomization will be stratified according to the occurrence of past nasal polyp surgery and country. The participants will be randomly assigned to one of the two treatment groups at a 1:1 ratio, receiving 100mg of De Mo Jishan anti-SC or placebo (all except SoC) for a total of two doses (26 weeks apart).

Throughout the study period (lead-in period + treatment period), participants will participate in the CRSwNP SoC. Depending on local practice, the SoC will include INCS, saline flush nasal cavity, occasional short-term use of systemic corticosteroids, and/or antibiotics. Depending on the local SoC/therapy, patients receiving INCS and/or LTRA treatments should continue these treatments as much as possible throughout the study, without interruption and without changing the dose. If the participants did not receive INCS or LTRA prior to screening, the participants were prohibited from starting any INCS or LTRA during the study.

Key primary endpoints include:

change from baseline in total endoscope NP score at week 52.

Mean nasal obstruction VAS score change from baseline 4 weeks prior to week 52.

Key inclusion criteria include:

when signing informed consent, men or women aged 18 years and older.

The endoscopy bilateral NP score assessed by the investigator was at least 5 points, with a top score of 8 points (with each nasal being 2 points at a minimum).

Participants who had at least one of the following at visit 1:

Nasal surgery was performed to remove NPs;

Systemic corticosteroids have been used for at least three consecutive days over 2 years to treat NP;

Medically unsuitable use of systemic corticosteroids sterols or intolerant systemic corticosteroids.

Participants with severe NP symptoms defined as moderate or severe (VRS score of 2 or 3) nasal obstruction or blockage or obstruction, as well as loss of sense of smell or runny nose (runny nose) symptoms.

At least 2 different symptoms described by chronic sinusitis symptoms exist at least 12 weeks prior to visit 1, one of which should be runny nose (anterior/posterior nasal drops), plus facial pain/pressure and/or hypoolfaction or loss.

EXAMPLE 7 phase III clinical protocol-eosinophilic granulomatosis with polyangiitis (EGPA)

This prophetic example describes an expected phase III clinical study.

This is a randomized, double-blind, double-mock, parallel-group, multicentric, non-inferior study over a period of 52 weeks aimed at studying the efficacy and safety of the Mo Jishan antibody (28Y 042-7F 11-1) compared to meperiab in adult participants with a history of recurrent or refractory EGPA who are receiving stable corticosteroid therapy with or without stable immunosuppressive therapy.

The subject needs to take a stable dose of OCS, i.e., 7.5 mg/day or more of prednisolone/prednisone (but not >50 mg/day), at least 4 weeks before baseline. Participants receiving other immunosuppressive therapies must maintain a stable dose at least 4 weeks before baseline (randomized group/visit 2) and should continue with immunosuppressive therapy during the study.

The participants will be randomly allocated at a 1:1 ratio to receive 200mg of De Mo Jishan antibody (administered as a 2x 100mg injection, once every 26 weeks of SC) as an additional treatment for SoC therapy, or 300mg of meperiab (administered once every 4 weeks of SC) as an additional treatment for standard therapy (SoC therapy).

Throughout the regimen, de Mo Jishan anti-treatment refers to the administration of 200mg De Mo Jishan anti-as an additional treatment to SoC treatment every 26 weeks of SC, while the treatment of meperimumab refers to the administration of meperimumab as an additional treatment to SoC treatment every 4 weeks of SC.

The study will include screening/introduction period (1 to 4 weeks), intervention period (52 weeks) and follow-up period (4 weeks).

Approximately 192 participants will be screened to ensure 160 randomly assigned participants (approximately 80 participants will be randomly assigned to 200mg of De Mo Jishan antibody, approximately 80 participants will be randomly assigned to 300mg of meperiab).

Intervention group and duration:

The participants will receive 200mg of De Mo Jishan antibody every 26 weeks (weeks 0 and 26) or 300mg of meperiab every 4 weeks, administered using a pre-filled safety syringe (PFS) SC while continuing their SoC EGPA therapy. The duration of treatment was 52 weeks followed by a 4 week non-treatment follow-up period. The last dose of De Mo Jishan antibody will be administered at week 26 and the last dose of meperiab will be administered at week 48.

