JPWO2020215019A5

JPWO2020215019A5 -

Info

Publication number: JPWO2020215019A5
Application number: JP2021561599A
Authority: JP
Publication date: 2023-04-25

Description

一実施形態では、α４β７阻害薬、例えば、抗α４β７抗体（例えば、ベドリズマブ）、またはその抗原結合部分は、処置のために、ＩＬ－２３阻害薬（例えば、抗ｐ４０、抗ｐ１９抗体、抗ＩＬ－２３Ｒ抗体、またはその抗原結合部分）の前に投与される。他の実施形態では、抗α４β７抗体（例えば、ベドリズマブ）、またはその抗原結合部分は、ＩＬ－２３阻害薬（例えば、抗ｐ４０、抗ｐ１９抗体、もしくは抗ＩＬ－２３Ｒ抗体、またはその抗原結合部位）の後に投与される。さらに他の実施形態では、抗α４β７抗体（例えば、ベドリズマブ）、またはその抗原結合部分は、ＩＬ－２３阻害薬（例えば、抗ｐ４０、抗ｐ１９抗体、もしくは抗ＩＬ－２３Ｒ抗体、またはその抗原結合部位）と同時に投与される。
In one embodiment, the α4β7 inhibitor, eg, an anti-α4β7 antibody (eg, vedolizumab), or antigen-binding portion thereof, is used for treatment with an IL-23 inhibitor (eg, anti-p40, anti-p19 antibody, anti-IL-23 23R antibody, or antigen-binding portion thereof). In other embodiments, the anti-α4β7 antibody (eg, vedolizumab), or antigen binding portion thereof, is an IL-23 inhibitor (eg, an anti-p40, anti-p19 antibody, or anti-IL-23R antibody, or antigen binding portion thereof) administered after In still other embodiments, the anti-α4β7 antibody (eg, vedolizumab), or antigen-binding portion thereof, is an IL-23 inhibitor (eg, an anti-p40, anti-p19 antibody, or anti-IL-23R antibody, or antigen-binding portion thereof). ) at the same time .

