# US 2020/0399382 A1 · Combined antagonists against il-5/il-5r and either il-4/il-4r or il-13/il-13r

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2020/0399382 A1
- Document ID: US20200399382A1
- Status: Published application
- Kind: A1
- Application number: 16/966,237
- Filed: 2019-02-15
- Published: 2020-12-24
- Earliest claimed: 2018-02-15
- Assignees: argenx BVBA
- Applicants: argenx BVBA
- Inventors: Christophe BLANCHETOT; Marie GODAR; Bart LAMBRECHT
- Web page: https://patentgrep.com/patent/US20200399382A1

## CPC

- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- C07K 16/244: {Interleukins [IL]}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/22: from camelids, e.g. camel, llama or dromedary
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention relates to combination therapies and to their use in the treatment of chronic airway disease, particularly use in the treatment of asthma. The combination therapies comprise (i) an antagonist of IL-5:IL-5R and (ii) an antagonist of IL-4:IL-4R and/or an antagonist of IL-13:IL-13R. The present invention also provides bispecific antibodies comprising an antigen binding domain that binds to IL-4Rα and an antigen binding domain that binds to IL-5. The bispecific antibodies may be used for the treatment of chronic airway disease, particularly asthma.

## Claims

### Claim 1

A combination comprising:
(i) an antagonist of IL-5:IL-5R; and
(ii) an antagonist of IL-4:IL-4R and/or an antagonist of IL-13:IL-13R.

### Claim 2 (depends on 1)

The combination of claim 1, comprising:
(i) an antagonist of IL-5:IL-5R; and
(ii) an antagonist of IL-4Rα.

### Claim 3 (depends on 1, 2)

The combination of claim 1 or claim 2, which inhibits signalling via IL-5, IL-4 and IL-13.

### Claim 4 (depends on 1, 2, 3)

The combination of any one of claims 1-3, wherein the antagonist of (i) is an antibody molecule and/or at least one antagonist of (ii) is an antibody molecule.

### Claim 5 (depends on 1, 2, 3, 4)

The combination of any one of claims 1-4, wherein the antagonist of (i) is an antibody molecule that binds to IL-5, preferably human IL-5.

### Claim 6 (depends on 2, 3, 4, 5)

The combination of any one of claims 2-5, wherein the antagonist of (ii) is an antibody molecule that binds to IL-4Rα, preferably human IL-4Rα.

### Claim 7 (depends on 4, 5, 6)

The combination of any one of claims 4-6, wherein the antibody molecule of (i) and/or the antibody molecule of (ii) is independently selected from the group consisting of: an antibody light chain variable domain (VL); an antibody heavy chain variable domain (VH); a single chain antibody (scFv); a F(ab′)2 fragment; a Fab fragment; an Fd fragment; an Fv fragment; a one-armed (monovalent) antibody; diabodies, triabodies, tetrabodies, VHH antibodies or any antigen-binding molecule formed by combination, assembly or conjugation of such antigen binding fragments.

### Claim 8 (depends on 4, 5, 6)

The combination of any one of claims 4-6, wherein the antibody molecule of (i) and/or the antibody molecule of (ii) is an IgG antibody.

### Claim 9 (depends on 4, 5, 6, 7, 8)

The combination of any one of claims 4-8, wherein the antibody molecule of (i) and/or the antibody molecule of (ii) is a humanised or germlined variant of a non-human antibody.

### Claim 10 (depends on 9)

The combination of claim 9, wherein the non-human antibody is camelid-derived.

### Claim 11 (depends on 4, 5, 6, 7, 8, 9, 10)

The combination of any one of claims 4-10, wherein the antibody molecule of (i) and/or the antibody molecule of (ii) comprises the CH1 domain, hinge region, CH2 domain and/or CH3 domain of a human IgG.

### Claim 12 (depends on 4, 5, 6, 7, 8, 9, 10, 11)

The combination of any one of claims 4-11, wherein the antibody molecule of (i) and/or the antibody molecule of (ii) exhibits high homology to a human IgG, preferably IgG1.

### Claim 13 (depends on 4, 5, 6, 7, 8, 9, 10, 11, 12)

The combination of any one of claims 4-12, wherein the antibody molecule of (i) and/or the antibody molecule of (ii) comprises an Fc domain derived from a human IgG, preferably IgG1.