The main end point is:

remission occurs at both week 36 and week 52

Relief is defined as a bermingham vasculitis activity score, BVAS =0 and OCS dose of 4 mg/day

EGPA remission and recurrence includes two components:

Symptom change

Variation in OCS dose.

Key inclusion criteria include:

age of greater than or equal to 18 years

-Diagnosing an EGPA for at least 6 months based on the following history or manifestation: asthma plus eosinophilia (> 1.0x10 ⁹/L and/or >10% leukocytes) and at least two additional EGPA characteristics

History of recurrent or refractory disease

The stable dosage of prednisolone orally taken at least 4 weeks before the base line is more than or equal to 7.5 mg/day (but not more than 50 mg/day). If IS treatment IS received, stability must be maintained 4 weeks before baseline and during the study.

Example 8 phase III clinical protocol-eosinophilia (HES)

This prophetic example describes an expected phase III clinical study: this is a 52 week, randomized, placebo controlled, double blind, parallel group, multicenter study of the anti-Mo Jishan in uncontrolled HES adults (. Gtoreq.18 years) receiving standard of care (SoC) treatment.

The study will enroll male and female patients diagnosed with HES and receiving at least 4 weeks of stable HES treatment prior to randomization (visit 2). Eligible participants had to have uncontrolled HES with a history of recurrent episodes (episodes > 2 over the last 12 months) and blood eosinophil counts > 1,000 cells/μl during screening. Historical HES episodes are defined as recorded clinical symptoms associated with HES or worsening of blood eosinophil count, requiring intensive treatment.

The participant will take part in the screening visit (visit 1) and must sign up for consent before any screening activity is initiated. Participants meeting inclusion and exclusion criteria will be randomly allocated at a 2:1 ratio to receive 200mg of de Mo Jishan antibody (2 injections, 100mg each) or placebo (SC administration while continuing their SoC HES treatment) every 6 months (weeks 0 and 26).

Participant management during the study will follow conventional medical care, i.e., the participants will be instructed to contact their researchers for evaluation, or seek necessary emergency care according to their usual practices as symptoms worsen. Researchers will use HES Core ASSESSMENTS V2 to assess whether HES episodes are present (unplanned episode visit).

Approximately 120 participants will be randomly assigned (approximately 80 participants randomly assigned to 200mg of De Mo Jishan antibody, 40 participants randomly assigned to placebo).

Participants will receive 200mg of des Mo Jishan antibody or placebo every 6 months (weeks 0 and 26) via pre-filled safety syringe SC administration while continuing their SoC HES treatment. The duration of the study intervention was 52 weeks. The last dose of study intervention will be administered at week 26. All participants will have an additional follow-up period of up to 4 weeks, i.e. 30 weeks after the last dose was administered.

The main end point is:

the ratio of 200mg SC plus SoC to placebo plus SoC per 26 weeks of de Mo Jishan was determined to exceed the frequency of HES episodes in HES participants for 52 weeks, whether treatment was stopped for any reason, and whether or not an alternative HES medication was received,

The frequency of HES episodes during the 52 week treatment period was determined.

HES episode definitions:

HES-related clinical manifestations are based on changes in clinical signs/symptoms recorded by the doctor, and therefore require:

Maintenance OCS dose escalation

Any cytotoxic and/or immunosuppressive HES therapies are added or added.

Treatment period received 2 or more blind active OCS courses (eosinophil onset)

Key inclusion criteria include:

male and female with age equal to or more than 18 years old

The pre-random grouping diagnosis is HES:

1,500 eosinophils/μl blood eosinophils were present at least 2 times at an interval of 1 month or more, and no obvious non-hematologic secondary cause, and

Signs or symptoms of organ involvement and/or dysfunction directly associated with eosinophils

There was a history of 2 or more HES episodes within 12 months prior to screening:

the clinical symptoms associated with HES or worsening of blood eosinophil count require an increase or upgrade of OCS or cytotoxic/immunosuppressive therapy.

At least one HES episode occurred in the past 12 months and was not associated with a decrease in HES treatment within 4 weeks prior to the episode.