The present invention includes the following embodiments.
[1]
A method of treating a human patient in need thereof, said method comprising administering to said human patient an α4β7 inhibitor and an IL-23 inhibitor.
[2]
The method of [1] above, wherein the α4β7 inhibitor is an anti-α4β7 antibody.
[3]
The method of [2] above, wherein the anti-α4β7 antibody is humanized.
[4]
The anti-α4β7 antibody comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO:4, a CDR2 domain as set forth in SEQ ID NO:3, and a CDR1 domain as set forth in SEQ ID NO:2; a CDR3 domain as set forth in SEQ ID NO:8. , the light chain variable region comprising the CDR2 domain set forth in SEQ ID NO:7 and the CDR1 domain set forth in SEQ ID NO:6.
[5]
A method of treating a human patient in need of treatment, said method comprising administering to said human patient an anti-α4β7 antibody and an IL-23 inhibitor,
The anti-α4β7 antibody is an IgG1 antibody; comprises a heavy chain variable region comprising the CDR3 domain set forth in SEQ ID NO:4, the CDR2 domain set forth in SEQ ID NO:3, and the CDR1 domain set forth in SEQ ID NO:2; SEQ ID NO:8 a light chain variable region comprising a CDR3 domain as set forth in SEQ ID NO:7, a CDR2 domain as set forth in SEQ ID NO:7, and a CDR1 domain as set forth in SEQ ID NO:6.
[6]
The method of [1] or [5] above, wherein the human patient has an autoimmune disease.
[7]
The method of [6] above, wherein the autoimmune disease is arthritis or psoriasis.
[8]
The method of [6] above, wherein the autoimmune disease is rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, or axial spondyloarthritis.
[9]
The method of [1] or [5] above, wherein the human patient has inflammatory bowel disease (IBD).
[10]
The method of [1] or [5] above, wherein the human patient has an autoimmune disease and inflammatory bowel disease.
[11]
The method of [9] or [10] above, wherein the IBD is ulcerative colitis or Crohn's disease.
[12]
The method according to [11] above, wherein the ulcerative colitis is moderate to severe active ulcerative colitis.
[13]
The method according to [11] above, wherein the Crohn's disease is moderate to severe active Crohn's disease.
[14]
The method of any one of [1] to [13] above, wherein the anti-α4β7 antibody is administered prior to the IL-23 inhibitor.
[15]
The method according to any one of [1] to [13] above, wherein the anti-α4β7 antibody is administered after the IL-23 inhibitor.
[16]
The method according to any one of [1] to [13] above, wherein the anti-α4β7 antibody is administered simultaneously with the IL-23 inhibitor.
[17]
Any of [2] to [16] above, wherein the anti-α4β7 antibody 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: 5. The method described in Crab.
[18]
The method according to any one of [2] to [17] above, wherein the anti-α4β7 antibody is a humanized antibody.
[19]
The method according to any one of [2] to [18] above, wherein the anti-α4β7 antibody is vedolizumab.
[20]
The human patient receives a first dose of 300 mg of the anti-α4β7 antibody at week 0, followed by a second dose of 300 mg of the anti-α4β7 antibody at week 2, followed by a third dose of 300 mg of the anti-α4β7 antibody at week 6. The method according to any one of [2] to [19] above, wherein administration is administered.
[21]
The method of [20] above, further comprising administering 300 mg of the anti-α4β7 antibody to the human patient every 8 weeks starting 8 weeks after the third administration.
[22]
The method of [21] above, further comprising administering 300 mg of the anti-α4β7 antibody to the human patient every 4 weeks if the human patient has not shown clinical improvement.
[23]
The method of [22] above, wherein said human patient has ulcerative colitis or Crohn's disease and said clinical improvement is clinical remission.
[24]
The method of [20] above, further comprising administering 300 mg of the anti-α4β7 antibody to the human patient every 4 weeks from 8 weeks after the third administration.
[25]
The method of any one of [20] to [24] above, wherein the anti-α4β7 antibody is administered intravenously.
[26]
The method of [20] above, further comprising administering 108 mg of the anti-α4β7 antibody to the human patient every two weeks starting eight weeks after the third administration.
[27]
The human patient receives a first dose of 300 mg of the anti-α4β7 antibody at week 0, followed by a second dose of 300 mg of the anti-α4β7 antibody at week 2, followed by a third dose of 108 mg of the anti-α4β7 antibody at week 6. The method of any of [2]-[19] above, wherein administration is followed by a dose of 108 mg every two weeks thereafter.
[28]
The method of [26] or [27] above, wherein the 108 mg dose is administered subcutaneously.
[29]
The method of [28] above, wherein the 108 mg dose is self-administered.
[30]
The method according to any one of [1] to [29] above, wherein the IL-23 inhibitor is an antibody that binds to the p19 subunit of IL-23.
[31]
The method according to any one of [1] to [29] above, wherein the IL-23 inhibitor is an antibody that binds to the p40 subunit of IL-23.
[32]
The method according to any one of [1] to [29] above, wherein the IL-23 inhibitor is risankizumab, ustekinumab, guselkumab, or tildrakizumab.
[33]
The method according to any one of [1] to [27] above, wherein the IL-23 inhibitor is an antibody that binds to IL-23R.
[34]
Any of the above [1] to [33], wherein said patient is characterized as a non-responder or non-remissioner at 6 and/or 10 weeks after initiation of treatment with an α4β7 inhibitor. described method.
[35]
Any of the above [1] to [33], wherein the patient is characterized by elevated levels of serum IL-22 at or 6 weeks after the initiation of treatment with an α4β7 inhibitor. The method described in Crab.
[36]
The method of [34] or [35] above, wherein the α4β7 inhibitor is an anti-α4β7 antibody.
[37]
The method of [36] above, wherein the anti-α4β7 antibody is vedolizumab.
[38]
