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1. WO2020113270 - MÉTHODE DE TRAITEMENT D'AFFECTIONS NEUTROPHILES

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CLAIMS:

1. A method for reducing circulating neutrophils in a human subject without causing sustained grade 3 or grade 4 neutropenia for greater than seven consecutive days, the method comprising administering to the subject a dose of between O.lmg/kg and l.Omg/kg of an antibody that inhibits G-CSF signaling.

2. The method of claim 1, wherein the subject suffers from a neutrophil-mediated condition.

3. A method for treating a neutrophil-mediated condition, the method comprising administering to a subject suffering from the neutrophil-mediated condition a dose of between O.lmg/kg and l.Omg/kg of an antibody that inhibits G-CSF signaling.

4. The method of claim 3, wherein administration of the antibody does not cause sustained grade 3 or grade 4 neutropenia in the subject for greater than seven consecutive days.

5. The method of claim 1 or 4, wherein administration of the antibody does not induce grade 4 neutropenia.

6. The method of claim 1 or 4, wherein administration of the antibody does not induce neutropenia or the antibody induces grade 2 or grade 3 neutropenia for two consecutive days or less.

7. The method of claim 1 or 4, wherein administration of the antibody does not induce neutropenia for more than 2 consecutive days or more than 1 day.

8. The method of claim 1 or 4, wherein the neutropenia is not associated with a fever.

9. The method of any one of claims 1 to 8, wherein the antibody is administered at a dose of between O.lmg/kg and 0.6mg/kg.

10. The method of any one of claims 1 to 9, wherein the antibody is administered at a dose of O.lmg/kg or 0.3mg/kg or 0.6mg/kg.

11. The method of any one of claims 1 to 10, wherein the antibody is administered multiple times, wherein the antibody is administered once every 14 to 28 days.

12. The method of any one of claims 1 to 11, wherein the antibody is administered multiple times, wherein the antibody is administered once every 21 days.

13. The method of any one of claims 1 to 12, wherein the antibody binds to G-CSFR and inhibits G-CSF signalling.

14. The method of any one of claims 1 to 13, wherein the antibody binds to or specifically binds to granulocyte -colony stimulating factor receptor (G-CSFR) and competitively inhibits the binding of antibody C1.2G comprising a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 4 and a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 5 to G-CSFR.

15. The method of any one of claims 1 to 14, wherein the antibody binds to an epitope comprising residues within one or two or three or four regions selected from 111-115, 170-176, 218-234 and/or 286-300 of SEQ ID NO: 1.

16. The method of any one of claims 1 to 15, wherein the antibody comprises:

(i) a heavy chain variable region (VH) comprising an amino acid sequence set forth in SEQ ID NO: 4 and a light chain variable region (VL) comprising an amino acid sequence set forth in SEQ ID NO: 5;

(ii) a VH comprising an amino acid sequence set forth in SEQ ID NO: 2 and a VL comprising an amino acid sequence set forth in SEQ ID NO: 3;

(iii) a VH comprising three CDRs of a VH comprising an amino acid sequence set forth in SEQ ID NO: 4 and a VL comprising three CDRs of a VL comprising an amino acid sequence set forth in SEQ ID NO: 5; or

(iv) a VH comprising three CDRs of a VH comprising an amino acid sequence set forth in SEQ ID NO: 2 and a VL comprising three CDRs of a VL comprising an amino acid sequence set forth in SEQ ID NO: 3.

17. The method of any one of claims 1 to 16, wherein the antibody comprises:

(i) a heavy chain comprising a sequence set forth in SEQ ID NO: 14 and a light chain comprising a sequence set forth in SEQ ID NO: 15; or

(ii) a heavy chain comprising a sequence set forth in SEQ ID NO: 16 and a light chain comprising a sequence set forth in SEQ ID NO: 15.

18. The method of any one of claims 2 to 17, wherein the neutrophil-mediated condition is an autoimmune disease, an inflammatory disease, cancer or ischemia-reperfusion injury.

19. The method of claim 18, wherein the autoimmune disease or the inflammatory disease is arthritis, uveitis, multiple sclerosis, pulmonary inflammation, chronic obstructive pulmonary disease, psoriasis, or severe asthma.

20. The method of any one of claims 2 to 18, wherein the neutrophil-mediated condition is a neutrophilic dermatosis or a neutrophilic skin lesion.

21. The method of claim 20, wherein the neutrophilic dermatosis is selected from the group consisting of amicrobial pustulosis of the folds (APF); plaque psoriasis; CARD14-mediated pustular psoriasis (CAMPS); cryopyrin associated periodic syndromes (CAPS); deficiency of interleukin- 1 receptor (DIRA); deficiency of interleukin-36 receptor antagonist(DIRTA); hidradenitis suppurativa (HS); palmoplantar pustulosis; pyogenic arthritis; pyoderma gangrenosum and acne (PAPA); pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH); pyoderma gangrenosum(PG); skin lesions of Behcet’s disease; Still’s disease; Sweet syndrome; subcorneal pustulosis (Sneddon-Wilkinson); pustular psoriasis; palmoplantar pustulosis; acute generalized exanthematic pustulosis; infantile acropustulosis; synovitis, acne, pustulosis; hyperostosis and osteitis (SAPHO) syndrome; bowel-associated dermatosis-arthritis syndrome (BAD AS); neutrophilic dermatosis of the dorsal hands; neutrophilic eccrine hidradenitis; erythema elevatum diutinum; and Pyoderma gangrenosum.

22. The method of claim 20, wherein the neutrophilic dermatosis is hidradenitis suppurativa (HS) or palmoplantar pustulosis (PPP).

23. A method for treating a neutrophilic dermatosis, the method comprising administering to a subject suffering from a neutrophilic dermatosis a dose of between 0.1 mg/kg and 1 mg/kg of an antibody that binds to or specifically binds to granulocyte-colony stimulating factor receptor (G-CSFR), wherein the antibody is administered multiple times once every 21 days and wherein the antibody comprises:

(i) a heavy chain comprising a sequence set forth in SEQ ID NO: 14 and a light chain comprising a sequence set forth in SEQ ID NO: 15; or

(ii) a heavy chain comprising a sequence set forth in SEQ ID NO: 16 and a light chain comprising a sequence set forth in SEQ ID NO: 15.