EXAMPLE 9 phase III clinical protocol-chronic sinusitis with nasal polyps (CRSsNP)

This is a prophetic example, widely describing prospective phase III clinical studies:

This is a randomized, double-blind, placebo-controlled parallel group phase 3 study of the efficacy and safety of 100mg of SC Mo Jishan antibody (28Y 042-7F 11-1) against participants ≡12 years old who had CRSsNP and had a baseline BEC ≡300 cells/. Mu.l. The purpose of this study was to evaluate the effectiveness and safety of Mo Jishan against 100mg sc+soc, administered by field personnel via a pre-filled safety syringe device, once every 26 weeks for 52 weeks. Efficacy of the Mo Jishan antibody will be assessed using a common primary endpoint of change in LMK CT score from baseline to week 52 and change in nasal obstruction VRS score from baseline to week 52.

The study population may consist of adolescent (. Gtoreq.12-17 years) and adult (. Gtoreq.18 years) participants with CRSsNP. In addition, participants may have a Blood Eosinophil Count (BEC) of 300 cells/. Mu.L or more at the time of screening, a CT scan LMK score of 8 or more prior to random grouping, and a double sided screen Dou Hunzhuo. Furthermore, in order for participants to qualify, they must have no loss of olfactory and runny nose (anterior/posterior) symptoms of any severity for at least 12 weeks prior to visit 1, with or without facial pain/pressure, at least 12 weeks NC prior to the first visit, and an NC score of ∈2 at the first visit (daily comment points) and at the second visit (weekly average score). Participants also required sTSS (NC, runny nose, facial pain/pressure) scores ∈5 on visit 1 (daily comment points) and visit 2 (weekly average scores). The participants must receive prior SCS treatment at any time during the past 2 years; and/or medical contraindications/intolerances to SCS; and/or a prior surgical history of CRS recorded at screening visit, and symptoms are recurring despite treatment with appropriate care standards. Participants (except japan) must receive intranasal corticosteroid (INCS) treatment daily for at least 8 weeks prior to screening [ including intranasal liquid steroid washout/rinsing ]. The study will include a 4 week lead-in period followed by a randomized 52 week double-blind placebo-controlled treatment period and a 4 week safety follow-up period. The total study time was about 60 weeks (including the follow-up period). The random groupings will be stratified based on the occurrence of past sinus surgery and the country.

The participants will be randomly assigned to one of the two treatment groups at a 1:1 ratio, receiving 100mg of de Mo Jishan anti-SC or placebo (all but SoC), for a total of two doses (26 weeks apart). Throughout the study period (lead-in period + treatment period), participants will participate in the CRSsNP SoC. Depending on local practice, the SoC may include INCS, saline flush nasal cavity, occasional short-term use of systemic corticosteroids, and/or antibiotics.

The main objective of this study was to evaluate the superiority of de Mo Jishan anti-SoC versus placebo + SoC by the following common main endpoint:

a) Variation of mean nasal obstruction VRS score from baseline to week 52

B) The change in sinus turbidity from baseline to week 52 was assessed by CT scan using the Lund Mackay score (LMK) score.

Sequence(s)

SEQ ID NO 1-full length heavy chain

SEQ ID NO 2-full length light chain

SEQ ID NO 3-VH sequence

SEQ ID NO 4-VL sequence

SEQ ID NO 5–CDRH1

GSSVH

SEQ ID NO 6–CDRH2

VIWASGGTDYNSALMS

SEQ ID NO 7–CDRH3

DPPSGLLRLDY

SEQ ID NO 8–CDRL1

KSSQSLLNSGNQKNYLA

SEQ ID NO 9–CDRL2

GASTRES

SEQ ID NO 10–CDRL3

QNVHSFPFT

SEQ ID NO 11-human IL-5 (mature protein)

SEQ ID NO 12-human IL-5 receptor subunit alpha isoform 1 (mature protein)

SEQ ID NO 13-DNA encoding the full-length heavy chain and the leader sequence

SEQ ID NO 14-DNA encoding the full-length light chain and the leader sequence

SEQ ID NO 15-DNA encoding a heavy chain variable region

SEQ ID NO 16-DNA encoding a light chain variable region

SEQ ID NO 17-DNA encoding a full-length heavy chain

SEQ ID NO 18-DNA encoding a full-length light chain

SEQ ID NO 19-heavy chain FR4 sequence

WGRGTLVTVSS

Having now fully described the invention, it will be apparent to those skilled in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the appended claims.

