Methods of use for interleukin-4 receptor alpha antibodies

Abstract

Provided herein are antigen binding proteins that specifically bind to interleukin-4 receptor (IL4R), their compositions and methods of use. Also provided herein are methods of using the IL4R antigen binding proteins for treatment of allergic or inflammatory diseases.

Description

Attorney Docket No.: CBP-006WO METHODS OF USE FOR INTERLEUKIN-4 RECEPTOR ALPHA ANTIBODIES CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application Nos. 63 / 696,370, filed on September 18, 2024, and 63 / 838,545, filed on July 3, 2025, the entire contents of each of which are incorporated by reference herein for all purposes. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been filed electronically in XML format and is hereby incorporated by reference in its entirety. Said XML file copy, created on XXXX, is named XXX and is XXX bytes in size. BACKGROUND

[0003] Asthma is a chronic respiratory illness that causes inflammation of small and large airways. It affects over 22 million adults in the United States, and approximately 40% of this population have at least one exacerbation per year. Asthma leads to approximately 1 million emergency department (ED) visits and hundreds of thousands of hospitalizations per year. Approximately 50% of patients discharged from an ED after treatment for an acute asthma exacerbation either return or seek medical elsewhere within four weeks of discharge, due to worsening of the initial exacerbation or a second exacerbation.

[0004] Chronic obstructive pulmonary disease (COPD) is a group of chronic respiratory illnesses caused by damage to the lungs, resulting in swelling and irritation (inflammation) inside the airways that limit airflow into and out of the lungs (obstruction). COPD affects approximately 16 million adults in the United States, and of this population, approximately 30% to 50% of adults have at least one exacerbation per year. COPD leads to approximately 1.3 million ED visits and hundreds of thousands of hospitalizations per year. Approximately 50% of the patients treated in the ED either return or seek medical elsewhere within four weeks of discharge, due to worsening of the initial exacerbation or a second exacerbation.

[0005] There is a clear need for more effective therapies to address acute exacerbations of asthma and COPD. Asthma and COPD can be manifested by human interleukin-4 receptor (IL4R) and human interleukin-13 receptor (IL13), and there remains a need in the field to develop a novel antibody formulations targeting IL4R and IL13, which can meet manufacturing and clinical application requirements for high antibody concentration, long- term stability, no aggregation, and low viscosity, among the others.Attorney Docket No.: CBP-006WO SUMMARY

[0006] Provided herein are antigen binding proteins against human interleukin-4 receptor alpha and their methods of use for treating allergic and inflammatory diseases, such as asthma, e.g., acute asthma, and chronic obstructive pulmonary disease (COPD).

[0007] In one aspect, the present disclosure provides methods of treating acute asthma in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the antibody or antibody fragment is administered while the subject is having an asthma exacerbation.

[0008] In some embodiments, the asthma exacerbation has been ongoing for greater than or equal to 2 hours. In some embodiments, the subject has received greater than or equal to 2 treatments with inhaled bronchodilators before administration of the antibody or antibody fragment. In some embodiments, before administration of the antibody or antibody fragment, the subject has a forced expiratory volume in 1 second (FEV1), optionally pre-bronchodilator FEV1, of less than about 85% of predicted normal. In some embodiments, before administration of the antibody or antibody fragment, the subject has a FEV1, optionally pre- bronchodilator FEV1, of about 40% to about 85% of predicted normal. In some embodiments, before administration of the antibody or antibody fragment, the subject has a peak expiratory flow (PEF) of less than or equal to about 70% of predicted normal. In some embodiments, the subject had a least one previous asthma exacerbation requiring urgent care within the past about 12 months (e.g., past month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months).

[0009] In some embodiments, the subject is admitted to a medical facility for the asthma exacerbation (e.g., is showing one or more symptoms of asthma or an asthma exacerbation).

[0010] In another aspect, the present disclosure provides methods of treating chronic obstructive pulmonary disease (COPD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-Attorney Docket No.: CBP-006WO H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8.

[0011] In some embodiments, the subject is having (and / or identified as having) a COPD exacerbation. In some embodiments, the subject has one or more symptoms of COPD.

[0012] In another aspect, the present disclosure provides methods of treating a chronic obstructive pulmonary disease (COPD) exacerbation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR- H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8.

[0013] In some embodiments, before administration of the antibody or antibody fragment, the subject has a forced expiratory volume in 1 second (FEV1), optionally pre-bronchodilator FEV1, of less than about 85% predicted normal. In some embodiments, before administration of the antibody or antibody fragment, the subject has an FEV1, optionally pre-bronchodilator FEV1, of about 40% to about 85% of predicted normal. In some embodiments, before administration of the antibody or antibody fragment, the subject has a peak expiratory flow (PEF) of less than or equal to about 70% of predicted normal.

[0014] In some embodiments, the subject is admitted to a medical facility for the COPD exacerbation and optionally is showing one more symptoms of COPD or COPD exacerbation.

[0015] In some embodiments, the subject is administered the antibody or antibody fragment within about 24 hours to about 72 hours of the onset of the COPD exacerbation.

[0016] In another aspect, the present disclosure provides methods of treating a subject having an allergic or inflammatory condition comprising: (i) determining that the subject has anAttorney Docket No.: CBP-006WO exacerbation of the allergic or inflammatory condition, and (ii) administering to the subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR- L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the allergic or inflammatory condition is asthma or chronic obstructive pulmonary disease (COPD).

[0017] In another aspect, the present disclosure provides methods of treating asthma, the method comprising: administering to a subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the asthma is beta2-agonist resistant asthma.

[0018] In some embodiments, the antibody or antibody fragment is administered while the subject is having an asthma exacerbation.

[0019] In another aspect, the present disclosure provides methods of treating asthma, the method comprising: administering to a subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the subject is resistant or tolerant toAttorney Docket No.: CBP-006WO treatment with a beta2-agonist. In some embodiments, the method results in a complete response.

[0020] In another aspect, the present disclosure provides methods of treating a subject having asthma, the method comprising: (i) treating a subject having an asthma exacerbation with a beta2-agonist, wherein the treatment results in a partial response or no response; (ii) treating the subject by administering a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR- H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8, wherein the treatment with the antibody or antibody fragment results in a complete or significantly improved response.

[0021] In another aspect, the present disclosure provides methods of treating COPD, the method comprising: administering to a subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in COPD is beta2-agonist resistant COPD.

[0022] In some embodiments, the antibody or antibody fragment is administered while the subject is having COPD exacerbation.

[0023] In another aspect, the present disclosure provides methods of treating COPD, the method comprising: administering to a subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1Attorney Docket No.: CBP-006WO comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the subject is resistant or tolerant to treatment with a beta2-agonist.

[0024] In some embodiments, the method results in a complete response.

[0025] In another aspect, the present disclosure provides methods of treating a subject having COPD, the method comprising: (i) treating a subject having a COPD exacerbation with a beta2-agonist, wherein the treatment results in a partial response or no response; and (ii) treating the subject by administering a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8, wherein the treatment with the antibody or antibody fragment results in a complete or significantly improved response.

[0026] In another aspect, the present disclosure provides methods of treating a subject having an exacerbation of an allergic or inflammatory condition comprising: (i) determining that the subject has an exacerbation of the allergic or inflammatory condition, (ii) determining that the subject has tolerance to the beta2-agonist, (iii) administering to the subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR- L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and (iv) administering to the subject a therapeutically effective amount of the beta2-agonist, wherein the allergic or inflammatory condition is asthma or chronic obstructive pulmonary disease (COPD).

[0027] In another aspect, the present disclosure provides methods of treating a subject having an exacerbation of an allergic or inflammatory condition comprising administering to theAttorney Docket No.: CBP-006WO subject a therapeutically effective amount of the beta2-agonist and a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8, wherein the allergic or inflammatory condition is asthma or chronic obstructive pulmonary disease (COPD) and wherein the method results in a complete response or significantly improved response.

[0028] In some embodiments, the subject is known to have or suspected of having tolerance to a beta2-agonist. In some embodiments, the subject has a history of diagnosis of tolerance to a beta2-agonist. In some embodiments, the subject has an Arg16Gly modification at amino acid position 16 of beta2- antibody fragment is administered prior to administering the beta2-agonist. In some embodiments, the antibody or antibody fragment and the beta2-agonist are administered simultaneously.

[0029] In some embodiments, the allergic or inflammatory condition is asthma. In some embodiments, the allergic or inflammatory condition is COPD.

[0030] In some embodiments, the subject is admitted to a medical facility for the exacerbation of the allergic or inflammatory condition (e.g., is showing one or more symptoms of the allergic or inflammatory condition or an exacerbation thereof).

[0031] In some embodiments, the subject is treated with the antibody or antibody fragment within the first 72 hours of the onset of the exacerbation. In some embodiments, the subject is treated with the antibody or antibody fragment within the first 48 hours of the onset of the exacerbation. In some embodiments, the subject is treated with the antibody or antibody fragment within the first 24 hours of the onset of the exacerbation.

[0032] In some embodiments, the antibody or antibody fragment comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 2.

[0033] In some embodiments, the subject has type 2 inflammation. In some embodiments, the subject has a respiratory condition resulting in type 2 inflammation.Attorney Docket No.: CBP-006WO

[0034] In some embodiments, the subject has, is at risk of having, or has a history of having eosinophilia. In some embodiments, the subject has, is at risk of having, or has a history of having hypereosinophilia.

[0035] In some embodiments, prior to treatment, the subject has a blood eosinophil count of In some embodiments, prior to treatment, the subject has a FeNO level of greater than about 20 ppb. In some embodiments, the subject has received prior systemic treatment with an anti-inflammatory agent, optionally steroids. In some embodiments, the subject has had at least one prior exacerbation requiring prescription for an anti-inflammatory agent, optionally systemic steroids.

[0036] In some embodiments, following the treatment, the subject exhibits a higher FEV1relative to a subject not administered the antibody or antibody fragment. In some embodiments, following the treatment, the subject exhibits a higher PEF relative to a subject not administered the antibody or antibody fragment.

[0037] In some embodiments, the antibody or antibody fragment is administered by intravenous injection. In some embodiments, the antibody or antibody fragment is administered by subcutaneous injection.

[0038] In some embodiments, administration of about 150 mg or about 300 mg every other week results in rapid and / or sustained improvements in one or more symptoms of asthma (e.g., lung function), optionally wherein the subject has moderate-to-severe asthma (e.g., uncontrolled asthma). In some embodiments, the administration of about 150 mg or about 300 mg Q2W is preceded by an initial loading dose of about 600 mg of the antibody or antibody fragment.

[0039] In some embodiments, administration of about 150 mg or about 300 mg Q2W results in rapid and / or sustained improvements in one or more symptoms of asthma (e.g., lung function), optionally wherein the subject has moderate-to-severe asthma (e.g., uncontrolled asthma). In some embodiments, the administration of about 150 mg or about 300 mg Q2W is preceded by an initial loading dose of about 600 mg of the antibody or antibody fragment.

[0040] In some embodiments, administration of a therapeutically effective amount of the antibody or antibody fragment results in a lower blood eosinophil count than a comparator (e.g., an alternative anti-IL4R antibody, e.g. dupilumab). In some embodiments, administration of a therapeutically effective amount of the antibody or antibody fragment does not result in eosinophilia. Eosinophilia is a common occurence when administering comparators.Attorney Docket No.: CBP-006WO

[0041] In some embodiments, the antibody or antibody fragment is humanized. In some embodiments, the antibody or antibody fragment is a monoclonal antibody. In some embodiments, the antibody or antibody fragment comprises a human Ig constant domain.

[0042] In some embodiments, the antibody or antibody fragment comprises a human IgG4 constant region. In some embodiments, the antibody or antibody fragment binds interleukin 4

[0043] In some embodiments, a beta2-agonist used herein is selected from the group consisting of albuterol, bitolterol mesylate, formoterol, fenoterol isoprenaline, levalbuterol, metaproterenol, salmeterol, terbutaline, and ritodrine.

[0044] In another aspect, the present disclosure provides methods of treating acute asthma in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the antibody or antibody fragment is administered to the subject having acute asthma. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0046] FIG. 1A illustrates a summary of asthma-related statistics in the United States.

[0047] FIG. 1B illustrates a summary of COPD-related statistics in the United States.

[0048] FIG. 2 illustrates current standard of care (SOC), SOC progression, hospital admissions, and long-term care for asthma and COPD. “LOS” refers to length of stay.

[0049] FIG. 3A illustrates a comparison of the number of annual hospitalizations due to asthma to the number of annual hospitalizations due to COPD in the United states from 2016 to 2019.

[0050] FIG. 3B illustrates a comparison of the number of annual emergency department (“ED”) visits due to asthma and COPD in the European Union (EU) in 2024.Attorney Docket No.: CBP-006WO

[0051] FIG. 3C illustrates a comparison of the number of annual hospitalizations due to asthma and due to COPD in the European Union (EU) in 2024.

[0052] FIG. 4 illustrates the study plan for investigating the efficacy and safety of Antibody A in patients with moderate to severe persistent asthma. “Q2W” refers to administrations every other week following the initial loading dose.