IL-22 levels in the serum of said human patient increased from the time of initiation to 10 weeks after initiation of treatment with said anti-α4β7 antibody, from the initiation of treatment with said anti-α4β7 antibody to 6 weeks after initiation of treatment with said anti-α4β7 antibody, or The method of [5] above, wherein there is no reduction, a less than 2-fold reduction, or a less than 3-fold reduction from 6 to 10 weeks after initiation of treatment with an α4β7 antibody. .
[39]
The patient is characterized by elevated levels of serum IL-22 at or 6 weeks after the initiation of treatment with the anti-α4β7 antibody, wherein the serum IL-22 level is No decrease, less than 2-fold decrease, or less than 3-fold decrease from start to week 10, start to week 6, or week 6 to week 10, above The method according to [5].
[40]
The method of [1] or [5] above, wherein said patient is characterized as having elevated levels of IL-22 and/or STAT5A compared to control levels.
[41]
The method of [40] above, wherein said control level is the level of one or more of a subject not suffering from IBD, a healthy subject, non-inflamed colon tissue from said patient, or non-colon tissue.
[42]
The method of [40] or [41] above, wherein said patient's IL-22 and/or STAT5A levels are measured prior to or on the first day of treatment with said anti-α4β7 antibody.
[43]
said patient's IL-22 and/or STAT5A levels are measured 1, 2, 3, 4, 5, 6, 7, 8, 9, and/or 10 days prior to treatment with said anti-α4β7 antibody. The method of [42].
[44]
The method of any of [35]-[42] above, wherein the patient's IL-22 and/or STAT5A nucleic acid and/or protein levels are measured.
[45]
said IL-22 and/or STAT5A levels are 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% compared to control levels , 90%, 100%, or more.
[46]
A method of treating inflammatory bowel disease in a patient in need thereof, comprising administering to said patient an anti-α4β7 antibody and an antibody that binds to the p19 subunit of IL-23, said The anti-α4β7 antibody is administered to the human patient for an initial dose of 300 mg of the anti-α4β7 antibody at week 0, followed by a second dose of 300 mg of the anti-α4β7 antibody at week 2, and a dose of 300 mg of the anti-α4β7 antibody at week 6. a third dose, followed by a dose of 300 mg of said anti-α4β7 antibody every 8 weeks starting 8 weeks after said third dose;
The anti-α4β7 antibody comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO:4, a CDR2 domain as set forth in SEQ ID NO:3, and a CDR1 domain as set forth in SEQ ID NO:2; a CDR3 domain as set forth in SEQ ID NO:8. , a light chain variable region comprising the CDR2 domain set forth in SEQ ID NO:7 and the CDR1 domain set forth in SEQ ID NO:6;
The above method, wherein the patient is characterized as having elevated levels of IL-22 and/or STAT5A compared to control levels.
[47]
A method of treating inflammatory bowel disease in a patient in need thereof, comprising administering to said patient an anti-α4β7 antibody and an antibody that binds to the p40 subunit of IL-23, said The anti-α4β7 antibody is administered to the human patient for an initial dose of 300 mg of the anti-α4β7 antibody at week 0, followed by a second dose of 300 mg of the anti-α4β7 antibody at week 2, and a dose of 300 mg of the anti-α4β7 antibody at week 6. a third dose, followed by a dose of 300 mg of said anti-α4β7 antibody every 8 weeks starting 8 weeks after said third dose;
The anti-α4β7 antibody comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO:4, a CDR2 domain as set forth in SEQ ID NO:3, and a CDR1 domain as set forth in SEQ ID NO:2; a CDR3 domain as set forth in SEQ ID NO:8. , a light chain variable region comprising the CDR2 domain set forth in SEQ ID NO:7 and the CDR1 domain set forth in SEQ ID NO:6;
The above method, wherein the patient is characterized as having elevated levels of IL-22 and/or STAT5A compared to control levels.
[48]
A method of treating inflammatory bowel disease in a patient in need thereof, comprising administering to said patient an anti-α4β7 antibody and an antibody that binds to the p19 subunit of IL-23, said Anti-α4β7 antibodies were administered with the first dose of 300 mg of said anti-α4β7 antibody at week 0, followed by the second dose of 300 mg of said anti-α4β7 antibody at week 2, followed by the third dose of 108 mg of said anti-α4β7 antibody at week 6. administration, followed by a dose of 108 mg every 2 weeks thereafter,
The anti-α4β7 antibody comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO:4, a CDR2 domain as set forth in SEQ ID NO:3, and a CDR1 domain as set forth in SEQ ID NO:2; a CDR3 domain as set forth in SEQ ID NO:8. , a light chain variable region comprising the CDR2 domain set forth in SEQ ID NO:7 and the CDR1 domain set forth in SEQ ID NO:6;
The above method, wherein the patient is characterized as having elevated levels of IL-22 and/or STAT5A compared to control levels.
[49]
A method of treating inflammatory bowel disease in a patient in need thereof, comprising administering to said patient an anti-α4β7 antibody and an antibody that binds to the p40 subunit of IL-23, said Anti-α4β7 antibodies were administered with the first dose of 300 mg of said anti-α4β7 antibody at week 0, followed by the second dose of 300 mg of said anti-α4β7 antibody at week 2, followed by the third dose of 108 mg of said anti-α4β7 antibody at week 6. administration, followed by a dose of 108 mg every 2 weeks thereafter,
The anti-α4β7 antibody comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO:4, a CDR2 domain as set forth in SEQ ID NO:3, and a CDR1 domain as set forth in SEQ ID NO:2; a CDR3 domain as set forth in SEQ ID NO:8. , a light chain variable region comprising the CDR2 domain set forth in SEQ ID NO:7 and the CDR1 domain set forth in SEQ ID NO:6;
The above method, wherein the patient is characterized as having elevated levels of IL-22 and/or STAT5A compared to control levels.
[50]
Any of the above [46]-[49], wherein said control level is the level of one or more of a subject not suffering from IBD, a healthy subject, non-inflamed colon tissue from said patient, or non-colon tissue The method described in Crab.