Claims

1. A pharmaceutical composition comprising about 100mg to about 300mg of an antigen binding protein that binds IL-5 and a pharmaceutically acceptable excipient, wherein the antigen binding protein comprises a heavy chain variable region having the CDRH1 amino acid sequence set forth in SEQ ID No. 5, the CDRH2 amino acid sequence set forth in SEQ ID No. 6, and the CDRH3 amino acid sequence set forth in SEQ ID No. 7; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region for use in treating an IL-5 mediated disease selected from the group consisting of: EGPA, HES, CRSsNP and CRSwNP.

2. The pharmaceutical composition for use according to claim 1, comprising about 100mg or about 200mg of the antigen binding protein.

3. The pharmaceutical composition for use according to claim 1 or claim 2, comprising about 100mg of the antigen binding protein for use in the treatment of CRSsNP or CRSwNP.

4. The pharmaceutical composition for use according to claim 1 or claim 2, comprising about 200mg of the antigen binding protein for use in the treatment of EGPA or HES.

5. The pharmaceutical composition of any one of claims 1-4, wherein the heavy chain variable region of the antigen binding protein further comprises a heavy chain FR4 amino acid sequence as set forth in SEQ ID No. 19.

6. The pharmaceutical composition of any one of claims 1-5, wherein the heavy chain Fc domain is an IgG1 Fc domain.

7. The pharmaceutical composition of any one of claims 1-6, wherein 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.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the antigen binding protein is an antibody comprising 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.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition is for subcutaneous administration.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the pharmaceutical composition is administered about once every 6 months.

11. The pharmaceutical composition of any one of claims 1 to 9, wherein the pharmaceutical composition is administered about once every 26 weeks (Q26W).

12. The pharmaceutical composition of claim 4, wherein the composition is administered to treat HES or EGPA, and wherein, for example, two doses of 100mg are administered separately or consecutively, about once every 6 months.

13. The pharmaceutical composition of claim 4, wherein the composition is administered to treat HES or EGPA, and wherein about two doses of 100mg are administered once every 26 weeks (Q26W).

14. The pharmaceutical composition of any one of claims 1 to 13, wherein the pharmaceutical composition is administered to a human subject.

15. The pharmaceutical composition of claim 14, wherein the human subject has (a) an absolute blood eosinophil count at the start of treatment of (i) greater than or equal to 200 or 300 eosinophils per μl blood or (ii) greater than or equal to 150 eosinophils per μl blood or (iii) greater than or equal to 100 eosinophils per μl blood and/or (b) a blood eosinophil count greater than or equal to 300 eosinophils per μl blood over the last 12 months.

16. The pharmaceutical composition according to any one of claims 1 to 15, comprising an aqueous liquid formulation at a pH of about 6.0 containing the antigen binding protein and histidine, trehalose, arginine, EDTA and/or polysorbate 80.

17. An antigen binding protein that binds to IL-5 comprising a heavy chain variable region having the amino acid sequence CDRH1 shown in SEQ ID No. 5, the amino acid sequence CDRH2 shown in SEQ ID No. 6, and the amino acid sequence CDRH3 shown in SEQ ID No. 7; and a light chain variable region having the CDRL1 amino acid sequence set forth in SEQ ID No. 8, the CDRL2 amino acid sequence set forth in SEQ ID No. 9, and the CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region for use in treating an IL-5 mediated disease selected from the group consisting of: EGPA, HES, CRSsNP and CRSwNP.

18. The use of an antigen binding protein of claim 17, wherein the IL 5-mediated disease is selected from the group consisting of: EGPA and HES, and wherein the dose is about 200mg.

19. The antigen binding protein for use according to claim 18, wherein the 200mg dose is administered in two 100mg doses, for example by administering two 100mg doses separately, sequentially or simultaneously.

20. An antigen binding protein for use in treating an IL-5 mediated disorder by administration to a subject at a dose of about 100mg, at a frequency of about every 6 months, the IL-5 mediated disorder selected from the group consisting of: CRSsNP and CRSwNP.