[0053] FIG. 5 illustrates the changes in FEV1 (primary endpoint) in the overall study population at Week 12 with the indicated treatments. “Q2W” refers to administrations every other week following the initial loading dose. Error bars = standard error.

[0054] FIG. 6 illustrates the changes in FEV1 (primary endpoint) in a high blood eosinophil subgroup at Week 12 with the indicated treatments. “Q2W” refers to administrations every other week following the initial loading dose. Error bars = standard error.

[0055] FIG. 7 illustrates the changes in pre-bronchodilator FEV1 relative to baseline over the 24 week treatment span of the study.

[0056] FIG. 8 illustrates the percent of the Day 7 FEV1improvement attributable to Day 1 and Day 2 of the treatment.

[0057] FIG. 9 illustrates the placebo-adjusted improvement from baseline in FEV1at Weeks 12 and 24 of the study. DETAILED DESCRIPTION 1. Definitions

[0058] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.Attorney Docket No.: CBP-006WO

[0059] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise. The terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated.

[0060] As used herein, the term “comprising” also specifically includes embodiments “consisting of” and “consisting essentially of” the recited elements, unless specifically indicated otherwise.

[0061] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s).

[0062] The terms “interleukin 4 receptor,” “IL-4R,” and “IL4R” are used herein interchangeably. IL4R is referred to as “hIL-4R” or “hIL4R” in humans. Human IL-4R is aheterodimer formed by two polypeptide chains, in which the alpha chain (hIL-4R ,UniProtKB: P24394) has a high affinity for IL-4. Studies have shown that the cell surfacereceptor alpha chain of IL-13 (IL-13R chain) also forms another form of IL-4R complexwith IL-4R chain. Since the IL-4R chain in the IL-4R complex plays a leading role inbinding to IL-4 and other cytokines are involved, the IL-4R chain is currently being studiedas a major target.

[0063] As used herein, the terms “IL4R antibody” and “anti-IL4R antibody” are synonymous.

[0064] As used herein, the terms “Antibody A” and “CBP-201” are used interchangeably to refer to an exemplary IL4R antibody having the sequences shown in Table .

[0065] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region typically comprises three domains, abbreviated CH1, CH2, and CH3. Each light chain typically comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL.

[0066] As used herein, the term “antigen binding protein” is used in its broadest sense to encompass antibodies. Similarly, the term “antibody” is used herein in its broadest sense andAttorney Docket No.: CBP-006WO includes certain types of immunoglobulin molecules comprising one or more antigen-binding domains that specifically bind to an antigen or epitope. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multi-specific antibodies.

[0067] The term “alternative scaffold” refers to a molecule in which one or more regions may be diversified to produce one or more antigen-binding domains that specifically bind to an antigen or epitope. In some embodiments, the antigen-binding domain binds the antigen or epitope with specificity and affinity similar to that of an antibody. Exemplary alternativescaffolds include those derived from fibronectin (e.g. -sandwich (e.g.,iMab), lipocalin (e.g., Anticalins®), EETI-II / AGRP, BPTI / LACI-D1 / ITI-D2 (e.g., Kunitz domains), thioredoxin peptide aptamers, protein A (e.g., Affibody®), ankyrin repeats (e.g., DARPins), gamma-B-crystallin / ubiquitin (e.g., Affilins), CTLD3 (e.g., Tetranectins), Fynomers, and (LDLR-A module) (e.g., Avimers). Additional information on alternative scaffolds is provided in Binz et al., Nat. Biotechnol., 200523:1257-1268; Skerra, Current Opin. in Biotech., 200718:295-304; and Silacci et al., J. Biol. Chem., 2014, 289:14392- 14398; each of which is incorporated by reference in its entirety.

[0068] The terms “variable domain” and “variable region” are used interchangeably and refer to the portions of the antibody (or binding protein) or immunoglobulin domains that exhibit variability in their sequence and that are involved in determining the specificity and binding affinity of a particular antibody. Variability is not evenly distributed throughout the variable domains of antibodies; it is concentrated in sub-domains of each of the heavy and light chain variable regions. These sub-domains are called “hypervariable regions” or “complementarity determining regions” (CDRs). The more conserved (i.e., non-hypervariable) portions of the variable domains are called the “framework” regions (FRM or FR) and provide a scaffold for the six CDRs in three-dimensional space to form an antigen-binding surface. The variable heavy chain domain or “VH” is present on the heavy chain and variable light chain domain or “VL” is present on the light chain.

[0069] The term “antigen binding domain” or means the portion of an antibody that is capable of specifically binding to an antigen or epitope. One example of an antigen-binding domain is an antigen-binding domain formed by a VH -VL dimer of an antibody. Another example of an antigen-binding domain is an antigen-binding domain formed by diversification of certain loops from the tenth fibronectin type III domain of an Adnectin. Antigen-binding domains can be found in various contexts including antibodies and chimericAttorney Docket No.: CBP-006WO antigen receptors (CARs), for example CARs derived from antibodies or antibody fragments such as scFvs.

[0070] The terms “full length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a naturally occurring antibody structure and having heavy chains that comprise an Fc region. For example, when used to refer to an IgG molecule, a “full length antibody” is an antibody that comprises two heavy chains and two light chains.

[0071] The term “Fc region” means the C-terminal region of an immunoglobulin heavy chain that, in naturally occurring antibodies, interacts with Fc receptors and certain proteins of the complement system. The structures of the Fc regions of various immunoglobulins, and the glycosylation sites contained therein, are known in the art. See Schroeder and Cavacini, J. Allergy Clin. Immunol., 2010, 125:S41-52, incorporated by reference in its entirety. The Fc region may be a naturally occurring Fc region, or an Fc region modified as described in the art or elsewhere in this disclosure.

[0072] The VH and VL regions may be further subdivided into regions of hypervariability (“hypervariable regions (HVRs);” also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each VH and VL generally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding, and influence antigen specificity and binding affinity of the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, incorporated by reference in its entirety.

[0073] A “Complementary Determining Region (CDR)” refers to one of three hypervariable regions (H1, H2 or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH -sheet framework, or one of three hypervariable regions (L1, L2 or L3) within the non-framework region of the antibody VL -sheet framework. CDRs are variable region sequences interspersed within the framework region sequences. CDRs are well recognized in the art and have been defined by, for example, Kabat as the regions of most hypervariability within the antibody variable (V) domains. See Kabat et al., J Biol Chem, 1977, 252:6609- 6616 and Kabat, Adv Protein Chem, 1978, 32:1-75, each of which is incorporated by reference in its entirety. CDRs have also been defined structurally by Chothia as those residues that are not part of the conserved -sheet framework, and thus are able to adaptAttorney Docket No.: CBP-006WO different conformations. See Chothia and Lesk, J Mol Biol, 1987, 196:901-917, incorporated by reference in its entirety. Both the Kabat and Chothia nomenclatures are well known in the art. AbM, Contact and IMGT also define CDRs. CDR positions within a canonical antibody variable domain have been determined by comparison of numerous structures. See Morea et al., Methods, 2000, 20:267-279 and Al-Lazikani et al., J Mol Biol, 1997, 273:927-48, each of which is incorporated by reference in its entirety. Because the number of residues within a hypervariable region varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c and so forth next to the residue number in the canonical variable domain numbering scheme (Al-Lazikani et al., supra). Such terminology is well known to those skilled in the art.

[0074] A number of hypervariable region delineations are in use and are included herein. The Kabat CDRs are based on sequence variability and are the most commonly used. See Kabat et al. (1992) Sequences of Proteins of Immunological Interest, DIANE Publishing: 2719, incorporated by reference in its entirety. Chothia refers instead to the location of the structural loops (Chothia and Lesk, supra). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software. The Contact hypervariable regions are based on an analysis of the available complex crystal structures.

[0075] More recently, a universal numbering system ImMunoGeneTics (IMGT) Information SystemTM has been developed and widely adopted. See Lefranc et al., Dev Comp Immunol, 2003, 27:55-77, incorporated by reference in its entirety. IMGT is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of human and other vertebrates. The IMGT CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the "location" of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues are readily identified. Correspondence between the Kabat, Chothia and IMGT numbering is also well known in the art (Lefranc et al., supra).

[0076] The exact residue numbers which encompass a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody. The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described byAttorney Docket No.: CBP-006WO Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (“Chothia” numbering scheme); Martin (Enhanced Chothia or AbM) Abhinandan and Martin, Mol Immunol. 2008 Aug;45(14):3832-9; MacCallum et al., 1996, J. Mol. Biol. 262:732-745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegger and Plückthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme); each of which is incorporated by reference in its entirety.

[0077] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 as identified by the Kabat, Chothia, AbM, Contact, and IMGT schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0078] CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at bioinf.org.uk / abs / abnum / , and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety. Descriptions of the various antibody numbering schemes are available at bioinf.org.uk / abs / info.html.

[0079] Table 1: Positions for hypervariable regions as identified by various numbering schemes* The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0080] The light chain from any vertebrate species can be assigned to one of two types,

[0081] The heavy chain from any vertebrate species can be assigned to one of five different classes on the basis of differences in sequence and function. Humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.Attorney Docket No.: CBP-006WO

[0082] The term "constant region" or "constant domain" refers to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor. The terms refer to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable domain, which contains the antigen-binding site. The constant domain contains the CH1, CH2 and CH3 domains of the heavy chain and the CLdomain of the light chain.

[0083] An “antibody fragment” comprises a portion of an intact antibody, such as the antigen-binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’)2fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0084] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0085] “Fab” fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab fragments may be generated, for example, by recombinant methods or by papain digestion of a full-length antibody.

[0086] “F(ab’)2” fragments contain two Fab’ fragments joined, near the hinge region, by disulfide bonds. F(ab’)2fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab’) fragments can be dissociated, for example, by treatment with ß-mercaptoethanol.

[0087] “Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a VH domain and a VLdomain in a single polypeptide chain. The VHand VLare generally linked by a peptide linker. See Plückthun A. (1994). Any suitable linker may be used. In some embodiments, the linker is a (GGGGS)n (SEQ ID NO: 29). In some embodiments, n = 1, 2, 3, 4, 5, or 6. See Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol. 113 (pp. 269-315). Springer-Verlag, New York, incorporated by reference in its entirety.

[0088] “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv (i.e., VH -VL or VL -VH). Any suitable Fc domain known in the art or described herein may be used.

[0089] As used herein, “polypeptide,” which may be used interchangeably with “protein,” refers to a string of at least two amino acids attached to one another by a peptide bond. InAttorney Docket No.: CBP-006WO some embodiments, a polypeptide may include at least 3-5 amino acids, each of which is attached to others by way of at least one peptide bond. Those of ordinary skill in the art will appreciate that polypeptides can include one or more “non-natural” amino acids or other entities that nonetheless are capable of integrating into a polypeptide chain. In some embodiments, a polypeptide may be glycosylated, e.g., a polypeptide may contain one or more covalently linked sugar moieties. In some embodiments, a single “polypeptide” (e.g., an antibody polypeptide) may comprise two or more individual polypeptide chains, which may in some cases be linked to one another, for example by one or more disulfide bonds or other means.

[0090] A “monospecific antibody” is an antibody that comprises one or more binding sites that specifically bind to a single epitope. An example of a monospecific antibody is a naturally occurring IgG molecule which, while divalent (i.e., having two antigen-binding domains), recognizes the same epitope at each of the two antigen-binding domains. The binding specificity may be present in any suitable valency.

[0091] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and / or to reduce its immunogenicity in a subject.

[0092] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0093] “Humanized” forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. A humanized antibody is generally a human antibody (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biologicalAttorney Docket No.: CBP-006WO effect. In some instances, selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody. Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications may be made to further refine antibody function. For further details, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety.

[0094] A “human antibody” is one which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0095] An “isolated antibody” or “isolated nucleic acid” is an antibody or nucleic acid that has been separated and / or recovered from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or nonproteinaceous materials. In some embodiments, an isolated antibody is purified to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, for example by use of a spinning cup sequenator. In some embodiments, an isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or nonreducing conditions, with detection by Coomassie blue or silver stain. In some embodiments, an isolated antibody may include an antibody in situ within recombinant cells, since at least one component of the antibody’s natural environment is not present. In some aspects, an isolated antibody or isolated nucleic acid is prepared by at least one purification step. In some embodiments, an isolated antibody or isolated nucleic acid is purified to at least 80%, 85%, 90%, 95%, or 99% by weight. In some embodiments, an isolated antibody or isolated nucleic acid is purified to at least 80%, 85%, 90%, 95%, or 99% by volume. In some embodiments, an isolated antibody or isolated nucleic acid is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% antibody or nucleic acid by weight. In some embodiments, an isolated antibody or isolated nucleic acid is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% antibody or nucleic acid by volume.

[0096] “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope). Unless indicated otherwise, as used herein, “affinity” refers to intrinsic bindingAttorney Docket No.: CBP-006WO affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen or epitope). The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD). The kinetic components that contribute to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, including those described herein, such as surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).