### Claim 14 (depends on 13)

The combination of claim 13, wherein the Fc domain is modified by one or more amino acid substitutions to increase binding affinity to FcRn.

### Claim 15 (depends on 14)

The combination of claim 14, wherein the Fc domain comprises the amino acid substitutions: H433K and N434F.

### Claim 16 (depends on 14)

The combination of claim 14, wherein the Fc domain comprises the amino acid substitutions: M252Y, S254T, T256E, H433K and N434F.

### Claim 17 (depends on 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

The combination of any one of claims 2-16, wherein the antagonist of (ii) is an antibody molecule that binds to IL-4Rα, and wherein the antibody molecule comprises a variable heavy chain domain (VH) and a variable light chain domain (VL) wherein the VH and VL domains comprise the CDR sequences selected from the group consisting of:
(i) HCDR3 comprising or consisting of SEQ ID NO: 3; HCDR2 comprising or consisting of SEQ ID NO: 2; HCDR1 comprising or consisting of SEQ ID NO: 1; LCDR3 comprising or consisting of SEQ ID NO: 12; LCDR2 comprising or consisting of SEQ ID NO: 11; LCDR1 comprising or consisting of SEQ ID NO:10;
(ii) HCDR3 comprising or consisting of SEQ ID NO: 6; HCDR2 comprising or consisting of SEQ ID NO: 5; HCDR1 comprising or consisting of SEQ ID NO: 4; LCDR3 comprising or consisting of SEQ ID NO: 15; LCDR2 comprising or consisting of SEQ ID NO: 14; LCDR1 comprising or consisting of SEQ ID NO: 13; and
(iii) HCDR3 comprising or consisting of SEQ ID NO: 9; HCDR2 comprising or consisting of SEQ ID NO: 8; HCDR1 comprising or consisting of SEQ ID NO: 7; LCDR3 comprising or consisting of SEQ ID NO: 18; LCDR2 comprising or consisting of SEQ ID NO: 17; LCDR1 comprising or consisting of SEQ ID NO: 16.

### Claim 18 (depends on 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

The combination of any one of claims 2-16, wherein the antagonist of (ii) is an antibody molecule that binds to IL-4Rα, and wherein the antibody molecule comprises a variable heavy chain domain (VH) and a variable light chain domain (VL) wherein the VH and VL domains comprise the CDR sequences selected from the group consisting of:
(i) HCDR3 comprising or consisting of SEQ ID NO: 27; HCDR2 comprising or consisting of SEQ ID NO: 26; HCDR1 comprising or consisting of SEQ ID NO: 25; LCDR3 comprising or consisting of SEQ ID NO: 36; LCDR2 comprising or consisting of SEQ ID NO: 35; LCDR1 comprising or consisting of SEQ ID NO: 34;
(ii) HCDR3 comprising or consisting of SEQ ID NO: 30; HCDR2 comprising or consisting of SEQ ID NO: 29; HCDR1 comprising or consisting of SEQ ID NO: 28; LCDR3 comprising or consisting of SEQ ID NO: 39; LCDR2 comprising or consisting of SEQ ID NO: 38; LCDR1 comprising or consisting of SEQ ID NO: 37; and
(iii) HCDR3 comprising or consisting of SEQ ID NO: 33; HCDR2 comprising or consisting of SEQ ID NO: 32; HCDR1 comprising or consisting of SEQ ID NO: 31; LCDR3 comprising or consisting of SEQ ID NO: 42; LCDR2 comprising or consisting of SEQ ID NO: 41; LCDR1 comprising or consisting of SEQ ID NO:40.

### Claim 19 (depends on 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)

The combination of any one of claims 2-18, wherein the antagonist of (ii) is an antibody molecule that binds to IL-4Rα, and wherein the antibody molecule comprises a variable heavy chain domain (VH) and a variable light chain domain (VL) selected from the group consisting of:
(i) a VH domain comprising the amino acid sequence of SEQ ID NO: 19 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 20 or an amino acid sequence having at least 70% identity thereto;
(ii) a VH domain comprising the amino acid sequence of SEQ ID NO: 21 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 22 or an amino acid sequence having at least 70% identity thereto; and
(iii) a VH domain comprising the amino acid sequence of SEQ ID NO: 23 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 24 or an amino acid sequence having at least 70% identity thereto.

