Pharmaceutical compositions and administration regimens for the clinical use of anti-blood dendritic cell antigen 2 antibodies

Abstract

To provide a formulation and administration regimen of an anti-blood dendritic cell antigen 2 (BDCA2) antibody. [Solution] The formulations and administration regimens of the present invention are used in the treatment of BDCA2-related disorders such as systemic lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, and cytokine release syndrome. In one embodiment, the present invention provides a method for treating a human subject in need of a method for treating a condition selected from the group consisting of systemic lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, Sjögren's syndrome, cutaneous polymyositis, scleroderma, and cytokine release syndrome. The method comprises subcutaneous administration of an anti-BDCA2 antibody or its BDCA2-conjugated fragment to a human subject at a dose of 50 mg every four weeks.

Claims

1. The use of a pharmaceutical composition comprising an anti-blood dendritic cell antigen 2 (BDCA2) antibody or a BDCA2-binding fragment in the manufacture of a pharmaceutical for the treatment of systemic lupus erythematosus or cutaneous lupus erythematosus in human subjects, The anti-BDCA2 antibody or its BDCA2-binding fragment comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL are, (a) VH-CDR1 consists of the amino acid sequence described in SEQ ID NO: 1 or 17, VH-CDR2 consists of the amino acid sequence described in Sequence ID No.

2. VH-CDR3 consists of the amino acid sequence described in Sequence ID No.

3. VH complementarity determination region (CDR), and, (b) VL-CDR1 consists of the amino acid sequence described in Sequence ID No. 4, VL-CDR2 consists of the amino acid sequence described in Sequence ID No.

5. VL-CDR3 consists of the amino acid sequence described in Sequence ID No.

6. VL CDR Including; The pharmaceutical composition has a pH of 5.0 to 6.0; and The anti-BDCA2 antibody or its BDCA2-binding fragment is (i) administered subcutaneously to the human subjects at a dose of 50 mg every four weeks, wherein, optionally, a loading dose of the anti-BDCA2 antibody or BDCA2-binding fragment is administered to the human subjects two weeks after the initial dose of the anti-BDCA2 antibody or BDCA2-binding fragment, and optionally, the loading dose is 50 mg; or (ii) administered subcutaneously to the human subjects at a dose of 150 mg every four weeks, wherein, optionally, a loading dose of the anti-BDCA2 antibody or BDCA2-binding fragment is administered to the human subjects two weeks after the initial dose of the anti-BDCA2 antibody or BDCA2-binding fragment, and optionally, the loading dose is 150 mg; or (iii) The human subjects are subcutaneously administered a dose of 450 mg every four weeks, and optionally, a loading dose of the anti-BDCA2 antibody or BDCA2-binding fragment is administered to the human subjects two weeks after the initial administration of the anti-BDCA2 antibody or BDCA2-binding fragment, and optionally, the loading dose is 450 mg. use.

2. The pharmaceutical composition is (i) Below: (a) 50mg / ml to 225mg / ml; (b) 75mg / ml to 225mg / ml; (c) 125 mg / ml to 175 mg / ml; or (d) 150mg / ml The anti-BDCA2 antibody or its BDCA2-binding fragment in the concentration of; and / or (ii) Below: (a) 0.05% to 10%; (b) 1% to 5%; or (c) 3% Sucrose at a concentration of; and / or (iii) Below: (a) 50mM to 250mM; (b) 75 mM to 125 mM; or (c) 100 mM Arg. of HCl concentration The use according to claim 1, including the use described in claim 1.

3. The pharmaceutical composition is (i) Polysorbate 80 (PS80) at any concentration of 0.01% to 0.1%, 0.03% to 0.08%, or 0.05%; (ii) Histidine in concentrations of 5 mM to 50 mM, 15 mM to 25 mM, or 20 mM, at any choice; and / or (iii) Thiol-containing antioxidants at concentrations of 0.02 mM to 2 mM, The use according to claim 1 or 2, including the use described in claim 1 or 2.

4. The use according to claim 1, wherein the pharmaceutical composition has a pH of 5.3 to 6.0, 5.3 to 5.7, 5.5, 5.7, or 6.

0.

5. The pharmaceutical composition is The anti-BDCA2 antibody at a concentration of 150 mg / ml; 3% sucrose concentration; Histidine at a concentration of 20 mM; Thiol-containing antioxidant at a concentration of 0.4 mM; Arg. HCl at a concentration of 100 mM; and 0.05% concentration of PS80 The use according to claim 1, wherein the pharmaceutical composition comprises and has a pH of 5.

7.

6. The use according to claim 1, wherein the pharmaceutical composition is for the administration of at least four, seven, or ten doses of the anti-BDCA2 antibody or its BDCA2-binding fragment.

7. The use according to claim 1, wherein the anti-BDCA2 antibody or its BDCA2-conjugated fragment is for subcutaneous administration to the human subject at a dose of 50 mg every four weeks.