[0097] With regard to the binding of an antibody to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule. In some aspects, the affinity of a IL4R antibody for a non-target molecule is less than about 50% of the affinity for IL4R. In some aspects, the affinity of a IL4R antibody for a non-target molecule is less than about 40% of the affinity for IL4R. In some aspects, the affinity of a IL4R antibody for a non-target molecule is less than about 30% of the affinity for IL4R. In some aspects, the affinity of a IL4R antibody for a non-target molecule is less than about 20% of the affinity for IL4R. In some aspects, the affinity of a IL4R antibody for a non-target molecule is less than about 10% of the affinity for IL4R. In some aspects, the affinity of a IL4R antibody for a non-target molecule is less than about 1% of the affinity for IL4R. In some aspects, the affinity of a IL4R antibody for a non-target molecule is less than about 0.1% of the affinity for IL4R.

[0098] The term “kd” (sec-1), as used herein, refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the koff value.

[0099] The term “ka” (M-1×sec-1), as used herein, refers to the association rate constant of a particular antibody-antigen interaction. This value is also referred to as the kon value.

[0100] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. KD= kd / ka. In some embodiments, the affinity of an antibody is described in terms of the KDfor an interaction between such antibody and itsAttorney Docket No.: CBP-006WO antigen. For clarity, as known in the art, a smaller KDvalue indicates a higher affinity interaction, while a larger KD value indicates a lower affinity interaction.

[0101] The term “KA” (M-1), as used herein, refers to the association equilibrium constant of a particular antibody-antigen interaction. KA= ka / kd.

[0102] An “affinity matured” antibody is an antibody with one or more alterations (e.g., in one or more CDRs or FRs) relative to a parent antibody (i.e., an antibody from which the altered antibody is derived or designed) that result in an improvement in the affinity of the antibody for its antigen, compared to the parent antibody which does not possess the alteration(s). In some embodiments, an affinity matured antibody has nanomolar or picomolar affinity for the target antigen. Affinity matured antibodies may be produced using a variety of methods known in the art. For example, Marks et al. (Bio / Technology, 1992, 10:779-783, incorporated by reference in its entirety) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR and / or framework residues is described by, for example, Barbas et al., Proc. Nat. Acad. Sci. U.S.A., 1994, 91:3809-3813; Schier et al., Gene, 1995, 169:147-155; Yelton et al., J. Immunol., 1995, 155:1994-2004; Jackson et al., J. Immunol., 1995, 154:3310-33199; and Hawkins et al, J. Mol. Biol., 1992, 226:889-896; each of which is incorporated by reference in its entirety.

[0103] “Fc effector functions” refer to those biological activities mediated by the Fc region of an antibody, which activities may vary depending on the antibody isotype. Examples of antibody effector functions include C1q binding to activate complement dependent cytotoxicity (CDC), Fc receptor binding to activate antibody-dependent cellular cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP).

[0104] The term “epitope” means a portion of an antigen that is specifically bound by an antibody. Epitopes frequently include surface-accessible amino acid residues and / or sugar side chains and may have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to IL4R variants with different point-mutations, or to chimeric IL4R variants.

[0105] Percent “identity” between a polypeptide sequence and a reference sequence, is defined as the percentage of amino acid residues in the polypeptide sequence that areAttorney Docket No.: CBP-006WO identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0106] A “conservative substitution” or a “conservative amino acid substitution,” refers to the substitution of an amino acid with a chemically or functionally similar amino acid. Conservative substitution tables providing similar amino acids are well known in the art. By way of example, the groups of amino acids provided in Tables 2-4 are, in some embodiments, considered conservative substitutions for one another. Table 2: Selected groups of amino acids that are considered conservative substitutions for one another, in certain embodiments.Table 3: Additional selected groups of amino acids that are considered conservative substitutions for one another, in certain embodiments.Table 4: Further selected groups of amino acids that are considered conservative substitutions for one another, in certain embodiments.Attorney Docket No.: CBP-006WO

[0107] Additional conservative substitutions may be found, for example, in Creighton, Proteins: Structures and Molecular Properties 2nd ed. (1993) W. H. Freeman & Co., New York, NY. An antibody generated by making one or more conservative substitutions of amino acid residues in a parent antibody is referred to as a “conservatively modified variant.”

[0108] The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), Glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0109] The term “treating” (and variations thereof such as “treat” or “treatment”) refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed both for prophylaxis and during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

[0110] As used herein, the term “complete response” refers to the elimination of all signs or symptoms of asthma or chronic obstructive pulmonary disease (COPD) in response to a treatment. This does not always mean the asthma or COPD has been cured.

[0111] As used herein, the term “partial response” refers to the elimination or reduction of one or more symptoms of asthma or COPD but not all symptoms. In some embodiments, a partial response is a reduction of at least about a 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or a 99% decrease in a measurable symptom of asthma or COPD (e.g., FEV1). In some embodiments, “a partial response” refers to a significantly improved response in a measurable symptom of asthma or COPD (e.g., FEV1). The significantly improved response can refer to

[0112] As used herein, the term “therapeutically effective amount” or “effective amount” refers to an amount of an antibody or pharmaceutical composition provided herein that, when administered to a subject, is effective to treat a disease or disorder.Attorney Docket No.: CBP-006WO

[0113] The terms “subject,” “recipient”, “individual”, “host”, and “patient”, are used interchangeably herein and refer to refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. In some embodiments, the subject is an adult. In some embodiments, the subject is a child or infant. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, pigs and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has a disease or condition that can be treated with an antibody provided herein. In some aspects, the disease or condition is a cancer. In some aspects, the disease or condition involves neovascularization or vascular inflammation. In certain aspects, the disease or condition involving neovascularization is cancer.

[0114] The term “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective in treating a subject, and which contains no additional components which are unacceptably toxic to the subject in the amounts provided in the pharmaceutical composition.

[0115] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.

[0116] The terms “increase” and “activate” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0117] The terms “reduce” and “inhibit” refer to a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0118] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[0119] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.Attorney Docket No.: CBP-006WO 2. IL4R

[0120] Interleukin-4 (IL-4) is a cytokine produced primarily by activated T cells, monocytes, basophils, mast cells, and eosinophils. IL-4 is involved in a variety of biological processes, and its biological effects, as known in the art, include stimulating the proliferation of activated B cells and T cells and the differentiation of CD4+ T cells into type II helper T cells. Furthermore, studies have shown that IL-4 has multiple effects in mediating immune responses to diseases such as allergic diseases, autoimmune diseases, infectious diseases and tumors, and has therapeutic effects on tumors, autoimmune diseases and infectious diseases and the like. IL-4 can also regulate immune response to vaccine.

[0121] IL-13 is also a cytokine produced by activated T cells, which has different functions in different types of cells, such as monocytes, B cells, mast cells and keratinocytes. IL-13 can inhibit the release of inflammatory cytokines and chemokines from monocytes, induce the proliferation and differentiation of B cells, and promote the synthesis of IgE. IL-13 and IL-4 share many common properties in terms of biological functions, including inhibiting the release of inflammatory mediators from monocytes, inducing dendritic-like development of macrophages, promoting the expression of CD23 on the surface of monocytes and stimulating the synthesis of immunoglobulins by B cells. At the same time, IL-13 also has its own biological features, mainly including: promoting the differentiation of human monocytes and changes of antigens on cell surface; inducing the proliferation and differentiation of B cells, and promoting the secretion of antibodies from B cells; regulating the synthesis of IgE, thereby being associated with allergic reactions in the body; inhibiting the growth of tumor cells; inhibiting the replication of HIV; and the like.

[0122] The biological activity of IL-4 is mediated by a specific IL-4 receptor on cell surface (IL-4R, which is called “hIL-4R” in humans). Human IL-4R is a heterodimer formedby two polypeptide chains, in which the alpha chain (hIL-4R , UniProtKB: P24394) has ahigh affinity for IL-4. And studies have shown that the cell surface receptor alpha chain ofIL-13 (IL-13R chain) also forms another form of IL-4R complex with IL-4R chain. Sincethe IL-4R chain in the IL-4R complex plays a leading role in binding to IL-4 and othercytokines are involved, the IL-4R chain is currently being studied as a major target.Furthermore, human monoclonal antibodies against the IL-4R chain have been clinicallyproven to be effective in relieving and treating some conditions, such as asthma, eczema, atopic dermatitis and the like.Attorney Docket No.: CBP-006WO

[0123] Additional information on the mediation of IL-4R and therapeutic effects of anti- IL4R antigen binding proteins is provided in U.S. Patent No. 10,774,141 and U.S. Publication No. US20220348666A1, herein incorporated by reference in its entirety for all purposes. 2.1. IL4R Antigen Binding Proteins

[0124] Provided herein are antigen binding proteins that specifically bind to interleukin 4 receptor (IL4R). In some embodiments, provided herein are antigen binding proteins capable of binding to an epitope of IL4R. In various embodiments, the antigen binding proteins -4R , UniProtKB: P24394).

[0125] In some embodiments, the antigen binding proteins disclosed herein are capable of binding to IL-4R and functions as antagonists of IL-4R. Preferably, the antigen bindingprotein is capable of binding to IL-4R , preferably to mammal IL-4R , more preferably tohuman IL-4R , even more preferably to human soluble IL-4R , the sequence for which isprovided below: GNMKVLQEPT CVSDYMSIST CEWKMNGPTN CSTELRLLYQ LVFLLSEAHT CIPENNGGAGCVCHLLMDDV VSADNYTLDL WAGQQLLWKG SFKPSEHVKP RAPGNLTVHT NVSDTLLLTWSNPYPPDNYL YNHLTYAVNI WSENDPADFR IYNVTYLEPS LRIAASTLKS GISYRARVRAWAQCYNTTWS EWSPSTKWHN SYREPFEQH (SEQ ID NO: 28)

[0126] In some embodiments, the antigen binding proteins are isolated antibodies or fragments thereof. In some embodiments, the isolated antibodies or fragments thereof are monoclonal antibodies or fragments thereof. In some embodiments, the isolated antibodies or fragments thereof are chimeric antibodies or fragments thereof. In some embodiments, the isolated antibodies or fragments thereof are humanized antibodies or fragments thereof. In some embodiments, the isolated antibodies or antigen-binding fragments are human antibodies.

[0127] In some embodiments, an IL4R antigen binding protein of the present disclosure is an antibody. In some embodiments, the antibody comprises an immunoglobulin, preferably IgA, IgD, IgE, IgG or IgM, more preferably IgG1, IgG2, IgG3 or IgG4 subtype, further more preferably IgG2 or IgG4 subtype. In some embodiments, the IL4R antigen binding protein comprises an IgG4 subtype or human IgG4 subtype. 2.2. Sequences of IL4R Antigen Binding Proteins

[0128] In some embodiments, the sequences for IL4R antigen binding proteins of the present disclosure are provided in Table 5.Attorney Docket No.: CBP-006WO Table 5. Exemplary heavy chain variable domain, light chain variable domain, and complementarity-determining region sequences of IL4R antigen binding proteinsAttorney Docket No.: CBP-006WOAttorney Docket No.: CBP-006WOAttorney Docket No.: CBP-006WO2.2.1. Heavy and light chains

[0129] In some embodiments, an IL4R antigen binding protein provided herein comprises a heavy chain sequence as provided in Table 5.

[0130] In some embodiments, an antibody provided herein comprises a light chain sequence as provided in Table 5. 2.2.2. VHDomains

[0131] In some embodiments, an IL4R antigen binding protein provided herein comprises a variable heavy chain domain (VH) as provided in Table 5.

[0132] In some embodiments, an IL4R antigen binding protein provided herein comprises a VH sequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity to an illustrative VHsequence as provided in Table 5. In some embodiments, IL4R antigen binding protein provided herein comprises up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art orAttorney Docket No.: CBP-006WO described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies. 2.2.3. VLDomains

[0133] In some embodiments, an IL4R antigen binding protein provided herein comprises a variable light chain domain (VL) as provided in Table 5.

[0134] In some embodiments, an IL4R antigen binding protein provided herein comprises a VLsequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity to an illustrative VL sequence as provided in Table 5. In some embodiments, IL4R antigen binding protein provided herein comprises up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies. 2.2.4. VH-VLCombinations

[0135] In some embodiments, an IL4R antigen binding protein provided herein comprises a VH sequence as provided in Table 5 and a VL sequence as provided in Table 5.

[0136] In some embodiments, an IL4R antigen binding protein provided herein comprises a VHsequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity to an illustrative VHsequence as provided in Table 5, and a VLsequence having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity to an illustrative VL sequence as provided in Table 5. In some embodiments, the VHsequence as provided in Table 5 has up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions, and the VL sequence as provided in Table 5 has up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any otherAttorney Docket No.: CBP-006WO method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies. 2.2.5. CDRs

[0137] In some embodiments, provided IL4R antigen binding proteins comprise a heavy chain variable domain comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 with sequences as shown in Table 5. In some embodiments, provided IL4R antigen binding proteins further comprise a light chain variable domain comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 with sequences as shown in Table 5.

[0138] In some embodiments, provided IL4R antigen binding proteins comprise a heavy chain variable domain with heavy chain variable sequences as shown in Table 5. In some embodiments, provided IL4R antigen binding proteins comprise a heavy chain variable domain which is a variant of the heavy chain variable sequence shown in Table 5, in that the heavy chain variable domain has (1) CDR-H1, CDR-H2, and CDR-H3 with sequences as shown in Table 5 and (2) an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the heavy chain variable domain sequence shown in Table 5.