21. A method of treating an IL-5 mediated disease selected from the group consisting of: EGPA, HES, CRSsNP and CRSwNP, comprising administering to a human subject in need thereof, at about every 6 months, an antigen binding protein that binds to IL-5 comprising a heavy chain variable region having a CDRH1 amino acid sequence set forth in SEQ ID No. 5, a CDRH2 amino acid sequence set forth in SEQ ID No. 6, and a CDRH3 amino acid sequence set forth in SEQ ID No. 7, in an amount of about 100mg to about 300 mg; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region.

22. The method of claim 21, wherein the IL-5 mediated disorder to be treated is selected from the group consisting of: EGPA and HES, and wherein about 200mg of said antigen binding protein is administered about once every 6 months.

23. The method of claim 22, wherein the 200mg of the antigen binding protein is administered in two 100mg doses, e.g., by administering the two 100mg doses separately, sequentially or simultaneously.

24. The method of claim 21, wherein the IL-5 mediated disorder to be treated is selected from the group consisting of: CRSsNP and CRSwNP, and wherein about 100mg of said antigen binding protein is administered about once every 6 months.

25. The method of claim 22, wherein the disease is HES and the human subject is screened for blood eosinophil count at the beginning of treatment of >1500 eosinophils/μl, or is a patient who has been diagnosed with HES and has received standard HES treatment and has ≡1000 cells/μl.

26. The method of claim 22, wherein the disease is EGPA, which is a relapsing remitting or refractory eosinophilic granulomatosis with polyangiitis.

27. The method of claim 24, wherein the disease is (i) CRSsNP, and the human subject may have such type 2 or eosinophil-type and elevated eosinophil levels in the nasal mucosa, e.g., the human subject may have blood eosinophils; or (ii) CRSwNP, and the human subject has an endoscopic NP score of at least 5 points (top score of 8 points), with a minimum score of 2 points for each nasal cavity.

28. A method of reducing absolute blood eosinophil count in a subject, said method comprising:

a) Identifying a subject having a condition selected from EGPA, HES, CRSsNP and CRSwNP, and

B) Administering to the subject an antigen binding protein that binds IL-5 comprising a heavy chain variable region having a CDRH1 amino acid sequence as set forth in SEQ ID No. 5, a CDRH2 amino acid sequence as set forth in SEQ ID No. 6, and a CDRH3 amino acid sequence as set forth in SEQ ID No. 7, in an amount of about 100mg to about 300mg, about once every 6 months; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No. 8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No. 10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region;

Thereby reducing the absolute blood eosinophil count of the subject.

29. A prefilled syringe, comprising

A) About 100mg to about 300mg of an antigen binding protein that binds to IL-5, said antigen binding protein comprising a heavy chain variable region having a CDRH1 amino acid sequence as set forth in SEQ ID No. 5, a CDRH2 amino acid sequence as set forth in SEQ ID No. 6, and a CDRH3 amino acid sequence as set forth in SEQ ID No. 7; and a light chain variable region having a CDRL1 amino acid sequence set forth in SEQ ID No.8, a CDRL2 amino acid sequence set forth in SEQ ID No. 9, and a CDRL3 amino acid sequence set forth in SEQ ID No.10, and further comprising a heavy chain Fc domain having a tyrosine residue at position 252, a threonine residue at position 254, and a glutamic acid residue at position 256, and wherein the amino terminus of the heavy chain Fc domain is linked to the carboxy terminus of the heavy chain variable region; and

B) Pharmaceutically acceptable excipients.

For use in the treatment of an IL-5 mediated disease selected from the group consisting of: EGPA, HES, CRSsNP and CRSwNP.

30. The pre-filled syringe of claim 29, wherein the pre-filled syringe comprises about 100mg of the antigen binding protein.

31. The pre-filled syringe of claim 29, wherein the pre-filled syringe comprises about 200mg of the antigen binding protein.

32. The pre-filled syringe according to any one of claims 29 to 31, wherein the pre-filled syringe comprises an aqueous liquid formulation having a pH of about 6.0 containing the antigen binding protein and histidine, trehalose, arginine, EDTA and/or polysorbate 80.

33. The pre-filled syringe according to any one of claims 29 to 32 for use in the treatment of IL-5 mediated diseases, such as EGPA, HES, CRSsNP and CRSwNP.

34. The pre-filled syringe of any one of claims 29 to 33, wherein the pre-filled syringe is provided in a Secure Syringe Device (SSD) or an auto-injector.