### Claim 20 (depends on 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)

The combination of any one of claims 2-18, wherein the antagonist of (ii) is an antibody molecule that binds to IL-4Rα, and wherein the antibody molecule comprises a variable heavy chain domain (VH) and a variable light chain domain (VL) selected from the group consisting of:
(i) a VH domain comprising the amino acid sequence of SEQ ID NO: 43 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence having at least 70% identity thereto;
(ii) a VH domain comprising the amino acid sequence of SEQ ID NO: 45 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 46 or an amino acid sequence having at least 70% identity thereto; and
(iii) a VH domain comprising the amino acid sequence of SEQ ID NO: 47 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 48 or an amino acid sequence having at least 70% identity thereto.

### Claim 21 (depends on 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)

The combination of any one of claims 2-20, wherein the antagonist of (i) is an antibody molecule that binds to IL-5, and wherein the antibody molecule comprises a variable heavy chain domain (VH) and a variable light chain domain (VL) wherein the VH and VL domains comprise the CDR sequences selected from the group consisting of:
(i) HCDR3 comprising or consisting of SEQ ID NO: 51; HCDR2 comprising or consisting of SEQ ID NO: 50; HCDR1 comprising or consisting of SEQ ID NO: 49; LCDR3 comprising or consisting of SEQ ID NO: 54; LCDR2 comprising or consisting of SEQ ID NO: 53; LCDR1 comprising or consisting of SEQ ID NO: 52;
(ii) HCDR3 comprising or consisting of SEQ ID NO: 51; HCDR2 comprising or consisting of SEQ ID NO: 50; HCDR1 comprising or consisting of SEQ ID NO: 49; LCDR3 comprising or consisting of SEQ ID NO: 57; LCDR2 comprising or consisting of SEQ ID NO: 56; LCDR1 comprising or consisting of SEQ ID NO: 55;
(ii) HCDR3 comprising or consisting of SEQ ID NO: 51; HCDR2 comprising or consisting of SEQ ID NO: 50; HCDR1 comprising or consisting of SEQ ID NO: 49: X; LCDR3 comprising or consisting of SEQ ID NO: 59; LCDR2 comprising or consisting of SEQ ID NO: 56; LCDR1 comprising or consisting of SEQ ID NO: 58;
(iv) HCDR3 comprising or consisting of SEQ ID NO: 51; HCDR2 comprising or consisting of SEQ ID NO: 50; HCDR1 comprising or consisting of SEQ ID NO: 49; LCDR3 comprising or consisting of SEQ ID NO: 61; LCDR2 comprising or consisting of SEQ ID NO: 60; LCDR1 comprising or consisting of SEQ ID NO: 58; and
(v) HCDR3 comprising or consisting of SEQ ID NO: 51; HCDR2 comprising or consisting of SEQ ID NO: 50; HCDR1 comprising or consisting of SEQ ID NO: 49; LCDR3 comprising or consisting of SEQ ID NO: 62; LCDR2 comprising or consisting of SEQ ID NO: 56; LCDR1 comprising or consisting of SEQ ID NO: 58.

### Claim 22 (depends on 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)

The combination of any one of claims 2-20, wherein the antagonist of (i) is an antibody molecule that binds to IL-5, and wherein the antibody molecule comprises a variable heavy chain domain (VH) and a variable light chain domain (VL) wherein the VH and VL domains comprise the CDR sequences selected from the group consisting of:
(i) HCDR3 comprising or consisting of SEQ ID NO: 72; HCDR2 comprising or consisting of SEQ ID NO: 71; HCDR1 comprising or consisting of SEQ ID NO: 70; LCDR3 comprising or consisting of SEQ ID NO: 74; LCDR2 comprising or consisting of SEQ ID NO: 38; LCDR1 comprising or consisting of SEQ ID NO: 73; and
(ii) HCDR3 comprising or consisting of SEQ ID NO: 72; HCDR2 comprising or consisting of SEQ ID NO: 71; HCDR1 comprising or consisting of SEQ ID NO: 70; LCDR3 comprising or consisting of SEQ ID NO: 75; LCDR2 comprising or consisting of SEQ ID NO: 38; LCDR1 comprising or consisting of SEQ ID NO: 73.