[0139] In some embodiments, provided IL4R antigen binding proteins comprise a heavy chain variable domain as described herein and further comprise a light chain variable region which has (1) CDR-L1, CDR-L2, and CDR-L3 with sequences as shown in Table 5 and (2) an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the light chain variable domain sequence shown in Table 5.

[0140] In some aspects, the CDRs are Exemplary CDRs. In some aspects, the CDRs are Kabat CDRs. In some aspects, the CDRs are Chothia CDRs. In some aspects, the CDRs are AbM CDRs. In some aspects, the CDRs are Contact CDRs. In some aspects, the CDRs are IMGT CDRs. Variant CDRs

[0141] In some embodiments of any of the IL4R antigen binding proteins provided herein, the IL4R antigen binding protein CDRs may comprise up to 1, 2, 3, 4, 5, 6, 7, or 8Attorney Docket No.: CBP-006WO amino acid substitutions to any of the CDR sequences described herein. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the IL4R antigen binding proteins described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies. 2.3. Monospecific and Multispecific IL4R Antibodies

[0142] In some embodiments, the IL4R antigen binding proteins provided herein are monospecific antibodies.

[0143] In some embodiments, the IL4R antigen binding proteins provided herein are multispecific antibodies.

[0144] In some embodiments, a multispecific antibody provided herein binds more than one antigen. In some embodiments, a multispecific antibody binds two antigens. In some embodiments, a multispecific antibody binds three antigens. In some embodiments, a multispecific antibody binds four antigens. In some embodiments, a multispecific antibody binds five or more antigens. In some embodiments, a multispecific antibody binds multiple antigens.

[0145] In some embodiments, a multispecific antibody provided herein binds more than one epitope on an IL4R antigen. In some embodiments, a multispecific antibody binds two epitopes on a IL4R antigen. In some embodiments, a multispecific antibody binds three epitopes on a IL4R antigen.

[0146] Many multispecific antibody constructs are known in the art, and the antibodies provided herein may be provided in the form of any suitable multispecific suitable construct.

[0147] In some embodiments, the multispecific antibody comprises an immunoglobulin comprising at least two different heavy chain variable regions each paired with a common light chain variable region (i.e., a “common light chain antibody”). The common light chain variable region forms a distinct antigen-binding domain with each of the two different heavy chain variable regions. See Merchant et al., Nature Biotechnol., 1998, 16:677-681, incorporated by reference in its entirety.

[0148] In some embodiments, the multispecific antibody comprises an immunoglobulin comprising an antibody or fragment thereof attached to one or more of the N- or C-termini ofAttorney Docket No.: CBP-006WO the heavy or light chains of such immunoglobulin. See Coloma and Morrison, Nature Biotechnol., 1997, 15:159-163, incorporated by reference in its entirety. In some aspects, such antibody comprises a tetravalent bispecific antibody.

[0149] In some embodiments, the multispecific antibody comprises a hybrid immunoglobulin comprising at least two different heavy chain variable regions and at least two different light chain variable regions. See Milstein and Cuello, Nature, 1983, 305:537- 540; and Staerz and Bevan, Proc. Natl. Acad. Sci. USA, 1986, 83:1453-1457; each of which is incorporated by reference in its entirety.

[0150] In some embodiments, the multispecific antibody comprises immunoglobulin chains with alterations to reduce the formation of side products that do not have multispecificity. In some aspects, the antibodies comprise one or more “knobs-into-holes” modifications as described in U.S. Pat. No. 5,731,168, incorporated by reference in its entirety.

[0151] In some embodiments, the multispecific antibody comprises immunoglobulin chains with one or more electrostatic modifications to promote the assembly of Fc hetero- multimers. See WO 2009 / 089004, incorporated by reference in its entirety.

[0152] In some embodiments, the multispecific antibody comprises a bispecific single chain molecule. See Traunecker et al., EMBO J., 1991, 10:3655-3659; and Gruber et al., J. Immunol., 1994, 152:5368-5374; each of which is incorporated by reference in its entirety.

[0153] In some embodiments, the multispecific antibody comprises a heavy chain variable domain and a light chain variable domain connected by a polypeptide linker, where the length of the linker is selected to promote assembly of multispecific antibodies with the desired multispecificity. For example, monospecific scFvs generally form when a heavy chain variable domain and light chain variable domain are connected by a polypeptide linker of more than 12 amino acid residues. See U.S. Pat. Nos. 4,946,778 and 5,132,405, each of which is incorporated by reference in its entirety. In some embodiments, reduction of the polypeptide linker length to less than 12 amino acid residues prevents pairing of heavy and light chain variable domains on the same polypeptide chain, thereby allowing pairing of heavy and light chain variable domains from one chain with the complementary domains on another chain. The resulting antibodies therefore have multispecificity, with the specificity of each binding site contributed by more than one polypeptide chain. Polypeptide chains comprising heavy and light chain variable domains that are joined by linkers between 3 and 12 amino acid residues form predominantly dimers (termed diabodies). With linkers between 0 and 2 amino acid residues, trimers (termed triabodies) and tetramers (termed tetrabodies)Attorney Docket No.: CBP-006WO are favored. However, the exact type of oligomerization appears to depend on the amino acid residue composition and the order of the variable domain in each polypeptide chain (e.g., VH- linker-VL vs. VL-linker-VH), in addition to the linker length. A skilled person can select the appropriate linker length based on the desired multispecificity.

[0154] In some embodiments, the multispecific antibody comprises a diabody. See Hollinger et al., Proc. Natl. Acad. Sci. USA, 1993, 90:6444-6448, incorporated by reference in its entirety. In some embodiments, the multispecific antibody comprises a triabody. See Todorovska et al., J. Immunol. Methods, 2001, 248:47-66, incorporated by reference in its entirety. In some embodiments, the multispecific antibody comprises a tetrabody. See id., incorporated by reference in its entirety.

[0155] In some embodiments, the multispecific antibody comprises a trispecific F(ab’)3 derivative. See Tutt et al. J. Immunol., 1991, 147:60-69, incorporated by reference in its entirety.

[0156] In some embodiments, the multispecific antibody comprises a cross-linked antibody. See U.S. Patent No. 4,676,980; Brennan et al., Science, 1985, 229:81-83; Staerz, et al. Nature, 1985, 314:628-631; and EP 0453082; each of which is incorporated by reference in its entirety.

[0157] In some embodiments, the multispecific antibody comprises antigen binding domains assembled by leucine zippers. See Kostelny et al., J. Immunol., 1992, 148:1547- 1553, incorporated by reference in its entirety.

[0158] In some embodiments, the multispecific antibody comprises complementary protein domains. In some aspects, the complementary protein domains comprise an anchoring domain (AD) and a dimerization and docking domain (DDD). In some embodiments, the AD and DDD bind to each other and thereby enable assembly of multispecific antibody structures via the “dock and lock” (DNL) approach. Antibodies of many specificities may be assembled, including bispecific antibodies, trispecific antibodies, tetraspecific antibodies, quintspecific antibodies, and hexaspecific antibodies. Multispecific antibodies comprising complementary protein domains are described, for example, in U.S. Pat. Nos. 7,521,056; 7,550,143; 7,534,866; and 7,527,787; each of which is incorporated by reference in its entirety.

[0159] In some embodiments, the multispecific antibody comprises a dual action Fab (DAF) antibody as described in U.S. Pat. Pub. No. 2008 / 0069820, incorporated by reference in its entirety.Attorney Docket No.: CBP-006WO

[0160] In some embodiments, the multispecific antibody comprises an antibody formed by reduction of two parental molecules followed by mixing of the two parental molecules and reoxidation to assembly a hybrid structure. See Carlring et al., PLoS One, 2011, 6:e22533, incorporated by reference in its entirety.

[0161] In some embodiments, the multispecific antibody comprises a DVD-IgTM. Adual variable domain immunoglobulin that can bind to two or more antigens. DVD-IgsTMare described in U.S. Pat. No. 7,612,181, incorporated by reference in its entirety.

[0162] In some embodiments, the multispecific antibody comprises a DARTTM. DARTsTMare described in Moore et al., Blood, 2011, 117:454-451, incorporated by reference in its entirety.

[0163] In some embodiments, the multispecific antibody comprises a DuoBody®. DuoBodies®are described in Labrijn et al., Proc. Natl. Acad. Sci. USA, 2013, 110:5145- 5150; Gramer et al., mAbs, 2013, 5:962-972; and Labrijn et al., Nature Protocols, 2014, 9:2450-2463; each of which is incorporated by reference in its entirety.

[0164] In some embodiments, the multispecific antibody comprises an antibody fragment attached to another antibody or fragment. The attachment can be covalent or non-covalent. When the attachment is covalent, it may be in the form of a fusion protein or via a chemical linker. Illustrative examples of multispecific antibodies comprising antibody fragments attached to other antibodies include tetravalent bispecific antibodies, where an scFv is fused to the C-terminus of the CH3from an IgG. See Coloma and Morrison, Nature Biotechnol., 1997, 15:159-163. Other examples include antibodies in which a Fab molecule is attached to the constant region of an immunoglobulin. See Miler et al., J. Immunol., 2003, 170:4854- 4861, incorporated by reference in its entirety. Any suitable fragment may be used, including any of the fragments described herein or known in the art.

[0165] In some embodiments, the multispecific antibody comprises a CovX-Body. CovX-Bodies are described, for example, in Doppalapudi et al., Proc. Natl. Acad. Sci. USA, 2010, 107:22611-22616, incorporated by reference in its entirety.

[0166] In some embodiments, the multispecific antibody comprises an Fcab antibody, where one or more antigen-binding domains are introduced into an Fc region. Fcab antibodies are described in Wozniak-Knopp et al., Protein Eng. Des. Sel., 2010, 23:289-297, incorporated by reference in its entirety.

[0167] In some embodiments, the multispecific antibody comprises a TandAb®antibody. TandAb®antibodies are described in Kipriyanov et al., J. Mol. Biol., 1999, 293:41-56 andAttorney Docket No.: CBP-006WO Zhukovsky et al., Blood, 2013, 122:5116, each of which is incorporated by reference in its entirety.

[0168] In some embodiments, the multispecific antibody comprises a tandem Fab. Tandem Fabs are described in WO 2015 / 103072, incorporated by reference in its entirety.

[0169] In some embodiments, the multispecific antibody comprises a ZybodyTM. ZybodiesTMare described in LaFleur et al., mAbs, 2013, 5:208-218, incorporated by reference in its entirety. 2.4. Glycosylation Variants

[0170] In certain embodiments, an IL4R antigen binding protein provided herein may be altered to increase, decrease or eliminate the extent to which it is glycosylated. Glycosylation of polypeptides is typically either “N-linked” or “O-linked.”

[0171] “N-linked” glycosylation refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site.

[0172] “O-linked” glycosylation refers to the attachment of one of the sugars N- acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.

[0173] Addition or deletion of N-linked glycosylation sites to or from an IL4R antigen binding proteins or antibody provided herein may be accomplished by altering the amino acid sequence such that one or more of the above-described tripeptide sequences is created or removed. Addition or deletion of O-linked glycosylation sites may be accomplished by addition, deletion, or substitution of one or more serine or threonine residues in or to (as the case may be) the sequence of an antibody.

[0174] In some embodiments, an IL4R antigen binding protein provided herein comprises a glycosylation motif that is different from a naturally occurring antibody. Any suitable naturally occurring glycosylation motif can be modified in the antibodies provided herein. The structural and glycosylation properties of immunoglobulins, for example, are known in the art and summarized, for example, in Schroeder and Cavacini, J. Allergy Clin. Immunol., 2010, 125:S41-52, incorporated by reference in its entirety.Attorney Docket No.: CBP-006WO

[0175] In some embodiments, an IL4R antigen binding protein provided herein comprises an IgG1 Fc region with modification to the oligosaccharide attached to asparagine 297 (Asn 297). Naturally occurring IgG1 antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn 297 of the CH2 domain of the Fc region. See Wright et al., TIBTECH, 1997, 15:26-32, incorporated by reference in its entirety. The oligosaccharide attached to Asn 297 may include various carbohydrates such as mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure.

[0176] In some embodiments, the oligosaccharide attached to Asn 297 is modified to create antibodies having altered ADCC. In some embodiments, the oligosaccharide is altered to improve ADCC. In some embodiments, the oligosaccharide is altered to reduce ADCC.

[0177] In some aspects, an antibody provided herein comprises an IgG1 domain with reduced fucose content at position Asn 297 compared to a naturally occurring IgG1 domain. Such Fc domains are known to have improved ADCC. See Shields et al., J. Biol. Chem., 2002, 277:26733-26740, incorporated by reference in its entirety. In some aspects, such antibodies do not comprise any fucose at position Asn 297. The amount of fucose may be determined using any suitable method, for example as described in WO 2008 / 077546, incorporated by reference in its entirety.

