# US 2019/0169286 A1 · Composition for prophylaxis or treatment of il-8 related diseases

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- Number: US 2019/0169286 A1
- Document ID: US20190169286A1
- Status: Published application
- Kind: A1
- Application number: 16/323,142
- Filed: 2017-08-04
- Published: 2019-06-06
- Earliest claimed: 2016-08-05
- Assignees: Chugai Seiyaku Kabushiki Kaisha; Jichi Medical University; National Institutes of Biomedical Innovation, Health and Nutrition
- Applicants: Chugai Seiyaku Kabushiki Kaisha; Jichi Medical University; National Institutes of Biomedical Innovation, Health and Nutrition
- Inventors: Ayako KAKIUCHI; Atsuhiko KATO; Shuji HAYASHI; Izumi YANAGISAWA; Ryo KONNO; Sachiho NETSU; Tadashi SANKAI
- Web page: https://patentgrep.com/patent/US20190169286A1

## CPC

- C07K 16/244: {Interleukins [IL]}
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 45/00: Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 17/06: Antipsoriatics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 16/24: against cytokines, lymphokines or interferons
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/90: characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

For example, therapeutic methods and the like for novel IL-8-related diseases using an IL-8 signal inhibitor are provided. Alternatively, for example, therapeutic methods and the like for known or novel IL-8-related diseases using a novel anti-IL-8 antibody are provided.