Claims

A composition for treating an autoimmune disease or inflammatory bowel disease in a human patient comprising a humanized anti-α4β7 antibody, comprising:
The composition is administered in combination with an IL-23 inhibitor,
Said humanized anti-α4β7 antibody comprises a heavy chain variable region comprising the CDR3 domain as set forth in SEQ ID NO:4, the CDR2 domain as set forth in SEQ ID NO:3, and the CDR1 domain as set forth in SEQ ID NO:2; The above composition comprising a light chain variable region comprising a CDR3 domain, a CDR2 domain as set forth in SEQ ID NO:7, and a CDR1 domain as set forth in SEQ ID NO:6.

2. The composition of claim 1 , wherein said autoimmune disease is arthritis or psoriasis.

2. The composition of claim 1 , wherein the autoimmune disease is rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, or axial spondyloarthritis.

2. The composition of claim 1, wherein said inflammatory bowel disease (IBD) is ulcerative colitis or Crohn's disease .

2. The composition of claim 1, wherein said humanized anti -α4β7 antibody is administered before , after, or concurrently with said IL-23 inhibitor .

6. Any of claims 1-5, wherein the humanized anti -α4β7 antibody 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:5. A composition according to claim 1.

The composition of any one of claims 1-5 , wherein the humanized anti -α4β7 antibody is vedolizumab.

The human patient receives a first dose of 300 mg of the humanized anti -α4β7 antibody at week 0, followed by a second dose of 300 mg of the humanized anti -α4β7 antibody at week 2, followed by a dose of the humanized anti-α4β7 antibody at week 6. 2. The composition of claim 1 , wherein a third dose of 300 mg of the α4β7 antibody is administered.

9. The composition of Claim 8 , wherein said human patient is further administered 300 mg of said humanized anti -α4β7 antibody every eight weeks starting eight weeks after said third administration.

10. The composition of claim 9 , further wherein 300 mg of said humanized anti -α4β7 antibody is administered to said human patient every 4 weeks if said human patient has not shown clinical improvement.

11. The composition of claim 10 , wherein said human patient has ulcerative colitis or Crohn's disease and said clinical improvement is clinical remission.