[0178] In some embodiments, an IL4R antigen binding protein provided herein comprises a bisected oligosaccharide, such as a biantennary oligosaccharide attached to the Fc region of the antibody that is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003 / 011878; U.S. Pat. No. 6,602,684; and U.S. Pat. Pub. No. 2005 / 0123546; each of which is incorporated by reference in its entirety.

[0179] Other illustrative glycosylation variants which may be incorporated into the antibodies provided herein are described, for example, in U.S. Pat. Pub. Nos. 2003 / 0157108, 2004 / 0093621, 2003 / 0157108, 2003 / 0115614, 2002 / 0164328, 2004 / 0093621, 2004 / 0132140, 2004 / 0110704, 2004 / 0110282, 2004 / 0109865; International Pat. Pub. Nos. 2000 / 61739, 2001 / 29246, 2003 / 085119, 2003 / 084570, 2005 / 035586, 2005 / 035778; 2005 / 053742, 2002 / 031140; Okazaki et al., J. Mol. Biol., 2004, 336:1239-1249; and Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; each of which is incorporated by reference in its entirety.Attorney Docket No.: CBP-006WO

[0180] In some embodiments, an IL4R antigen binding protein provided herein comprises an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function. Examples of such antibody variants are described, for example, in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764; each of which is incorporated by reference in its entirety.

[0181] Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells, which are deficient in protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; U.S. Pat. Pub. No. 2003 / 0157108; WO 2004 / 056312; each of which is incorporated by reference in its entirety), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene or FUT8 knockout CHO cells (see Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; Kanda et al., Biotechnol. Bioeng., 2006, 94:680-688; and WO 2003 / 085107; each of which is incorporated by reference in its entirety).

[0182] In some embodiments, an IL4R antigen binding protein provided herein is an aglycosylated antibody. An aglycosylated antibody can be produced using any method known in the art or described herein. In some aspects, an aglycosylated antibody is produced by modifying the antibody to remove all glycosylation sites. In some aspects, the glycosylation sites are removed only from the Fc region of the antibody. In some aspects, an aglycosylated antibody is produced by expressing the antibody in an organism that is not capable of glycosylation, such as E. coli, or by expressing the antibody in a cell-free reaction mixture.

[0183] In some embodiments, an IL4R antigen binding protein provided herein has a constant region with reduced effector function compared to a native IgG1 antibody. In some embodiments, the affinity of a constant region of an Fc region of an antibody provided herein for Fc receptor is less than the affinity of a native IgG1 constant region for such Fc receptor. 2.5. Constant Regions, Fc Region and Amino Acid Sequence Variants

[0184] In some embodiments, an IL4R antigen binding protein provided herein comprises one or more constant regions.

[0185] In some embodiments, the IL4R antigen binding protein comprises a human Ig constant domain. In some embodiments, the IL4R antigen binding protein comprises a constant region from a human IgA, IgG, IgE, IgD, or IgM antibody. In some embodiments, the IL4R antigen binding protein comprises a constant region from human IgG. The human IgG can be human IgG1, human IgG2, human IgG3, or human IgG4.

[0186] In some embodiments, an IL4R antigen binding protein provided herein comprises an Fc region. The Fc region can be from a human IgA, IgG, IgE, IgD, or IgM antibody.Attorney Docket No.: CBP-006WO

[0187] In some embodiments, the IL4R antigen binding protein comprises a human IgG2 or IgG4 constant region. In some embodiments, the IL4R antigen binding protein comprises a human IgG4 constant region.

[0188] In some embodiments, the IL4R antigen binding protein comprises a human IgG Fc region. The human IgG Fc region can be a human IgG1 Fc region, human IgG2 Fc region, human IgG3 Fc region, human IgG4 Fc region.

[0189] In some embodiments, the IL4R antigen binding protein comprises a human IgG1 Fc region. The human IgG1 Fc region may comprise a hinge sequence. In some embodiments, the hinge sequence is epkscdkthtcp.

[0190] In certain embodiments, an IL4R antigen binding protein provided herein comprises an Fc region with one or more amino acid substitutions, insertions, or deletions in comparison to a naturally occurring Fc region. In some aspects, such substitutions, insertions, or deletions yield antibodies with altered stability, glycosylation, or other characteristics. In some aspects, such substitutions, insertions, or deletions yield aglycosylated antibodies.

[0191] In some aspects, the Fc region of an IL4R antigen binding protein provided herein is modified to yield an antibody with altered affinity for an Fc receptor, or an antibody that is more immunologically inert. In some embodiments, the IL4R antigen binding protein variants provided herein possess some, but not all, effector functions. Such antibodies may be useful, for example, when the half-life of the antibody is important in vivo, but when certain effector functions (e.g., complement activation and ADCC) are unnecessary or deleterious.

[0192] In some embodiments, the Fc region of an antibody provided herein is a human IgG4 Fc region comprising one or more of the hinge stabilizing mutations S228P and L235E. See Aalberse et al., Immunology, 2002, 105:9-19, incorporated by reference in its entirety. In some embodiments, the IgG4 Fc region comprises one or more of the following mutations: E233P, F234V, and L235A. See Armour et al., Mol. Immunol., 2003, 40:585-593, incorporated by reference in its entirety. In some embodiments, the IgG4 Fc region comprises a deletion at position G236.

[0193] In some embodiments, the Fc region of an antibody provided herein is a human IgG1 Fc region comprising one or more mutations to reduce Fc receptor binding. In some aspects, the one or more mutations are in residues selected from S228 (e.g., S228A), L234 (e.g., L234A), L235 (e.g., L235A), D265 (e.g., D265A), and N297 (e.g., N297A). In some aspects, the antibody comprises a PVA236 mutation. PVA236 means that the amino acid sequence ELLG, from amino acid position 233 to 236 of IgG1 or EFLG of IgG4, is replaced by PVA. See U.S. Pat. No. 9,150,641, incorporated by reference in its entirety.Attorney Docket No.: CBP-006WO

[0194] In some embodiments, the Fc region of an antibody provided herein is modified as described in Armour et al., Eur. J. Immunol., 1999, 29:2613-2624; WO 1999 / 058572; and / or U.K. Pat. App. No. 98099518; each of which is incorporated by reference in its entirety.

[0195] In some embodiments, the Fc region of an antibody provided herein is a human IgG2 Fc region comprising one or more of mutations A330S and P331S.

[0196] In some embodiments, the Fc region of an antibody provided herein has an amino acid substitution at one or more positions selected from 238, 265, 269, 270, 297, 327 and 329. See U.S. Pat. No. 6,737,056, incorporated by reference in its entirety. Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 with alanine. See U.S. Pat. No. 7,332,581, incorporated by reference in its entirety. In some embodiments, the antibody comprises an alanine at amino acid position 265. In some embodiments, the antibody comprises an alanine at amino acid position 297.

[0197] In certain embodiments, an IL4R antigen binding protein provided herein comprises an Fc region with one or more amino acid substitutions which improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of the Fc region. In some embodiments, an antibody provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330, as described in Lazar et al., Proc. Natl. Acad. Sci. USA, 2006,103:4005-4010, incorporated by reference in its entirety.

[0198] In some embodiments, an IL4R antigen binding protein provided herein comprises one or more alterations that improves or diminishes C1q binding and / or CDC. See U.S. Pat. No. 6,194,551; WO 99 / 51642; and Idusogie et al., J. Immunol., 2000, 164:4178-4184; each of which is incorporated by reference in its entirety.

[0199] In some embodiments, an IL4R antigen binding protein provided herein comprises one or more alterations to increase half-life. Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn) are described, for example, in Hinton et al., J. Immunol., 2006, 176:346-356; and U.S. Pat. Pub. No. 2005 / 0014934; each of which is incorporated by reference in its entirety. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 250, 256, 265, 272, 286, 303, 305, 307, 311, 312, 314, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, 428, and 434 of an IgG.

[0200] In some embodiments, an IL4R antigen binding protein provided herein comprises one or more Fc region variants as described in U.S. Pat. Nos. 7,371,826, 5,648,260, and 5,624,821; Duncan and Winter, Nature, 1988, 322:738-740; and WO 94 / 29351; each of which is incorporated by reference in its entirety.Attorney Docket No.: CBP-006WO 2.6. Pyroglutamate

[0201] As is known in the art, both glutamate (E) and glutamine (Q) at the N-termini of recombinant proteins can cyclize spontaneously to form pyroglutamate (pE) in vitro and in vivo. See Liu et al., J. Biol. Chem., 2011, 286:11211-11217, incorporated by reference in its entirety.

[0202] In some embodiments, provided herein are IL4R antigen binding protein comprising a polypeptide sequence having a pE residue at the N-terminal position. In some embodiments, provided herein are antibodies comprising a polypeptide sequence in which the N-terminal residue has been converted from Q to pE. In some embodiments, provided herein are IL4R antigen binding protein comprising a polypeptide sequence in which the N-terminal residue has been converted from E to pE. 2.7. Cysteine Engineered Antibody Variants

[0203] In certain embodiments, provided herein are cysteine engineered IL4R antigen binding protein, e.g. antibodies, also known as “thioMAbs,” in which one or more residues of the antibody are substituted with cysteine residues. In particular embodiments, the substituted residues occur at solvent accessible sites of the antibody. By substituting such residues with cysteine, reactive thiol groups are introduced at solvent accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, for example, to create an immunoconjugate.

[0204] In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 of the light chain; A118 of the heavy chain Fc region; and S400 of the heavy chain Fc region. Cysteine engineered antibodies may be generated as described, for example, in U.S. Pat. No. 7,521,541, which is incorporated by reference in its entirety. 3. Methods for Making IL4R Antigen Binding Proteins 3.1. Methods of Making Monoclonal Antibodies

[0205] Monoclonal antibodies may be obtained, for example, using the hybridoma method first described by Kohler et al., Nature, 1975, 256:495-497 (incorporated by reference in its entirety), and / or by recombinant DNA methods (see e.g., U.S. Patent No. 4,816,567, incorporated by reference in its entirety). Monoclonal antibodies may also be obtained, for example, using phage-display libraries (see e.g., U.S. Patent No. 8,258,082,Attorney Docket No.: CBP-006WO which is incorporated by reference in its entirety) or, alternatively, using yeast-based libraries (see e.g., U.S. Patent No. 8,691,730, which is incorporated by reference in its entirety).

[0206] In the hybridoma method, a mouse or other appropriate host animal is immunized to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alternatively, lymphocytes may be immunized in vitro. Lymphocytes are then fused with myeloma cells using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell. See Goding J.W., Monoclonal Antibodies: Principles and Practice 3rded. (1986) Academic Press, San Diego, CA, incorporated by reference in its entirety.

[0207] The hybridoma cells are seeded and grown in a suitable culture medium that contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells. For example, if the parental myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which substances prevent the growth of HGPRT-deficient cells.

[0208] Useful myeloma cells are those that fuse efficiently, support stable high-level production of antibody by the selected antibody-producing cells, and are sensitive media conditions, such as the presence or absence of HAT medium. Among these, preferred myeloma cell lines are murine myeloma lines, such as those derived from MOP-21 and MC- 11 mouse tumors (available from the Salk Institute Cell Distribution Center, San Diego, CA), and SP-2 or X63-Ag8-653 cells (available from the American Type Culture Collection, Rockville, MD). Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies. See e.g., Kozbor, J. Immunol., 1984, 133:3001, incorporated by reference in its entirety.

[0209] After the identification of hybridoma cells that produce antibodies of the desired specificity, affinity, and / or biological activity, selected clones may be subcloned by limiting dilution procedures and grown by standard methods. See Goding, supra. Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 medium. In addition, the hybridoma cells may be grown in vivo as ascites tumors in an animal.