### Claim 23 (depends on 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

The combination of any one of claims 2-22, wherein the antagonist of (i) is an antibody molecule that binds to IL-5, and wherein the antibody molecule comprises a variable heavy chain domain (VH) and a variable light chain domain (VL) selected from the group consisting of:
(i) a VH domain comprising the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 64 or an amino acid sequence having at least 70% identity thereto;
(ii) a VH domain comprising the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence having at least 70% identity thereto;
(iii) a VH domain comprising the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence having at least 70% identity thereto;
(iv) a VH domain comprising the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence having at least 70% identity thereto;
(v) a VH domain comprising the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence having at least 70% identity thereto; and
(vi) a VH domain comprising the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence having at least 70% identity thereto.

### Claim 24 (depends on 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

The combination of any one of claims 2-22, wherein the antagonist of (i) is an antibody molecule that binds to IL-5, and wherein the antibody molecule comprises a variable heavy chain domain (VH) and a variable light chain domain (VL) selected from the group consisting of:
(i) a VH domain comprising the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 77 or an amino acid sequence having at least 70% identity thereto;
(ii) a VH domain comprising the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 78 or an amino acid sequence having at least 70% identity thereto; and
(iii) a VH domain comprising the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence having at least 70% identity thereto and a VL domain comprising the amino acid sequence of SEQ ID NO: 79 or an amino acid sequence having at least 70% identity thereto.

### Claim 25 (depends on 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)

The combination of any of claims 4-24, wherein the antibody molecule of (i) and/or the antibody molecule of (ii) exhibits lower antigen-binding activity at acidic pH than at neutral pH.

### Claim 26 (depends on 25)

The combination of claim 25, wherein the antibody molecule of (i) is an antibody molecule that binds to IL-5 and the antibody molecule of (ii) is an antibody molecule that binds to IL-4Rα.

### Claim 27 (depends on 25, 26)

The combination of claim 25 or claim 26, wherein the ratio of antigen-binding activity at acidic pH and at neutral pH is at least 2 as measured by KD (at acidic pH)/KD (at neutral pH).

### Claim 28 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27)

The combination of any one of claims 1-27, wherein the antagonist of (i) and the antagonist(s) of (ii) are co-formulated.

### Claim 29 (depends on 28)

The combination of claim 28, wherein the antagonist of (i) is an antibody molecule that binds to IL-5 and the antagonist of (ii) is an antibody molecule that binds to IL-4Rα.

### Claim 30 (depends on 28, 29)

The combination of claim 28 or claim 29, wherein the antagonist of (i) and the antagonist of (ii) are formulated according to a ratio of 1:1 or 1:2 or 2:1.

### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27)

The combination of any one of claims 1-27, wherein the antagonist of (i) and the antagonist of (ii) are provided separately.

### Claim 32 (depends on 31)

The combination of claim 31, wherein the antagonist of (i) is an antibody molecule that binds to IL-5 and the antagonist of (ii) is an antibody molecule that binds to IL-4Rα.

### Claim 33 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27)

The combination of any one of claims 1-27 comprising an antibody molecule that binds to IL-4Rα and an antibody molecule that binds to IL-5, wherein the antibody molecules are combined in a multispecific antibody.

### Claim 34 (depends on 33)

The combination of claim 33, wherein the antibody molecule that binds to IL-4Rα and the antibody molecule that binds to IL-5 are combined in a bispecific antibody.

### Claim 35

The combination of any one of the preceding claims, wherein the combination comprises one or more additional therapeutic agents.

### Claim 36

A bispecific antibody comprising an antigen binding region that binds to IL-4Rα and an antigen binding region that binds to IL-5.

### Claim 37 (depends on 36)

The bispecific antibody of claim 36, wherein the antigen binding region that binds to IL-4Rα comprises a first variable heavy chain domain (VH) and variable light chain domain (VL) pairing and the antigen binding region that binds to IL-5 comprises a second variable heavy chain domain (VH) and variable light chain domain (VL) pairing.