## Claims

### Claim 1

A composition for treating or preventing an IL-8-related disease, which comprises as an active ingredient an isolated anti-IL-8 antibody that binds to human IL-8, wherein the IL-8-related disease is selected from the group consisting of:
endometriosis; adenomyosis; dysmenorrhea; adhesion; fibrotic diseases; pain in endometriosis, adenomyosis, or dysmenorrhea; infertility; and pain resulting from adhesion, fibrosis, or inflammation;
wherein the anti-IL-8 antibody is selected from the group consisting of:
(1) an anti-IL-8 antibody which binds to IL-8 in a pH-dependent manner, and comprises at least one amino acid substitution in at least one of:
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28;
(2) an anti-IL-8 antibody which binds to IL-8 in a pH-dependent manner, and comprises at least one amino acid substitution in at least one of:
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28,
wherein the anti-IL-8 antibody at least comprises amino acid substitutions of:
tyrosine at position 3 in the amino acid sequence of SEQ ID NO: 25, asparagine at position 1 and leucine at position 5 in the amino acid sequence of SEQ ID NO: 27, and glutamine at position 1 in the amino acid sequence of SEQ ID NO: 28;
(3) an anti-IL-8 antibody which binds to IL-8 in a pH-dependent manner, and comprises at least one amino acid substitution in at least one of:
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28,
wherein the anti-IL-8 antibody at least comprises amino acid substitutions of:
tyrosine at position 9 and arginine at position 11 in the amino acid sequence of SEQ ID NO: 24, and tyrosine at position 3 in the amino acid sequence of SEQ ID NO: 25;
(4) an anti-IL-8 antibody which binds to IL-8 in a pH-dependent manner, and comprises at least one amino acid substitution in at least one of:
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28,
wherein the anti-IL-8 antibody at least comprises amino acid substitutions of:
alanine at position 6, glycine at position 8, tyrosine at position 9, and arginine at position 11 in the amino acid sequence of SEQ ID NO: 24, and
tyrosine at position 3 in the amino acid sequence of SEQ ID NO: 25;
(5) an anti-IL-8 antibody which binds to IL-8 in a pH-dependent manner, and comprises at least one amino acid substitution in at least one of:
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28,
wherein the anti-IL-8 antibody at least comprises amino acid substitutions of:
asparagine at position 1 and leucine at position 5 in the amino acid sequence of SEQ ID NO: 27, and glutamine at position 1 in the amino acid sequence of SEQ ID NO: 28;
(6) an anti-IL-8 antibody which binds to IL-8 in a pH-dependent manner, and comprises at least one amino acid substitution in at least one of:
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28,
wherein the anti-IL-8 antibody at least comprises amino acid substitutions of: tyrosine at position 9 and arginine at position 11 in the amino acid sequence of SEQ ID NO: 24, tyrosine at position 3 in the amino acid sequence of SEQ ID NO: 25, asparagine at position 1 and leucine at position 5 in the amino acid sequence of SEQ ID NO: 27, and glutamine at position 1 in the amino acid sequence of SEQ ID NO: 28; and
(7) an anti-IL-8 antibody which binds to IL-8 in a pH-dependent manner, and comprises at least one amino acid substitution in at least one of:
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23,
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24,
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25,
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26,
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28,
wherein the anti-IL-8 antibody at least comprises amino acid substitutions of:
alanine at position 6, glycine at position 8, tyrosine at position 9, and arginine at position 11 in the amino acid sequence of SEQ ID NO: 24, tyrosine at position 3 in the amino acid sequence of SEQ ID NO: 25, asparagine at position 1 and leucine at position 5 in the amino acid sequence of SEQ ID NO: 27, and glutamine at position 1 in the amino acid sequence of SEQ ID NO: 28.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the anti-IL-8 antibody is selected from the group consisting of:
(8) the anti-IL-8 antibody of any one of (1) to (7) of claim 1, which comprises:
(a) the amino acid sequence of SEQ ID NO: 23 as HVR-H1,
(b) the amino acid sequence of SEQ ID NO: 29 as HVR-H2, and
(c) the amino acid sequence of SEQ ID NO: 30 as HVR-H3;
(9) the anti-IL-8 antibody of any one of (1) to (7) of claim 1, which comprises:
(d) the amino acid sequence of SEQ ID NO: 26 as HVR-L1,
(e) the amino acid sequence of SEQ ID NO: 31 as HVR-L2, and
(f) the amino acid sequence of SEQ ID NO: 32 as HVR-L3;
(10) the anti-IL-8 antibody of any one of (1) to (7) of claim 1, which comprises:
(a) the amino acid sequence of SEQ ID NO: 23 as HVR-H1,
(b) the amino acid sequence of SEQ ID NO: 24 as HVR-H2, and
(c) the amino acid sequence of SEQ ID NO: 30 as HVR-H3;
(11) the anti-IL-8 antibody of any one of (1) to (7) of claim 1, which comprises:
(d) the amino acid sequence of SEQ ID NO: 26 as HVR-L1,
(e) the amino acid sequence of SEQ ID NO: 107 as HVR-L2, and
(f) the amino acid sequence of SEQ ID NO: 32 as HVR-L3;
(12) the anti-IL-8 antibody of any one of (1) to (7) of claim 1, which comprises:
(a) the amino acid sequence of SEQ ID NO: 23 as HVR-H1,
(b) the amino acid sequence of SEQ ID NO: 29 as HVR-H2,
(c) the amino acid sequence of SEQ ID NO: 30 as HVR-H3,
(d) the amino acid sequence of SEQ ID NO: 26 as HVR-L1,
(e) the amino acid sequence of SEQ ID NO: 31 as HVR-L2, and
(f) the amino acid sequence of SEQ ID NO: 32 as HVR-L3;
(13) the anti-IL-8 antibody of (1) or (2) of claim 1, which comprises:
(a) the amino acid sequence of SEQ ID NO: 23 as HVR-H1,
(b) the amino acid sequence of SEQ ID NO: 24 as HVR-H2,
(c) the amino acid sequence of SEQ ID NO: 30 as HVR-H3,
(d) the amino acid sequence of SEQ ID NO: 26 as HVR-L1,
(e) the amino acid sequence of SEQ ID NO: 107 as HVR-L2, and
(f) the amino acid sequence of SEQ ID NO: 32 as HVR-L3;
(14) the anti-IL-8 antibody of any one of (1) to (7) of claim 1, which comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 34 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 35;
(15) the anti-IL-8 antibody of (1) or (2) of claim 1, which comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 109;
(16) the anti-IL-8 antibody of any one of (1) to (7) of claim 1, which comprises HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 which have at least 80% sequence identity with (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 30, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 32, respectively;
(17) the anti-IL-8 antibody of any one of (1) to (7) of claim 1, which comprises HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 which have at least 80% sequence identity with (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 30, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 32, respectively;
(18) the anti-IL-8 antibody of any one of (1) to (7) of claim 1, which comprises a heavy chain variable region and a light chain variable region which have at least 80% sequence identity with a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 34 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 35, respectively; and
(19) the anti-IL-8 antibody of any one of (1) to (7) of claim 1, which comprises a heavy chain variable region and a light chain variable region which have at least 80% sequence identity with a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 109, respectively.