[0210] DNA encoding the monoclonal antibodies may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the monoclonal antibodies). Thus, the hybridoma cells can serve as a useful source of DNA encoding antibodies with the desired properties. Once isolated, the DNA may be placed into expressionAttorney Docket No.: CBP-006WO vectors, which are then transfected into host cells such as bacteria (e.g., E. coli), yeast (e.g., Saccharomyces or Pichia sp.), COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce antibody, to produce the monoclonal antibodies. 3.2. Methods of Making Chimeric Antibodies

[0211] Illustrative methods of making chimeric antibodies are described, for example, in U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 1984, 81:6851- 6855; each of which is incorporated by reference in its entirety. In some embodiments, a chimeric antibody is made by using recombinant techniques to combine a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non- human primate, such as a monkey) with a human constant region. 3.3. Methods of Making Humanized Antibodies

[0212] Humanized antibodies may be generated by replacing most, or all, of the structural portions of a non-human monoclonal antibody with corresponding human antibody sequences. Consequently, a hybrid molecule is generated in which only the antigen-specific variable, or CDR, is composed of non-human sequence. Methods to obtain humanized antibodies include those described in, for example, Winter and Milstein, Nature, 1991, 349:293-299; Rader et al., Proc. Nat. Acad. Sci. U.S.A., 1998, 95:8910-8915; Steinberger et al., J. Biol. Chem., 2000, 275:36073-36078; Queen et al., Proc. Natl. Acad. Sci. U.S.A., 1989, 86:10029-10033; and U.S. Patent Nos. 5,585,089, 5,693,761, 5,693,762, and 6,180,370; each of which is incorporated by reference in its entirety. 3.4. Methods of Making Human Antibodies

[0213] Human antibodies can be generated by a variety of techniques known in the art, for example by using transgenic animals (e.g., humanized mice). See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. U.S.A., 1993, 90:2551; Jakobovits et al., Nature, 1993, 362:255-258; Bruggermann et al., Year in Immuno., 1993, 7:33; and U.S. Patent Nos. 5,591,669, 5,589,369 and 5,545,807; each of which is incorporated by reference in its entirety. Human antibodies can also be derived from phage-display libraries (see e.g., Hoogenboom et al., J. Mol. Biol., 1991, 227:381-388; Marks et al., J. Mol. Biol., 1991, 222:581-597; and U.S. Pat. Nos. 5,565,332 and 5,573,905; each of which is incorporated by reference in its entirety). Human antibodies may also be generated by in vitro activated B cells (see e.g., U.S. Patent. Nos. 5,567,610 and 5,229,275, each of which is incorporated by reference in its entirety). Human antibodies may also be derived from yeast-based libraries (see e.g., U.S. Patent No. 8,691,730, incorporated by reference in its entirety).Attorney Docket No.: CBP-006WO 3.5. Methods of Making Antibody Fragments

[0214] The antibody fragments provided herein may be made by any suitable method, including the illustrative methods described herein or those known in the art. Suitable methods include recombinant techniques and proteolytic digestion of whole antibodies. Illustrative methods of making antibody fragments are described, for example, in Hudson et al., Nat. Med., 2003, 9:129-134, incorporated by reference in its entirety. Methods of making scFv antibodies are described, for example, in Plückthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994); WO 93 / 16185; and U.S. Pat. Nos. 5,571,894 and 5,587,458; each of which is incorporated by reference in its entirety. 3.6. Methods of Making Variants

[0215] In some embodiments, an antibody provided herein is an affinity matured variant of a parent antibody, which may be generated, for example, using phage display-based affinity maturation techniques. Briefly, one or more CDR residues may be mutated and the variant antibodies, or portions thereof, displayed on phage and screened for affinity. Such alterations may be made in CDR “hotspots,” or residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see Chowdhury, Methods Mol. Biol., 2008, 207:179-196, incorporated by reference in its entirety), and / or residues that contact the antigen.

[0216] Any suitable method can be used to introduce variability into a polynucleotide sequence(s) encoding an antibody, including error-prone PCR, chain shuffling, and oligonucleotide-directed mutagenesis such as trinucleotide-directed mutagenesis (TRIM). In some aspects, several CDR residues (e.g., 4-6 residues at a time) are randomized. CDR residues involved in antigen binding may be specifically identified, for example, using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted for mutation.

[0217] The introduction of diversity into the variable regions and / or CDRs can be used to produce a secondary library. The secondary library is then screened to identify antibody variants with improved affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, for example, in Hoogenboom et al., Methods in Molecular Biology, 2001, 178:1-37, incorporated by reference in its entirety.Attorney Docket No.: CBP-006WO 4. Assays

[0218] A variety of assays known in the art may be used to identify and characterize anti- IL4R antigen binding proteins. 4.1. Binding, Competition, and Epitope Mapping Assays

[0219] Specific antigen-binding activity of the antibodies provided herein may be evaluated by any suitable method, including using SPR, BLI, RIA and MSD-SET, as described elsewhere in this disclosure. Additionally, antigen-binding activity may be evaluated by ELISA assays and Western blot assays.

[0220] Assays for measuring competition between two antibodies, or an antibody and another molecule (e.g., one or more ligands of IL4R) are described, for example, in Harlow and Lane, Antibodies: A Laboratory Manual ch.14, 1988, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y, incorporated by reference in its entirety.

[0221] Assays for mapping the epitopes to which the antibodies provided herein bind are described, for example, in Morris “Epitope Mapping Protocols,” in Methods in Molecular Biology vol. 66, 1996, Humana Press, Totowa, N.J., incorporated by reference in its entirety. In some embodiments, the epitope is determined by peptide competition. In some embodiments, the epitope is determined by mass spectrometry. In some embodiments, the epitope is determined by crystallography. 5. Comparators

[0222] In some embodiments, the IL4R antigen binding proteins disclosed herein are compared against a comparator (an alternative anti-IL4R binding protein, antibody or antibody fragment, e.g., dupilumab). Dupilumab has a heavy chain sequence of: EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGG NTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLD VWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVD GVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 30).Attorney Docket No.: CBP-006WO Dupilumab has a light chain sequence of: DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNR ASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 31). 6. Pharmaceutical Compositions

[0223] The present disclosure also includes pharmaceutical compositions that contain therapeutically effective amounts of the IL4R antigen binding proteins disclosed herein. Compositions can be formulated for use in a variety of drug delivery systems. One or more physiologically acceptable excipients or carriers can also be included in the composition for proper formulation and one of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference in its entirety. Suitable formulations for use in the present disclosure are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed., 1985, incorporated by reference in its entirety. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. For a brief review of methods for drug delivery, see, e.g., Langer (Science 249:1527-1533, 1990).

[0224] Exemplary formulations for an IL4R antigen binding protein of the present disclosure are provided, for example, in U.S. Application No. 17 / 436,981, the disclosure of which is incorporated by reference in its entirety. 7. Routes of Administration

[0225] The IL4R antigen binding proteins provided herein can be formulated in any appropriate pharmaceutical composition and administered by any suitable route of administration. Suitable routes of administration include, but are not limited to, the intravitreal, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes.

[0226] The IL4R antigen binding proteins disclosed herein may be administered to a subject intravenously as a bolus or by continuous infusion over a period of time, by intravitreal, intramuscular, intraperitoneal, intra-cerebrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, or intratumoral routes. They can also be administered byAttorney Docket No.: CBP-006WO peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects

[0227] In some embodiments, the step of administering comprises intravenous administration. In some embodiments, the step of administering comprises subcutaneous administration. 8. Therapeutic Applications

[0228] The IL4R antigen binding proteins provided herein may be useful for the treatment of any inflammatory or allergic disease or condition, e.g. one involving IL4R. In some embodiments, the inflammatory or allergic disease or condition is asthma. In some embodiments, the inflammatory or allergic disease or condition is chronic obstructive pulmonary disease (COPD). In some embodiments, the IL4R antigen binding proteins provided herein are used for treatment of any acute respiratory distress condition. In some embodiments, the IL4R antigen binding proteins provided herein are used for treatment of any acute respiratory condition that results in a type 2 inflammation response.

[0229] Type 2 inflammation is a specific type of immune response pattern. It describes an inflammatory pathway involving a subpopulation of CD4+T cells known as Th2 cells that secrete IL-4, IL-5, and IL-13 and stimulate Type 2 immunity, which is characterized by high IgE antibody titers and eosinophilia. Type 2 immune responses in the airway are mediated mainly by eosinophils, mast cells, basophils, Th2 cells, ILC2s, and IgE-producing B cells. Type 2 inflammation is often characterized by eosinophils, and may be accompanied by atopy, whereas non-type 2 inflammation is often characterized by neutrophils. 8.1. Asthma

[0230] Asthma is a chronic respiratory illness that causes inflammation of small and large airways. Symptoms include trouble breathing (shortness of breath), wheezing, coughing, and tightness / pain in the chest.

[0231] Acute episodes of asthmatic symptoms, interchangeably referred to herein as “asthma attacks,” “asthma exacerbations” or “acute exacerbations,” can be treated at home or in an outpatient office, but sometimes require a visit to a medical facility (e.g., the emergency department, urgent care center, and / or hospital ward). In some embodiments, an “asthma exacerbation” is defined as (i) an increase of asthma symptoms that do not resolve within, e.g., 2 hours after the use of asthma rescue therapy (e.g., albuterol or corticosteroids), (ii) an increase in asthma symptoms requiring an unscheduled medical visit, and / or (3) during aAttorney Docket No.: CBP-006WO scheduled study visit, the subject has acute asthma symptoms and a reduction of greater than or equal to about 20% in predicted peak expiratory flow or FEV1. For example, the subject has acute asthma symptoms and a reduction of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% in predicted peak expiratory flow or FEV1. Patients with frequent asthma exacerbations are at increased risk of future asthma exacerbations. Over 50% of patients fail to improve with current frontline standards of care.

[0232] A summary of current asthma-related statistics in the United States is provided in FIG. 1A. The annual number of hospitalizations for asthma from 2016 to 2019 in the United states is shown in FIG. 3A. The current total number of asthma-related emergency department (ED) visits and hospitalizations in 2024 in the EU are shown in FIGS. 3B and 3C, respectively.

[0233] Many inflammatory cells, such as eosinophils, mast cells and lymphocytes are involved in asthma and its specific pathogenesis is still unclear. Since cytokines such as IL-4 play an important role in the occurrence and development of bronchial asthma, the antibodiesspecific for IL-4 have become effective ways to treat asthma. Inhibition of IL-4 / IL-4R canhave an effective immunomodulatory effect on asthma.

[0234] The standard of care (SOC) for asthma includes, for example, inhaled bronchodilators (e.g., fast-acting / short-acting inhaled bronchodilators) and oral / IV corticosteroids. Inhaled bronchodilators relaxe the muscle bands that tighten around your airways (e.g., bronchi) and include, without limitation short-acting beta-agonists like albuterol and levalbuterol, long-acting beta-agonists such as salmeterol and formoterol, and anticholinergics including ipratropium and tiotropium. In some severe cases, patients require one or more of the following: IV magnesium sulfate, heliox therapy, and noninvasive ventilation, and intubation. Intubation is typically considered for patients that are non- responsive to initial therapies. An overview of the SOC, disease progression, exemplary admission rates, and long term care is provided in FIG. 2.

[0235] In some embodiments, the subject has eosinophilia. In some embodiments, the subject has hypereosinophilia. Generally, patients with eosinophilia can report with eosinophils counts > about 1500 and patients with hypereosinophilia can report with > about 3000 .

[0236] Hypereosinophilia has also been reported following treatment with dupilumab, anIL- - . InAttorney Docket No.: CBP-006WO some embodiments, a therapeutically effective amount of the antibody or antibody fragment as disclosed herein, is administered to a subject that has hypereosinophilia or a has a history of hypereosinophilia. In some embodiments, a therapeutically effective amount of the antibody or antibody fragment as disclosed herein, is administered to a subject that has a baseline eosinophils level of greater than about . In some embodiments, a therapeutically effective amount of the antibody or antibody fragment as disclosed herein, is administered to a subject that has a baseline eosinophils level of greater than about 450, about 500, or about 550 . In some embodiments, a therapeutically effective amount of the antibody or antibody fragment as disclosed herein, is administered to a subject that previously received a comparator and exhibited one or more symptoms of hypereosinophilia. In some embodiments, that administration reduces or eliminates the one or more symptoms of hypereosinophilia relative to a comparator.

[0237] “Type 2 asthma” or “asthma with type 2 inflammation” refers to a phenotype of asthma characterized by the production of cytokines such as interleukin (IL)-4, IL-5 and IL- 13, which are often produced by the adaptive immune system on recognition of allergens. In subjects with mild or moderate asthma, type 2 inflammation rapidly improves when inhaled corticosteroid (ICS) are taken regularly and correctly. In severe asthma, type 2 inflammation is relatively refractory to high dose of ICS. Severe type 2 asthma may respond to oral corticosteroid (OCS) but they can have serious adverse effects.

[0238] “Uncontrolled asthma” also known as “refractory asthma” refers to asthma that is not controlled by maintenance medications, in particular bronchodilators and / or corticoids, such as inhaled corticoids or even in some cases oral corticoids. In other words, in a subject suffering from uncontrolled asthma or refractory asthma, the maintenance medications do not achieve their aim, for example of preventing or lessening airway inflammation, preventing or lessening asthma symptoms and / or asthma associated limitations, and preventing asthma exacerbation. In one embodiment, uncontrolled asthma is defined by the presence of at least one of the following: limitations of activities, loss of sleep quality and in particular night-time awakening(s), and / or need for rescue treatment at least twice per week.

[0239] Use of IL4R antigen binding proteins as disclosed herein for long-term treatment of asthma has been demonstrated. The inventors of the present disclosure have identified that the IL4R antigen binding proteins provided herein can also be used for acute treatment of asthma (e.g., within the first 72 hours, 48 hours, 36 hours, 24 hours, 12 hours, etc., following an asthma attack). Here, in some embodiments, immediate administration of IL4R antigen binding proteins is shown to yield most of the symptomatic improvement (e.g., lung function)Attorney Docket No.: CBP-006WO within, for example, the first day or first two days post-treatment. Treatment with the IL4R antigen binding proteins results in rapid onset and sustained improvements in asthma subjects experiencing an asthma attack (interchangeably referred to herein as an asthma exacerbation).