9. The composition of claim 8 , wherein said human patient is further administered 300 mg of said humanized anti -α4β7 antibody every 4 weeks beginning 8 weeks after said third administration.

The composition of any one of claims 8-12 , wherein the humanized anti -α4β7 antibody is administered intravenously.

9. The composition of claim 8 , wherein said human patient is further administered 108 mg of said anti-α4β7 antibody every two weeks beginning eight weeks after said third administration.

The human patient receives a first dose of 300 mg of the humanized anti -α4β7 antibody at week 0, followed by a second dose of 300 mg of the humanized anti -α4β7 antibody at week 2, followed by a dose of the humanized anti-α4β7 antibody at week 6. Patients receiving a third dose of 108 mg of an α4β7 antibody followed by a dose of 108 mg every two weeks thereafter, wherein the 108 mg dose is administered subcutaneously, and the 108 mg dose is self-administered. 2. The composition of claim 1 , which is

Clause 1, wherein said IL-23 inhibitor is selected from the group consisting of an antibody that binds to the p19 subunit of IL-23, an antibody that binds to the p40 subunit of IL-23 and an antibody that binds to IL-23R. 6. The composition according to any one of 1 to 5 .

6. The composition of any one of claims 1-5 , wherein the IL-23 inhibitor is risankizumab, ustekinumab, guselkumab, or tildrakizumab.

Said patient is characterized as a non-responder or non-responder at 6 and/or 10 weeks after initiation of treatment with a humanized anti -α4β7 antibody , or said patient is characterized by said humanized anti-α4β7 antibody A composition according to any one of claims 1 to 5 , characterized by an elevated level of IL-22 in the serum at the start of treatment with the antibody or 6 weeks after the start.

IL-22 levels in the serum of said human patient from the time of initiation to 10 weeks after initiation of treatment with said humanized anti -α4β7 antibody, from the time of initiation to 6 weeks after initiation of treatment with said humanized anti -α4β7 antibody or no reduction, less than 2-fold reduction, or less than 3-fold reduction from 6 to 10 weeks after initiation of treatment comprising said humanized anti -α4β7 antibody , or ,
The patient is characterized by elevated levels of serum IL-22 at or 6 weeks after the initiation of treatment with the anti-α4β7 antibody, wherein the serum IL-22 level is no decrease, less than 2-fold decrease, or less than 3-fold decrease from start to week 10, start to week 6, or week 6 to week 10;
A composition according to any one of claims 1-5 .

2. The composition of claim 1 , wherein said patient is characterized as having elevated levels of IL-22 and/or STAT5A compared to control levels.

21. The composition of claim 20 , wherein said control level is the level of one or more of a subject not suffering from IBD, a healthy subject, non-inflamed colon tissue from said patient, or non-colon tissue.

22. The composition of claim 20 or 21 , wherein said patient's IL-22 and/or STAT5A levels are measured prior to or on the first day of treatment with said anti-α4β7 antibody.

said patient's IL-22 and/or STAT5A levels are measured 1, 2, 3, 4, 5, 6, 7, 8, 9, and/or 10 days prior to treatment with said humanized anti -α4β7 antibody 23. The composition of claim 22 .

19. The composition of claim 18 , wherein said patient's IL-22 nucleic acid and/or protein levels and /or STAT5A nucleic acid and/ or protein levels are measured.

said IL-22 and/or STAT5A levels are 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% compared to control levels , 90%, 100 %, or more .

A composition for treating inflammatory bowel disease in a patient comprising a humanized anti-α4β7 antibody, said composition being administered to said patient in combination with an antibody that binds to the p19 subunit of IL-23,
The humanized anti -α4β7 antibody is administered according to the following dosing regimen:
an initial dose of 300 mg of the humanized anti -α4β7 antibody at week 0 , followed by a second dose of 300 mg of the humanized anti -α4β7 antibody at week 2, and a third dose of 300 mg of the humanized anti -α4β7 antibody at week 6; subsequently administered to said patient according to a dosing regimen in which a dose of 300 mg of said humanized anti -α4β7 antibody is administered every 8 weeks starting 8 weeks after said third administration;
said humanized anti -α4β7 antibody comprising a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO:4, a CDR2 domain as set forth in SEQ ID NO:3, and a CDR1 domain as set forth in SEQ ID NO:2; a light chain variable region comprising a CDR3 domain, a CDR2 domain set forth in SEQ ID NO:7, and a CDR1 domain set forth in SEQ ID NO:6;
Said composition , wherein said patient is characterized as having elevated levels of IL-22 and/or STAT5A compared to control levels.

