Pharmaceutical composition containing anti-IL-4R antibody and use thereof

1 . A pharmaceutical composition, comprising an anti-IL-4R antibody or an antigen-binding fragment thereof, a buffer, a surfactant, and a viscosity modifier, wherein:

the buffer is a histidine-acetic acid buffer, and the buffer has a pH of 4.5 to 6.0, the histidine-acetic acid buffer has a concentration of 10 mM to 60 mM; the surfactant has a concentration of 0.1 mg/mL to 1.2 mg/mL, the viscosity modifier is selected from the group consisting of MgCl 2 , histidine and arginine hydrochloride, and the viscosity modifier has a concentration of 5 mM to 220 mM;

the anti-IL-4R antibody or the antigen-binding fragment thereof has a concentration of 100 mg/mL to 200 mg/mL, and the anti-IL-4R antibody or the antigen-binding fragment thereof comprises:

(i) a heavy chain variable region comprising an HCDR1, an HCDR2 and an HCDR3 set forth in SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, respectively; and

a light chain variable region comprising an LCDR1, an LCDR2 and an LCDR3 set forth in SEQ ID NO: 38, SEQ ID NO: 7 and SEQ ID NO: 40, respectively;

(ii) a heavy chain variable region comprising an HCDR1, an HCDR2 and an HCDR3 set forth in SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, respectively; and

a light chain variable region comprising an LCDR1, an LCDR2 and an LCDR3 set forth in SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, respectively;

(iii) a heavy chain variable region comprising an HCDR1, an HCDR2 and an HCDR3 set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, respectively; and

a light chain variable region comprising an LCDR1, an LCDR2 and an LCDR3 set forth in SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, respectively; or

(iv) a heavy chain variable region comprising an HCDR1, an HCDR2 and an HCDR3 set forth in SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, respectively; and

a light chain variable region comprising an LCDR1, an LCDR2 and an LCDR3 set forth in SEQ ID NO: 42, SEQ ID NO: 39 and SEQ ID NO: 8, respectively.

2 . The pharmaceutical composition according to claim 1 , wherein the histidine-acetic acid buffer has a concentration of 10 mM to 30 mM.

3 . The pharmaceutical composition according to claim 1 , wherein the anti-IL-4R antibody or the antigen-binding fragment thereof has a concentration of 100 mg/ml to 180 mg/mL.

4 . The pharmaceutical composition according to claim 1 , wherein the viscosity modifier has a concentration of 5 mM to 220 mM, or 5 mM to 148 mM.

5 . The pharmaceutical composition according to claim 4 , wherein the anti-IL-4R antibody or the antigen-binding fragment thereof has a concentration of 120 mg/ml to 150 mg/mL; and the viscosity modifier is selected from the group consisting of 50 mM to 90 mM MgCl 2 , 50 mM to 100 mM histidine, and 10 mM to 200 mM.

6 . The pharmaceutical composition according to claim 1 , wherein the surfactant is polysorbate.

7 . The pharmaceutical composition according to claim 6 , wherein the surfactant has a concentration 0.4 mg/mL to 1.0 mg/mL.

8 . The pharmaceutical composition according to claim 1 , further comprising a stabilizer, the stabilizer has a concentration of 20 mg/mL to 70 mg/mL, or 40 mg/ml to 60 mg/mL.

9 . The pharmaceutical composition according to claim 1 , comprising:

(a) 100 mg/mL to 150 mg/mL anti-IL-4R antibody or antigen-binding fragment thereof; (b) 10 mM to 30 mM histidine-acetic acid buffer, pH 4.5-5.5; (c) 80 mM to 148 mM viscosity modifier; and (d) 0.4 mg/mL to 1.2 mg/mL polysorbate 80;

or,

(a) 100 mg/mL to 120 mg/mL anti-IL-4R antibody or antigen-binding fragment thereof; (b) 10 mM to 20 mM histidine-acetic acid buffer, pH 4.5-5.5; (c) 5 mM to 50 mM histidine; (d) 0.4 mg/mL to 1.0 mg/mL polysorbate 80; and (e) 50 mg/mL to 60 mg/mL sucrose;