### Claim 3

A composition for treating or preventing an IL-8-related disease, which comprises as an active ingredient an isolated anti-IL-8 antibody that binds to human IL-8, wherein the IL-8-related disease is selected from the group consisting of:
endometriosis; adenomyosis; dysmenorrhea; adhesion; fibrotic diseases; pain in endometriosis, adenomyosis, or dysmenorrhea; infertility; and pain resulting from adhesion, fibrosis, or inflammation, and
wherein the anti-IL-8 antibody is selected from the group consisting of:
(I) an anti-IL-8 antibody which comprises an Fc region comprising amino acid substitution at one or more positions selected from the group consisting of positions 235, 236, 239, 327, 330, 331, 428, 434, 436, 438, and 440 according to EU numbering;
(II) an anti-IL-8 antibody which comprises an Fc region comprising amino acid substitution at all positions selected from the group consisting of positions 434, 438, and 440 according to EU numbering;
(III) an anti-IL-8 antibody which comprises an Fc region comprising all of amino acid substitution with Ala at position 434; amino acid substitution with Glu, Arg, Ser, or Lys at position 438; and amino acid substitution with Glu, Asp, or Gln at position 440, according to EU numbering;
(IV) an anti-IL-8 antibody which comprises an Fc region comprising all of amino acid substitution with Ala at position 434; amino acid substitution with Glu, Arg, Ser, or Lys at position 438; and amino acid substitution with Glu, Asp, or Gln at position 440, and further comprising Ile or Leu at position 428, and/or Ile, Leu, Val, Thr, or Phe at position 436, according to EU numbering;
(V) an anti-IL-8 antibody which comprises an Fc region comprising one or more amino acid substitutions selected from the group consisting of L235R, G236R, S239K, A327G, A330S, P331S, M428L, N434A, Y436T, Q438R, and S440E according to EU numbering;
(VI) an anti-IL-8 antibody which comprises an Fc region comprising a combination of amino acid substitutions selected from the group consisting of:
N434A/Q438R/S440E;
N434A/Q438R/S440D;
N434A/Q438K/S440E;
N434A/Q438K/S440D;
N434A/Y436T/Q438R/S440E;
N434A/Y436T/Q438R/S440D;
N434A/Y436T/Q438K/S440E;
N434A/Y436T/Q438K/S440D;
N434A/Y436V/Q438R/S440E;
N434A/Y436V/Q438R/S440D;
N434A/Y436V/Q438K/S440E;
N434A/Y436V/Q438K/S440D;
N434A/R435H/F436T/Q438R/S440E; N434A/R435H/F436T/Q438R/S440D;
N434A/R435H/F436T/Q438K/S440E; N434A/R435H/F436T/Q438K/S440D;
N434A/R435H/F436V/Q438R/S440E; N434A/R435H/F436V/Q438R/S440D;
N434A/R435H/F436V/Q438K/S440E; N434A/R435H/F436V/Q438K/S440D;
M428L/N434A/Q438R/S440E;
M428L/N434A/Q438R/S440D;
M428L/N434A/Q438K/S440E;
M428L/N434A/Q438K/S440D;
M428L/N434A/Y436T/Q438R/S440E; M428L/N434A/Y436T/Q438R/S440D;
M428L/N434A/Y436T/Q438K/S440E; M428L/N434A/Y436T/Q438K/S440D;
M428L/N434A/Y436V/Q438R/S440E; M428L/N434A/Y436V/Q438R/S440D;
M428L/N434A/Y436V/Q438K/S440E; and
M428L/N434A/Y436V/Q438K/S440D
according to EU numbering;
(VII) an anti-IL-8 antibody which comprises an Fc region comprising a combination of amino acid substitutions:
L235R/G236R/S239K/M428L/N434A/Y436T/Q438R/S440E; or
L235R/G236R/A327G/A330S/P331S/M428L/N434A/Y436T/Q438R/S440E,
according to EU numbering; and
(VIII) an anti-IL-8 antibody comprising the Fc region of any one of (I) to (VII) above, wherein the Fc region has at least one property selected from the group consisting of (a) to (e) below:
(a) the FcRn-binding affinity of the Fc region at an acidic pH has been increased relative to the FcRn-binding affinity of a native Fc region;
(b) the binding affinity of the Fc region for a pre-existing ADA has been reduced relative to the binding affinity of a native Fc region for the pre-existing ADA;
(c) the plasma half-life of the Fc region has been increased relative to the plasma half-life of a native Fc region;
(d) the plasma clearance of the Fc region has been reduced relative to the plasma clearance of a native Fc region; and
(e) the binding affinity of the Fc region for an effector receptor has been reduced relative to the binding affinity of a native Fc region for the effector receptor.