### Claim 38 (depends on 37)

The bispecific antibody of claim 37, wherein the antibody is an IgG antibody having a first VH-VL pairing that binds to IL-4Rα and a second VH-VL pairing that binds to IL-5.

### Claim 39 (depends on 36, 37)

The bispecific antibody of claim 36 or claim 37, wherein the antibody is an IgG antibody having at least one scFv fragment linked thereto.

### Claim 40 (depends on 39)

The bispecific antibody of claim 39, wherein the antigen binding region that binds to IL-4Rα is comprised within the IgG and the antigen binding region that binds to IL-5 is comprised within the at least one scFv fragment.

### Claim 41 (depends on 36, 37, 38, 39, 40)

The bispecific antibody of any one of claims 36-40, wherein the antigen binding region that binds to IL-4Rα comprises a first variable heavy chain domain (VH) and variable light chain domain (VL) pairing and the antigen binding region that binds to IL-5 comprises a second variable heavy chain domain (VH) and variable light chain domain (VL) pairing, wherein the first VH-VL domain pairing comprises the CDR sequences selected from:
(i) HCDR3 comprising or consisting of SEQ ID NO: 3; HCDR2 comprising or consisting of SEQ ID NO: 2; HCDR1 comprising or consisting of SEQ ID NO: 1; LCDR3 comprising or consisting of SEQ ID NO: 12; LCDR2 comprising or consisting of SEQ ID NO: 11; LCDR1 comprising or consisting of SEQ ID NO: 10;
(ii) HCDR3 comprising or consisting of SEQ ID NO: 6; HCDR2 comprising or consisting of SEQ ID NO: 5; HCDR1 comprising or consisting of SEQ ID NO: 4; LCDR3 comprising or consisting of SEQ ID NO: 15; LCDR2 comprising or consisting of SEQ ID NO: 14; LCDR1 comprising or consisting of SEQ ID NO: 13; and
(iii) HCDR3 comprising or consisting of SEQ ID NO: 9; HCDR2 comprising or consisting of SEQ ID NO: 8; HCDR1 comprising or consisting of SEQ ID NO: 7; LCDR3 comprising or consisting of SEQ ID NO: 18; LCDR2 comprising or consisting of SEQ ID NO: 17; LCDR1 comprising or consisting of SEQ ID NO: 16; and
wherein the second VH-VL domain pairing comprises the CDR sequences selected from:
(i) HCDR3 comprising or consisting of SEQ ID NO: 51; HCDR2 comprising or consisting of SEQ ID NO: 50; HCDR1 comprising or consisting of SEQ ID NO: 49; LCDR3 comprising or consisting of SEQ ID NO: 54; LCDR2 comprising or consisting of SEQ ID NO: 53; LCDR1 comprising or consisting of SEQ ID NO: 52;
(ii) HCDR3 comprising or consisting of SEQ ID NO: 51; HCDR2 comprising or consisting of SEQ ID NO: 50; HCDR1 comprising or consisting of SEQ ID NO: 49; LCDR3 comprising or consisting of SEQ ID NO: 57; LCDR2 comprising or consisting of SEQ ID NO: 56; LCDR1 comprising or consisting of SEQ ID NO: 55;
(ii) HCDR3 comprising or consisting of SEQ ID NO: 51; HCDR2 comprising or consisting of SEQ ID NO: 50; HCDR1 comprising or consisting of SEQ ID NO: 49: X; LCDR3 comprising or consisting of SEQ ID NO: 59; LCDR2 comprising or consisting of SEQ ID NO: 56; LCDR1 comprising or consisting of SEQ ID NO: 58;
(iv) HCDR3 comprising or consisting of SEQ ID NO: 51; HCDR2 comprising or consisting of SEQ ID NO: 50; HCDR1 comprising or consisting of SEQ ID NO: 49; LCDR3 comprising or consisting of SEQ ID NO: 61; LCDR2 comprising or consisting of SEQ ID NO: 60; LCDR1 comprising or consisting of SEQ ID NO: 58; and
(v) HCDR3 comprising or consisting of SEQ ID NO: 51; HCDR2 comprising or consisting of SEQ ID NO: 50; HCDR1 comprising or consisting of SEQ ID NO: 49; LCDR3 comprising or consisting of SEQ ID NO: 62; LCDR2 comprising or consisting of SEQ ID NO: 56; LCDR1 comprising or consisting of SEQ ID NO: 58.