[0240] In some embodiments, administering a therapeutically effective amount of IL4R antigen binding protein results in an improvement in lung function as early as about 6, about 12, or about 24 hours after treatment and is well tolerated over the following about 24 weeks. In some embodiments, it is well tolerated over the following about 1 week, about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, about 24 weeks. In some embodiments, the improvement in lung function is the subject exhibiting a higher forced expiratory volume in 1 second (FEV1) relative to a subject (i) not administered the IL4R antigen binding protein disclosed herein or (ii) that received an alternative anti-IL4R treatment. In some embodiments, the improvement in lung function is the subject exhibiting a higher peak expiratory flow (PEF) relative to a subject (i) not administered the IL4R antigen binding protein disclosed herein or (ii) that received an alternative anti-IL4R treatment.

[0241] In some embodiments, administering a therapeutically effective amount of IL4R antigen binding protein results in reduction of asthma symptoms relative to baseline, e.g., prior to treatment or under an alternative treatment. In some embodiments, administering a therapeutically effective amount of IL4R antigen binding protein results in reduction of frequency of asthma exacerbations relative to baseline, e.g., prior to treatment or under an alternative treatment.

[0242] In some embodiments, administering a therapeutically effective amount of IL4R antigen binding protein results in reduction of readmission to medical facilities for treatment of asthma, e.g., relative to baseline, e.g., prior to treatment or under an alternative treatment. 8.2. Chronic Obstructive Pulmonary Disease (COPD)

[0243] COPD refers to a group of chronic respiratory illnesses caused by damage to the lungs resulting in swelling and irritation (inflammation) inside the airways that limit airflow into and out of the lungs (obstruction). Symptoms include trouble breathing, persistent (e.g., daily) coughing with mucus and whistling in the lungs (wheezing). Long-term irritant exposure, e.g., cigarette smoke, is a common cause of chronic COPD.

[0244] Acute episodes of COPD symptoms, also referred to herein as “COPD exacerbations,” can be treated in an outpatient or inpatient setting depending on severity.Attorney Docket No.: CBP-006WO

[0245] A summary of current COPD-related statistics in the United States is provided in FIG. 1B. The annual number of hospitalizations for COPD from 2016 to 2019 in the United states is shown in FIG. 3A. The current total number of COPD-related emergency department (ED) visits and hospitalizations in 2024 in the EU are shown in FIGS. 3B and 3C, respectively.

[0246] There are currently no approved biologic treatments for COPD in the United States. Similar to asthma, the SOC for COPD includes, for example, fast-acting inhaled bronchodilators and oral / IV corticosteroids. Additionally, in some cases, patients are also given antibiotics to combat any bacterial infection(s). In some severe cases, patients require one or more of the following: IV magnesium sulfate, heliox therapy, and noninvasive ventilation, and intubation. Intubation is typically considered for patients that are non- responsive to initial therapies. An overview of the SOC, disease progression, exemplary admission rates, and long term care is provided in FIG. 2.

[0247] In some embodiments, the present disclosure provides methods of treating COPD at any stage (acute treatment, chronic / long-term treatment, etc.).

[0248] In some embodiments, administering a therapeutically effective amount of IL4R antigen binding protein results in an overall improvement in lung function. In some embodiments, the improvement in lung function is the subject exhibiting a higher forced expiratory volume in 1 second (FEV1) relative to a subject (i) not administered the IL4R antigen binding protein disclosed herein or (ii) that received an alternative anti-IL4R treatment. In some embodiments, the improvement in lung function is the subject exhibiting a higher peak expiratory flow (PEF) relative to a subject (i) not administered the IL4R antigen binding protein disclosed herein or (ii) that received an alternative anti-IL4R treatment.

[0249] For acute treatments, in some embodiments, administering a therapeutically effective amount of IL4R antigen binding protein results in an improvement in lung function as early as about 6, about 12, or about 24 hours after treatment and is well tolerated over the following 24 weeks. In some embodiments, it is well tolerated over the following about 1 week, about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, about 24 weeks. In some embodiments, the improvement in lung function is the subject exhibiting a higher forced expiratory volume in 1 second (FEV1) relative to a subject (i) not administered the IL4R antigen binding protein disclosed herein or (ii) that received an alternative anti-IL4R treatment. In some embodiments, the improvement in lung function is the subject exhibiting a higher peak expiratory flow (PEF) relative to a subject (i) notAttorney Docket No.: CBP-006WO administered the IL4R antigen binding protein disclosed herein or (ii) that received an alternative anti-IL4R treatment.

[0250] In some embodiments, administering a therapeutically effective amount of IL4R antigen binding protein results in reduction of COPD symptoms relative to baseline, e.g., prior to treatment or under an alternative treatment. In some embodiments, administering a therapeutically effective amount of IL4R antigen binding protein results in reduction of frequency of COPD exacerbations relative to baseline, e.g., prior to treatment or under an alternative treatment.

[0251] In some embodiments, administering a therapeutically effective amount of IL4R antigen binding protein results in reduction of readmission to medical facilities for treatment of COPD, e.g., relative to baseline, e.g., prior to treatment or under an alternative treatment. 9. Reversal of Beta2-Agonist Resistance

[0252] Beta2 ( 2)-agonists (e.g., albuterol, bitolterol mesylate, formoterol, fenoterolisoprenaline, levalbuterol, metaproterenol, salmeterol, terbutaline, ritodrine, etc.) act on the 2-adrenergic receptor ( 2AR) in the lungs, leading to increased cAMP, smooth muscledilatation, and bronchodilation. Beta2-agonists are often included as the first line therapy for reversal of airway obstruction and relief of clinical asthma symptoms or asthma exacerbation. Prolonged exposure to beta-agonists can lead to desensitization and down-regulation of beta- 2 receptors (tolerance / resistance to beta2-agonists), potentially reducing their effectiveness. This tolerance impacts asthma treatment by potentially leading to a poorer response to emergency beta-agonist treatment during exacerbations.

[0253] In some embodiments, the present disclosure provides methods of reversing tolerance to a beta2-agonist by administering a therapeutically effective amount of IL4R antigen binding protein, as disclosed herein. In some embodiments, the IL4R antigen binding protein is dupilimab. In some embodiments, the IL4R antigen binding protein comprises three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR- H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8.Attorney Docket No.: CBP-006WO

[0254] The present disclosure provides methods for treating asthma or COPD by administering to a subject a therapeutically effective amount of an IL4R antigen binding protein as disclosed herein, wherein the asthma is beta2-agonist resistant asthma or beta2- agonist COPD. In some embodiments, administration of the IL4R antigen binding protein is contemplated while the subject is having an asthma or COPD exacerbation. In some embodiments, the administration of the IL4R antigen binding protein results in a complete response.

[0255] In some embodiments, the antibody or antibody fragment is administered by intravenous injection.

[0256] In some embodiments, the subject is known to have or suspected of having tolerance to a beta2-agonist. In some embodiments, the subject has a history of diagnosis of tolerance to a beta2-agonist. In some embodiments, the subject has genetic variations orpolymorphisms, within the beta2- , that have beenlinked to differences in responsiveness to beta2-agonists (e.g., Arg16Gly modification at at

[0257] Methods of determining beta2-agonist resistance are known to those of ordinary skill in the art. For example, in some cases, beta2-agonist resistance is determined by measuring the response to the beta2-agonist following induced bronchoconstriction in a controlled setting. Bronchoconstriction can be induced by exposing a subject to, e.g., methacholine, hypertonic saline, mannitol, exercise, and then administering a beta2 agonist in incremental doses, and then measuring the bronchodilator response, e.g., FEV1 measurements at each interval and finding the area under the resulting FEV1 response curve (AUC). Tolerance is indicated by a reduced FEV1AUC over time (e.g. after 1, 2, 3, 4 or more weeks of treatment with the beta2-agonist).

[0258] In some embodiments, determining beta2 agonist resistance is determined by treating a subject having an asthma or COPD (e.g., an exacerbation thereof) with a beta2- agonist, wherein the treatment results in a partial response or no response. In some embodiments, a response refers to a reduction or elimination of a symptom of asthma or COPD. A subject has “no response” when there is no significant change in their condition (or symptoms) relative to baseline, based on one or more of the following: asthma control questionnaire score (ACQ), qualitative and quantitative data collected in a symptom diary, at- home lung function measurements, included FEV1and / or PEF values.Attorney Docket No.: CBP-006WO 10. Additional Therapeutic Applications of IL4R Antigen Binding Proteins

[0259] Furthermore, in some embodiments, where a subject is administered a therapeutically effective amount of IL4R antigen binding protein, there is an improvement in the subjects condition relative to baseline, based on one or more of the following: asthma control questionnaire score (ACQ), qualitative and quantitative data collected in a symptom diary, at-home lung function measurements, included FEV1 and / or PEF values, resistance to beta2-agonists, etc.

[0260] In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a FEV1, optionally pre-bronchodilator FEV1, of less than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a FEV1, optionally pre-bronchodilator FEV1, of less than about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a FEV1, optionally pre-bronchodilator FEV1, of less than about 40% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a FEV1, optionally pre-bronchodilator FEV1, of less than about 50% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a FEV1, optionally pre- bronchodilator FEV1, of less than about 60% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a FEV1, optionally pre-bronchodilator FEV1, of less than about 70% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a FEV1, optionally pre-bronchodilator FEV1, of less than about 80% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a FEV1, optionally pre-bronchodilator FEV1, of less thanAttorney Docket No.: CBP-006WO about 85% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a FEV1, optionally pre-bronchodilator FEV1, of about 40% to about 85% of predicted normal.

[0261] In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a peak expiratory flow (PEF) of less than or equal to about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a peak expiratory flow (PEF) of less than or equal to about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a peak expiratory flow (PEF) of about 40% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a peak expiratory flow (PEF) of about 50% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a peak expiratory flow (PEF) of about 60% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a peak expiratory flow (PEF) of about 70% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a peak expiratory flow (PEF) of about 80% of predicted normal. In some embodiments, a subject is administered a therapeutically effective amount of IL4R antigen binding protein, wherein, prior to administration, the subject has a peak expiratory flow (PEF) of about 85% of predicted normal.

[0262] In some embodiments, where a subject is administered a therapeutically effective amount of IL4R antigen binding protein, there is a reduction relative to baseline in PD markers including one or more of the following: fractional exhaled nitric oxide (FeNO), blood eosinophil count, eosinophil cationic protein (ECP), periostin, thymus and activation- regulated chemokine / C-C motif chemokine 17 (TARC / CCL17) TARC, etc.Attorney Docket No.: CBP-006WO

[0263] In some embodiments, where a subject is administered a therapeutically effective amount of IL4R antigen binding protein, there is a reduction in their use of rescue medication relative to baseline, e.g., prior to treatment or under an alternative treatment.

[0264] In some aspects, the present disclosure provides methods of treating asthma, acute asthma, COPD, or a respiratory condition with type 2 inflammation response in a subject, the method comprising administering to the subject a therapeutically effective amount of an IL4R antigen binding protein as disclosed herein, e.g., an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR- H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the IL4R antigen binding protein is administered to the subject having an acute exacerbation as evident by symptoms of the condition or disease. 11. Combination Therapies

[0265] In some embodiments, an IL4R antigen binding protein provided herein is administered with at least one additional therapeutic agent. Any suitable additional therapeutic agent may be administered with an IL4R antigen binding protein provided herein.

[0266] In some embodiments, an IL4R antigen binding protein provided herein is administered in combination with a controller therapy, e.g., a short-acting beta2-agonist (e.g., fenoterol, albuterol, etc.), a long-acting ß agonist (LABA), a leukotriene receptor antagonist (LTRA), or theophylline.

[0267] In embodiments where an IL4R antigen binding protein provided herein and the additional therapeutic agent are included in different pharmaceutical compositions, administration of the IL4R antigen binding protein can occur prior to, simultaneously, and / or following, administration of the additional therapeutic agent. EXAMPLES

[0268] The following are examples of methods and compositions of the invention. It is understood that various other embodiments may be practiced, given the general description provided herein.Attorney Docket No.: CBP-006WO

[0269] Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0270] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rdEd. (Plenum Press) Vols A and B(1992). Example 1: Synthesis of IL4R antigen binding protein

[0271] Methods for making IL4R antigen binding proteins as disclosed herein are provided in U.S. Patent No. 10,774,141, herein incorporated by reference in its entirety for all purposes.

[0272] Briefly, the sequence coding for the light chain variable region of the antibody was inserted into vector pFUSE2ss-CLIg-hK (Invivogen, Catalog Number: pfuse2ss-hclk) using EcoRI and BsiWI restriction sites to construct a light chain expression vector. The sequence coding for the heavy chain variable region of the antibody was inserted into vector pFUSEss-CHIg-hG2 (Invivogen, Catalog Number: pfusess-hchg2) or vector pFUSEss-CHIg- hG4 (Invivogen, Catalog Number: pfusess-hchg4) using EcoRI and NheI restriction sites to construct a heavy chain expression vector.