### Claim 4

A composition for treating of preventing an IL-8-related disease, which comprises as an active ingredient an isolated anti-IL-8 antibody that binds to human IL-8, wherein the IL-8-related disease is selected from the group consisting of:
endometriosis; adenomyosis; dysmenorrhea; adhesion; fibrotic diseases; pain in endometriosis, adenomyosis, or dysmenorrhea; infertility; and pain resulting from adhesion, fibrosis, or inflammation, and
wherein the anti-IL-8 antibody is selected from the group consisting of:
(A) an anti-IL-8 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 38;
(B) an anti-IL-8 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 38;
(C) an anti-IL-8 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 106 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;
(D) an anti-IL-8 antibody comprising heavy and light chains which have at least 80% sequence identity with a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 38, respectively;
(E) an anti-IL-8 antibody comprising heavy and light chains which have at least 80% sequence identity to a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 38, respectively; and
(F) an anti-IL-8 antibody comprising heavy and light chains which have at least 80% sequence identity with a heavy chain comprising the amino acid sequence of SEQ ID NO: 106 and a light chain comprising the amino acid sequence of SEQ ID NO: 44, respectively.

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

The composition of any one of claims 1 to 4, wherein the fibrotic disease is selected from the group consisting of fibrosis in endometriosis or adenomyosis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, psoriasis, hepatic fibrosis, renal fibrosis, and pulmonary fibrosis.

### Claim 6

A composition for treating or preventing an IL-8-related disease, which comprises an IL-8 signal inhibitor as an active ingredient, wherein the IL-8-related disease is selected from the group consisting of human endometriosis; adenomyosis; dysmenorrhea; adhesion; pain in human endometriosis, adenomyosis, or dysmenorrhea; infertility; and pain resulting from adhesion, fibrosis, or inflammation.

### Claim 7 (depends on 6)

The composition of claim 6 for suppressing infiltration of immune cells to a lesion or surrounding environment thereof in an IL-8-related disease.

### Claim 8 (depends on 6, 7)

The composition of claim 6 or 7 for inhibiting the production of aromatase or a fibrotic factor.

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

The composition of any one of claims 6 to 8, which does not affect the sexual cycle.

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

The composition of any one of claims 6 to 9 for suppressing adhesion or fibrosis in endometriosis or adenomyosis.

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

The composition of any one of claims 6 to 10 for (1) atrophying endometrial epithelial cells or stromal cells in an endometriosis or adenomyosis patient, or (2) reducing endometrial interstitium in endometriosis.

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

The composition of any one of claims 6 to 11, wherein dysmenorrhea is dysmenorrhea with endometriosis or adenomyosis, or is dysmenorrhea suspected of endometriosis or adenomyosis.

### Claim 13 (depends on 6)

The composition of claim 6 wherein adhesion is formed after surgery.

### Claim 14 (depends on 6, 7, 8, 9, 10, 11, 12, 13)

The composition of any one of claims 6 to 13, wherein the IL-8 signal inhibitor is an IL-8 inhibitor, a CXCR1 inhibitor, or a CXCR2 inhibitor.

### Claim 15 (depends on 14)

The composition of claim 14 wherein the IL-8 inhibitor, the CXCR1 inhibitor, or the CXCR2 inhibitor is an anti-IL-8 antibody, an anti-CXCR1 antibody, or an anti-CXCR2 antibody, respectively.