### Claim 42 (depends on 36, 37, 38, 39, 40, 41)

The bispecific antibody of any one of claims 36-41, wherein the antigen binding region that binds to IL-4Rα and/or the second antigen binding region that binds to IL-5 is a humanized or germlined variant of a non-human antibody or an antigen-binding fragment thereof.

### Claim 43 (depends on 42)

The bispecific antibody of claim 42, wherein the non-human antibody is a camelid antibody or an antigen-binding fragment thereof.

### Claim 44 (depends on 36, 37, 38, 39, 40, 41, 42, 43)

The bispecific antibody of any one of claims 36-43 wherein the antigen binding region that binds to IL-4Rα and/or the antigen binding region that binds to IL-5 exhibits lower antigen-binding activity at acidic pH than at neutral pH.

### Claim 45 (depends on 44)

The bispecific antibody of claim 44, wherein the ratio of antigen-binding activity at acidic pH and at neutral pH is at least 2 as measured by KD (at acidic pH)/KD (at neutral pH).

### Claim 46 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45)

The combination of any one of claims 1-35 or the bispecific antibody of any one of claims 36-45 for use in the treatment of chronic airway disease in a human subject.

### Claim 47

An antagonist of IL-5:IL-5R for use in the treatment of chronic airway disease in a human subject, wherein the antagonist is administered in combination with an antagonist of IL-4:IL-4R and/or an antagonist of IL-13:IL-13R.

### Claim 48

An antagonist of IL-4:IL-4R and/or an antagonist of IL-13:IL-13R for use in the treatment of chronic airway disease in a human subject, wherein the antagonist is administered in combination with an antagonist of IL-5:IL-5R.

### Claim 49 (depends on 47, 48)

The antagonist for use according to claim 47 or claim 48, wherein the antagonist of IL5:IL-5R is an antibody molecule that binds to IL-5 and the antagonist of IL-4:IL-4R or IL-13:IL-13R is an antibody molecule that binds to IL-4Rα.

### Claim 50 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45)

A method for treating chronic airway disease in a human subject, said method comprising administering to the subject an effective amount of a combination as defined in any of claims 1-35 or a bispecific antibody as defined in any of claims 36-45.

### Claim 51 (depends on 50)

The method of claim 50, wherein the chronic airway disease is selected from: asthma; chronic rhinosinusitis (CRS); immunoglobulin G4-related disease (IgG4-RD); chronic obstructive pulmonary disease (COPD); chronic bronchitis; emphysema; chronic angioedema; diseases characterised by goblet cell metaplasia including Barrett's oesophagus; active eosinophilic esophagitis; nasal polyposis; chronic sinusitis; Churg Strauss Syndrome; allergic bronchopulmonary aspergillosis (ABPA); hypereosinophilic syndrome; bullous pemphigoid and cystic fibrosis.

### Claim 52 (depends on 50, 51)

The method of claim 50 or claim 51, wherein the chronic airway disease is characterised by increased mucus production.

### Claim 53 (depends on 50, 51, 52)

The method of any of claims 50-52, wherein the chronic airway disease is characterised by bronchial hyperresponsiveness.

### Claim 54 (depends on 50, 51, 52, 53)

The method of any of claims 50-53, wherein the chronic airway disease is asthma.

### Claim 55 (depends on 54)

The method of claim 54, wherein the method is for treating severe asthma, severe refractory asthma or type II asthma.

### Claim 56 (depends on 54)

The method of claim 54, wherein the method is for treating atopic or allergic asthma.

### Claim 57 (depends on 50, 51, 52, 53, 54, 55, 56)

The method of any one of claims 50-56, wherein goblet cell metaplasia (GCM) is decreased.

### Claim 58 (depends on 50, 51, 52, 53, 54, 55, 56, 57)

The method of any one of claims 50-57, wherein bronchial hyperresponsiveness (BHR) is decreased.

### Claim 59 (depends on 50, 51, 52, 53, 54, 55, 56, 57, 58)

The method of any one of claims 50-58, further comprising administering one or more additional therapeutic agents to treat the chronic airway disease.