or,

(a) 100 mg/mL to 140 mg/mL anti-IL-4R antibody or antigen-binding fragment thereof; (b) 10 mM to 30 mM histidine-acetic acid buffer, pH 4.5-5.5; (c) 10 mM to 40 mM viscosity modifier; (d) 0.4 mg/mL to 1.2 mg/mL polysorbate 80; and (e) 40 mg/mL to 70 mg/mL sucrose;

or,

(a) 100 mg/mL to 200 mg/mL anti-IL-4R antibody or antigen-binding fragment thereof; (b) 10 mM to 30 mM histidine-acetic acid buffer, pH 4.5-5.5; (c) 40 mM to 220 mM viscosity modifier; and (d) 0.4 mg/mL to 1.2 mg/mL polysorbate 80; or,

(a) 100 mg/mL to 140 mg/mL anti-IL-4R antibody or antigen-binding fragment thereof; (b) 10 mM to 30 mM histidine-acetic acid buffer, pH 4.5-5.5; (c) 10 mM to 40 mM viscosity modifier; (d) 0.4 mg/mL to 1.2 mg/mL polysorbate 80; and (e) 40 mg/mL to 70 mg/mL sucrose, wherein the viscosity modifier is histidine, arginine hydrochloride or MgCl 2 ;

or,

(a) 100 mg/mL to 180 mg/mL anti-IL-4R antibody or antigen-binding fragment thereof; (b) 10 mM to 30 mM histidine-acetic acid buffer, pH 4.5-5.5; (c) 40 mM to 90 mM MgCl 2 ; and (d) 0.4 mg/ml to 1.2 mg/mL polysorbate 80;

or,

(a) 100 mg/mL to 180 mg/mL anti-IL-4R antibody or antigen-binding fragment thereof; (b) 10 mM to 30 mM histidine-acetic acid buffer, pH 4.5-5.5; (c) 50 mM to 100 mM histidine; and (d) 0.4 mg/mL to 1.2 mg/mL polysorbate 80;

or,

(a) 100 mg/mL to 180 mg/mL anti-IL-4R antibody or antigen-binding fragment thereof; (b) 10 mM to 30 mM histidine-acetic acid buffer, pH 4.5-5.5; (c) 50 mM to 200 mM arginine hydrochloride; and (d) 0.4 mg/mL to 1.2 mg/mL polysorbate 80;

or,

(a) 100 mg/mL to 120 mg/mL anti-IL-4R antibody or antigen-binding fragment thereof; (b) 20 mM to 60 mM histidine-acetic acid buffer, pH 4.5-5.5; (c) 0.4 mg/mL to 1.2 mg/mL polysorbate 80; and (d) 40 mg/mL to 70 mg/mL sucrose;

or,

(a) 120 mg/mL anti-IL-4R antibody or antigen-binding fragment thereof; (b) 50 mM histidine-acetic acid buffer, pH 5.0; (c) 0.8 mg/mL polysorbate 80; and (d) 58 mg/mL sucrose;

or,

(a) about 150 mg/mL anti-IL-4R antibody or antigen-binding fragment thereof; (b) about 20 mM histidine-acetic acid buffer, pH about 5.0; (c) about 0.8 mg/mL polysorbate 80; and (d) about 120 mM arginine hydrochloride.

10 . The pharmaceutical composition according to claim 1 , wherein the anti-IL-4R antibody or the antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region shown as any one of the following:

(v) the heavy chain variable region has a sequence set forth in SEQ ID NO: 1 or having at least 90% identity to SEQ ID NO: 1, and the light chain variable region has a sequence set forth in SEQ ID NO: 2 or having at least 90% identity to SEQ ID NO: 2;

(vi) the heavy chain variable region has a sequence set forth in SEQ ID NO: 9 or having at least 90% identity to SEQ ID NO: 9, and the light chain variable region has a sequence set forth in SEQ ID NO: 10 or having at least 90% identity to SEQ ID NO: 10;

(vii) the heavy chain variable region has a sequence set forth in SEQ ID NO: 25, 26, 27, 43 or 47 or having at least 90% identity to SEQ ID NO: 25, 26, 27, 43 or 47, and the light chain variable region has a sequence set forth in SEQ ID NO: 28, 29, 30, 37 or 41 or having at least 90% identity to SEQ ID NO: 28, 29, 30, 37 or 41; or

(viii) the heavy chain variable region has a sequence set forth in SEQ ID NO: 31, 32 or 33 or having at least 90% identity to SEQ ID NO: 31, 32 or 33, and the light chain variable region has a sequence set forth in SEQ ID NO: 34, 35 or 36 or having at least 90% identity to SEQ ID NO: 34, 35 or 36.