[0273] The culture and transfection of Expi293 cells were performed in accordance with the handbook of Expi293™ Expression System Kit from Invitrogen (Catalog Number: A14635). The density of the cells was adjusted to 2 × 106 cells / ml for transfection, and 0.6 g of the light chain expression vector as described above and 0.4 g of the heavy chain expression vector as described above were added to each ml of cell culture, and the supernatant of the culture was collected four days later.Attorney Docket No.: CBP-006WO Example 2: Studies on Efficacy and Safety of IL4R antigen binding protein in Moderate-to-Severe Asthma Patients

[0274] A clinical study was conducted to evaluate the efficacy of administering an IL4R antigen binding protein in subjects with asthma. The study plan is illustrated in FIG. 4. Key Inclusion Criteria

[0275] The subjects selected had stabilized moderate-to-severe uncontrolled asthma, based primarily on the following key inclusion criteria: Existing treatment with medium to high dose ICS in combination with a second controller (e.g., long-acting ß agonist (LABA), leukotriene receptor antagonist (LTRA) the screening visit Pre-bronchodilator FEV1 of 40% to 85% of predicted normal at Visits 1 and 2, prior to randomization L o No eosinophil count requirement for patients on maintenance OCS At least 1 documented asthma exacerbation in the 12 months prior to the date of informed consent that required use of a systemic corticosteroid Methods:

[0276] The study methods are illustrated in FIG. 4. Briefly, the efficacy of the IL4R antigen binding protein was determined based primarily on changes in baseline of FEV1at Weeks 12 and 24 (in clinic with central overread). The secondary efficacy endpoints measured were as follows: Change from baseline in FEV1at other timepoints Asthma exacerbations PROs (ACQ, symptom diary, at-home lung function) PD markers (FeNO, eosinophils, ECP, periostin, TARC) Rescue medication use Results

[0277] The results revealed significantly improved lung function at Week 12 in patients that received the IL4R antigen binding protein treatment as an initial 600 mg loading dose followed by the indicated Q2W administration (FIG. 4). The results revealed that IL4R antigen binding protein treatment resulted in rapid, significant changes in FEV1 as early as Week 1, which were sustained for the duration of the 24-week study (FIG. 7). RapidlyAttorney Docket No.: CBP-006WO improved and sustained FEV1values were observed with the IL4R antigen binding protein treatment as early as 24 hours post initial treatment. The subjects’ home daily lung function data demonstrated 75% of improvement seen on Day 7 was observed by Day 1, with 100% by Day 2 (FIG. 8). Additionally, the IL4R antigen binding protein patients trended toward 50% fewer exacerbations compared to the placebo group. Some representative study results are shown in FIGS. 5-9. These results support the efficacy of acute treatment of asthma with the IL4R antigen binding proteins of the present disclosure. Example 3: Studies on effect of IL4R antigen binding protein on blood eosinophil counts in patients with asthma

[0278] A study was conducted to determine the effect of administering an IL4R antigen binding protein on blood eosinophil count.

[0279] Methods: A global, placebo-controlled study was conducted with 322 patients randomized 1:1:1 to Antibody A 150 mg every two weeks (Q2W; n=106), 300 mg Q2W (n=108) each with a loading dose of 600 mg or placebo (n=108). Rates of eosinophilia (eosinophils >1500 ) and hypereosinophilia (eosinophils >3000 ) were examined in the overall population and in patients with high eosinophils counts at baseline (eosinophils >500 ). Data from the higher 300 mg Q2W dose are discussed.

[0280] Results: Following 24 weeks of treatment with Antibody A, overall percent change from baseline eosinophil counts were reduced with treatment vs placebo early in treatment (Week 1: -4.6% vs -0.3%, respectively; Week 4: -11.9% vs -1.7%) with further reductions observed by Week 24 (-38.5% vs -10.7%). For those with baseline eosinophils during treatment compared to 18.8% on placebo and no person (0%) exhibited hypereosinophilia with a peak eosinophils level of >3000 . Consistent with previous studies, treatment with Antibody A was generally well tolerated.

[0281] Conclusions: Previous reports on dupilumab have shown eosinophilia in 42% and hypereosinophilia in 13% of patients (see Table 6) leading one to suppose that increases in eosinophils may be a class effect with IL-4R blockers. Eosinophil changes are similar in the placebo groups in Table 6, indicating that differences in the treatment groups must have been due to drug effect. Therefore, the results suggest that the effect on eosinophil levels seen with comparators, such as dupilumab, may not be a class effect and support the notion that Antibody A and dupilumab are distinct possibly due to molecular structural differences in their interactions with the IL-4R.Attorney Docket No.: CBP-006WO Table 6OTHER EMBODIMENTS

[0282] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features set forth herein.

Claims

Attorney Docket No.: CBP-006WO CLAIMS 1. A method of treating acute asthma in a subject, the method comprising: administering to the subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the antibody or antibody fragment is administered while the subject is having an asthma exacerbation.

2. The method of claim 1, wherein the asthma exacerbation has been ongoing for greater than or equal to about 2 hours.

3. The method of claim 1, wherein the subject has received greater than or equal to about 2 treatments with inhaled bronchodilators before administration of the antibody or antibody fragment.

4. The method of claim 1, wherein before administration of the antibody or antibody fragment, the subject has a forced expiratory volume in 1 second (FEV1), optionally pre-bronchodilator FEV1, of less than about 85% of predicted normal.

5. The method of claim 4, wherein before administration of the antibody or antibody fragment, the subject has a FEV1, optionally pre-bronchodilator FEV1, of about 40% to about 85% of predicted normal.

6. The method of claim 1, wherein before administration of the antibody or antibody fragment, the subject has a peak expiratory flow (PEF) of less than or equal to about 70% of predicted normal.

7. The method of claim 1, wherein the subject had a least one previous asthma exacerbation requiring urgent care within the past 12 months.

8. The method of claim 1, wherein the subject is admitted to a medical facility for the asthma exacerbation.

9. A method of treating chronic obstructive pulmonary disease (COPD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amountAttorney Docket No.: CBP-006WO of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO:

8.

10. The method of claim 9, wherein the subject is identified as having a COPD exacerbation.

11. A method of treating a chronic obstructive pulmonary disease (COPD) exacerbation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO:

8.

12. The method of any one of claims 9-11, wherein before administration of the antibody or antibody fragment, the subject has a forced expiratory volume in 1 second (FEV1), optionally pre-bronchodilator FEV1, of less than about 85% predicted normal.

13. The method of claim 12, wherein the subject before administration of the antibody or antibody fragment has a forced expiratory volume in 1 second (FEV1), optionally pre- bronchodilator FEV1, of about 40% to about 85% of predicted normal.

14. The method of claim 1, wherein the subject before administration of the antibody or antibody fragment has a peak expiratory flow (PEF) of less than or equal to about 70% of predicted normal.

15. The method of any one of claims 9-14, wherein the subject is admitted to a medical facility for the COPD exacerbation.Attorney Docket No.: CBP-006WO 16. The method of any one of claims 9-15, wherein the subject is administered the antibody or antibody fragment within about 24 hours to about 72 hours of the onset of the COPD exacerbation.

17. A method of treating a subject having an allergic or inflammatory condition comprising: (i) determining that the subject has an exacerbation of the allergic or inflammatory condition, and (ii) administering to the subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR- L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the allergic or inflammatory condition is asthma or chronic obstructive pulmonary disease (COPD).

18. A method of treating asthma, the method comprising: administering to a subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR- L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the asthma is beta2-agonist resistant asthma.

19. The method of claim 18, wherein the antibody or antibody fragment is administered while the subject is having an asthma exacerbation.

20. The method of claim 18, wherein the method results in a complete response.Attorney Docket No.: CBP-006WO 21. A method of treating asthma, the method comprising: administering to a subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR- L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the subject is resistant or tolerant to treatment with a beta2-agonist.

22. The method of claim 21, wherein the method results in a complete response.

23. A method of treating a subject having asthma, the method comprising: (i) treating a subject having an asthma exacerbation with a beta2-agonist, wherein the treatment results in a partial response or no response; and (ii) treating the subject by administering a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR- L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8, wherein the treatment with the antibody or antibody fragment results in a complete response.

24. A method of treating COPD, the method comprising: administering to a subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR- L2, and CDR-L3,Attorney Docket No.: CBP-006WO wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in COPD is beta2-agonist resistant COPD.

25. The method of claim 24, wherein the antibody or antibody fragment is administered while the subject is having COPD exacerbation.

26. A method of treating COPD, the method comprising: administering to a subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR- L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the subject is resistant or tolerant to treatment with a beta2-agonist.

27. The method of any one of claims 24-26, wherein the method results in a complete response.

28. A method of treating a subject having COPD, the method comprising: (i) treating a subject having a COPD exacerbation with a beta2-agonist, wherein the treatment results in a partial response or no response; and (ii) treating the subject by administering a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR- L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2Attorney Docket No.: CBP-006WO comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8, wherein the treatment with the antibody or antibody fragment results in a complete response.

29. A method of treating a subject having an exacerbation of an allergic or inflammatory condition comprising: (i) determining that the subject has an exacerbation of the allergic or inflammatory condition, (ii) determining that the subject has tolerance to the beta2-agonist, (iii) administering to the subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and (iv) administering to the subject a therapeutically effective amount of the beta2-agonist, wherein the allergic or inflammatory condition is asthma or chronic obstructive pulmonary disease (COPD).

30. A method of treating a subject having an exacerbation of an allergic or inflammatory condition comprising administering to the subject a therapeutically effective amount of the beta2-agonist and a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR- L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8,Attorney Docket No.: CBP-006WO wherein the allergic or inflammatory condition is asthma or chronic obstructive pulmonary disease (COPD) and wherein the method results in a complete response.

31. The method of claim 30, wherein the subject is known to have or suspected of having tolerance to a beta2-agonist.

32. The method of claim 30, wherein the subject has a history of diagnosis of tolerance to a beta2-agonist.

33. The method of any one of the preceding claims, wherein the subject has an Arg16Gly modification at amino acid position 16 of beta2- .

34. The method of any one of claims 30-33, wherein the antibody or antibody fragment is administered prior to administering the beta2-agonist.

35. The method of any one of claims 30-33, wherein the antibody or antibody fragment and the beta2-agonist are administered simultaneously.

36. The method of any one of the preceding claims, wherein the allergic or inflammatory condition is asthma.

37. The method of any one of the preceding claims, wherein the allergic or inflammatory condition is COPD.

38. The method of any one of claims 17-37, wherein the subject is admitted to a medical facility for the exacerbation of the allergic or inflammatory condition.

39. The method of any one of the preceding claims, wherein the subject is treated with the antibody or antibody fragment within the first 72 hours of the onset of the exacerbation.

40. The method of any one of the preceding claims, wherein the subject is treated with the antibody or antibody fragment within the first 48 hours of the onset of the exacerbation.

41. The method of any one of the preceding claims, wherein the subject is treated with the antibody or antibody fragment within the first 24 hours of the onset of the exacerbation.

42. The method of any one of the preceding claims, wherein the antibody or antibody fragment comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:

2.

43. The method of any one of the preceding claims, wherein the subject has type 2 inflammation.

44. The method of any one of the preceding claims, wherein the subject has or is at risk of having eosinophilia.

45. The method of any one of the preceding claims, wherein the subject has or is at risk of having hypereosinophilia.Attorney Docket No.: CBP-006WO 46. The method of any one of the preceding claims, wherein prior to treatment the subject has a blood eosinophil count of greater than or equal to about 500 or about 300 47. The method of any one of the preceding claims, wherein prior to treatment the subject has a FeNO level of greater than about 20 ppb.

48. The method of any one of the preceding claims, wherein the subject has received prior systemic treatment with an anti-inflammatory agent, optionally steroids.

49. The method of any one of the preceding claims, wherein the subject has had at least one prior exacerbation requiring prescription for an anti-inflammatory agent, optionally systemic steroids.

50. The method of any one of the preceding claims, wherein following the treatment the subject exhibits a higher FEV1 relative to a subject not administered the antibody or antibody fragment.

51. The method of any one of the preceding claims, wherein following the treatment the subject exhibits a higher PEF relative to a subject not administered the antibody or antibody fragment.

52. The method of any one of the preceding claims, wherein the antibody or antibody fragment is administered by intravenous injection.

53. The method of any one of the preceding claims, wherein the antibody or antibody fragment is administered by subcutaneous injection.

54. The method of any one of the preceding claims, wherein the antibody or antibody fragment is a humanized antibody.

55. The method of any one of the preceding claims, wherein the antibody or antibody fragment is a monoclonal antibody.

56. The method of any one of the preceding claims, wherein the antibody or antibody fragment comprises a human Ig constant domain.

57. The method of any one of the preceding claims, wherein the antibody or antibody fragment comprises a human IgG4 constant region.

58. The method of any one of the preceding claims, wherein the antibody or antibody fragment binds 59. The method of any one of claims 18-58, wherein the beta2-agonist is selected from the group consisting of albuterol, bitolterol mesylate, formoterol, fenoterol isoprenaline, levalbuterol, metaproterenol, salmeterol, terbutaline, and ritodrine.

60. A method of treating acute asthma in a subject, the method comprising:Attorney Docket No.: CBP-006WO administering to the subject a therapeutically effective amount of an antibody or antibody fragment comprising three heavy chain complementarity determining regions (CDRs), CDR-H1, CDR-H2, and CDR-H3, and three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 3, the CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 4, and the CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 5, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 6, the CDR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7, the CDR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; and wherein the antibody or antibody fragment is administered to the subject having acute asthma.

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