A composition for treating inflammatory bowel disease in a patient comprising a humanized anti-α4β7 antibody, said composition being administered to said patient in combination with an antibody that binds to the p40 subunit of IL-23,
The humanized anti -α4β7 antibody is administered according to the following dosing regimen:
an initial dose of 300 mg of the humanized anti -α4β7 antibody at week 0 , followed by a second dose of 300 mg of the humanized anti -α4β7 antibody at week 2, and a third dose of 300 mg of the humanized anti -α4β7 antibody at week 6; subsequently administered to said patient according to a dosing regimen in which a dose of 300 mg of said humanized anti -α4β7 antibody is administered every 8 weeks starting 8 weeks after said third administration;
said humanized anti -α4β7 antibody comprising a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO:4, a CDR2 domain as set forth in SEQ ID NO:3, and a CDR1 domain as set forth in SEQ ID NO:2; a light chain variable region comprising a CDR3 domain, a CDR2 domain set forth in SEQ ID NO:7, and a CDR1 domain set forth in SEQ ID NO:6;
Said composition , wherein said patient is characterized as having elevated levels of IL-22 and/or STAT5A compared to control levels.

A composition for treating inflammatory bowel disease in a patient comprising a humanized anti-α4β7 antibody, said composition being administered to said patient in combination with an antibody that binds to the p19 subunit of IL-23,
The humanized anti -α4β7 antibody is administered according to the following dosing regimen:
An initial dose of 300 mg of the humanized anti -α4β7 antibody at week 0, followed by a second dose of 300 mg of the humanized anti -α4β7 antibody at week 2, followed by 3 doses of 108 mg of the humanized anti -α4β7 antibody at week 6. administered to said patient according to a dosing regimen in which a dose of 108 mg is administered at the first dose followed by every 2 weeks thereafter;
said humanized anti -α4β7 antibody comprising a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO:4, a CDR2 domain as set forth in SEQ ID NO:3, and a CDR1 domain as set forth in SEQ ID NO:2; a light chain variable region comprising a CDR3 domain, a CDR2 domain set forth in SEQ ID NO:7, and a CDR1 domain set forth in SEQ ID NO:6;
Said composition , wherein said patient is characterized as having elevated levels of IL-22 and/or STAT5A compared to control levels.

A composition for treating inflammatory bowel disease in a patient comprising a humanized anti-α4β7 antibody, said composition being administered to said patient in combination with an antibody that binds to the p40 subunit of IL-23, The humanized anti -α4β7 antibody is administered according to the following dosing regimen:
An initial dose of 300 mg of the humanized anti -α4β7 antibody at week 0, followed by a second dose of 300 mg of the humanized anti -α4β7 antibody at week 2, followed by 3 doses of 108 mg of the humanized anti -α4β7 antibody at week 6. administered to said patient according to a dosing regimen in which a dose of 108 mg is administered at the first dose followed by every 2 weeks thereafter;
said humanized anti -α4β7 antibody comprising a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO:4, a CDR2 domain as set forth in SEQ ID NO:3, and a CDR1 domain as set forth in SEQ ID NO:2; a light chain variable region comprising a CDR3 domain, a CDR2 domain set forth in SEQ ID NO:7, and a CDR1 domain set forth in SEQ ID NO:6;
Said composition , wherein said patient is characterized as having elevated levels of IL-22 and/or STAT5A compared to control levels.

30. Any one of claims 26-29 , wherein said control level is the level of one or more of a subject not suffering from IBD, a healthy subject, non-inflamed colon tissue from said patient, or non-colon tissue. The composition according to .