11 . The pharmaceutical composition according to claim 10 , wherein the anti-IL-4R antibody or the antigen-binding fragment thereof comprises a heavy chain and a light chain shown below:

a heavy chain set forth in SEQ ID NO: 17 and a light chain set forth in SEQ ID NO: 18; or

a heavy chain set forth in SEQ ID NO: 19 and a light chain set forth in SEQ ID NO: 20; or

a heavy chain set forth in SEQ ID NO: 44 and a light chain set forth in SEQ ID NO: 45; or

a heavy chain set forth in SEQ ID NO: 44 and a light chain set forth in SEQ ID NO: 46; or

a heavy chain set forth in SEQ ID NO: 48 and a light chain set forth in SEQ ID NO: 46.

12 . A method for preparing the pharmaceutical composition according to claim 11 , comprising a step of buffer-exchanging a stock solution of the anti-IL-4R antibody or the antigen-binding fragment thereof.

13 . A lyophilized formulation comprising an anti-IL-4R antibody or an antigen-binding fragment thereof, wherein the lyophilized formulation is obtained by lyophilizing the pharmaceutical composition according to claim 1 .

14 . A reconstituted solution comprising an anti-IL-4R antibody or an antigen-binding fragment thereof, wherein the reconstituted solution is obtained by reconstituting the lyophilized formulation according to claim 13 .

15 . An article of manufacture, comprising a container containing the pharmaceutical composition according to claim 1 .

16 . A method for treating an immune disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 1 , wherein the immune disease or disorder is an IL-4R-mediated disease or disorder.

17 . The pharmaceutical composition according to claim 4 , wherein the viscosity modifier is:

i) 5 mM to 220 mM arginine hydrochloride;

ii) 5 mM to 100 mM histidine; or

iii) 5 mM to 90 mM MgCl 2 .

18 . The pharmaceutical composition according to claim 5 , wherein the viscosity modifier is 50 mM to 180 mM arginine hydrochloride.

19 . The pharmaceutical composition according to claim 6 , wherein the surfactant is polysorbate 80 or polysorbate 20.

20 . The pharmaceutical composition according to claim 8 , wherein the stabilizer is trehalose or sucrose.

21 . The pharmaceutical composition according to claim 10 , wherein the anti-IL-4R antibody or the antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region shown as any one of the following:

(ix) the heavy chain variable region has a sequence set forth in SEQ ID NO: 43 or having at least 90% identity to SEQ ID NO: 43, and the light chain variable region has a sequence set forth in SEQ ID NO: 37 or having at least 90% identity to SEQ ID NO: 37;

(x) the heavy chain variable region has a sequence set forth in SEQ ID NO: 43 or having at least 90% identity to SEQ ID NO: 43, and the light chain variable region has a sequence set forth in SEQ ID NO: 41 or having at least 90% identity to SEQ ID NO: 41; or

(xi) the heavy chain variable region has a sequence set forth in SEQ ID NO: 47 or having at least 90% identity to SEQ ID NO: 47, and the light chain variable region has a sequence set forth in SEQ ID NO: 41 or having at least 90% identity to SEQ ID NO: 41.

22 . The method according to claim 16 , wherein the immune disease or disorder is selected from the group consisting of: asthma, nasal polyps, chronic sinusitis, allergic skin disorder, eosinophilic esophagitis, chronic obstructive pulmonary disease, allergic rhinitis, arthritis, inflammatory diseases, allergic reaction, autoimmune lymphoproliferative syndrome, autoimmune hemolytic anemia, Barrett's esophagus, autoimmune uveitis, tuberculosis, and renal disease.