8. The use according to claim 1, wherein the anti-BDCA2 antibody or its BDCA2-conjugated fragment is for subcutaneous administration to the human subject at a dose of 150 mg every four weeks.

9. The use according to claim 1, wherein the anti-BDCA2 antibody or its BDCA2-conjugated fragment is for subcutaneous administration to the human subject at a dose of 450 mg every four weeks.

10. The use according to claim 9, wherein the pharmaceutical composition is for administering a loading dose of 450 mg of the anti-BDCA2 antibody or its BDCA2-binding fragment two weeks after the initial administration of the anti-BDCA2 antibody or its BDCA2-binding fragment.

11. The use according to claim 8, wherein the pharmaceutical composition is for administering a loading dose of 150 mg of the anti-BDCA2 antibody or its BDCA2-conjugated fragment two weeks after the initial administration of the anti-BDCA2 antibody or its BDCA2-conjugated fragment.

12. The use according to any one of claims 1 to 11, wherein VH has a sequence that is at least 80% identical to sequence number 7, and VL has a sequence that is at least 80% identical to sequence number 8.

13. The use according to any one of claims 1 to 11, wherein VH has a sequence that is at least 90% identical to sequence number 7, and VL has a sequence that is at least 90% identical to sequence number 8.

14. The use according to any one of claims 1 to 11, wherein VH consists of the amino acid sequence described in SEQ ID NO: 7, and VL consists of the amino acid sequence described in SEQ ID NO:

8.

15. The use according to any one of claims 1 to 11, wherein the anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, the immunoglobulin heavy chain having a sequence that is at least 80% identical to SEQ ID NO: 9, and the immunoglobulin light chain having a sequence that is at least 80% identical to SEQ ID NO:

10.

16. The use according to any one of claims 1 to 11, wherein the anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, the immunoglobulin heavy chain having a sequence that is at least 90% identical to SEQ ID NO: 9, and the immunoglobulin light chain having a sequence that is at least 90% identical to SEQ ID NO:

10.

17. The use according to any one of claims 1 to 11, wherein the anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, the immunoglobulin heavy chain consists of the amino acid sequence described in SEQ ID NO: 9, and the immunoglobulin light chain consists of the amino acid sequence described in SEQ ID NO:

10.

18. The use according to any one of claims 1 to 17, wherein the pharmaceutical composition is administered as a sterile preparation using a syringe, injection device, or pump, and the sterile preparation is adapted for subcutaneous administration of the anti-BDCA2 antibody or its BDCA2-conjugated fragment in fixed doses of 18 mg, 22 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, 150 mg, or 450 mg.

19. The use according to claim 18, wherein the pharmaceutical composition is administered as a sterile preparation using a syringe, injection device, or pump, and the sterile preparation is adapted for subcutaneous administration of the anti-BDCA2 antibody or its BDCA2-conjugated fragment at a fixed dose of 450 mg.

20. The use according to claim 18, wherein the pharmaceutical composition is administered as a sterile preparation using a syringe, injection device, or pump, and the sterile preparation is adapted for subcutaneous administration of the anti-BDCA2 antibody or its BDCA2-conjugated fragment at a fixed dose of 150 mg.

21. A pharmaceutical composition for treating systemic lupus erythematosus or cutaneous lupus erythematosus in a human subject, comprising an anti-blood dendritic cell antigen 2 (BDCA2) antibody or a BDCA2-conjugated fragment thereof, The anti-BDCA2 antibody or its BDCA2-binding fragment comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL are, (a) VH-CDR1 consists of the amino acid sequence described in SEQ ID NO: 1 or 17, VH-CDR2 consists of the amino acid sequence described in Sequence ID No.

2. VH-CDR3 consists of the amino acid sequence described in Sequence ID No.

3. VH complementarity determination region (CDR), and, (b) VL-CDR1 consists of the amino acid sequence described in Sequence ID No. 4, VL-CDR2 consists of the amino acid sequence described in Sequence ID No.

5. VL-CDR3 consists of the amino acid sequence described in Sequence ID No.

6. VL CDR Including; The pharmaceutical composition has a pH of 5.0 to 6.0; and The anti-BDCA2 antibody or its BDCA2-binding fragment is (i) administered subcutaneously to the human subjects at a dose of 50 mg every four weeks, wherein, optionally, a loading dose of the anti-BDCA2 antibody or BDCA2-binding fragment is administered to the human subjects two weeks after the initial dose of the anti-BDCA2 antibody or BDCA2-binding fragment, and optionally, the loading dose is 50 mg; or (ii) administered subcutaneously to the human subjects at a dose of 150 mg every four weeks, wherein, optionally, a loading dose of the anti-BDCA2 antibody or BDCA2-binding fragment is administered to the human subjects two weeks after the initial dose of the anti-BDCA2 antibody or BDCA2-binding fragment, and optionally, the loading dose is 150 mg; or (iii) The human subjects are subcutaneously administered a dose of 450 mg every four weeks, and optionally, a loading dose of the anti-BDCA2 antibody or BDCA2-binding fragment is administered to the human subjects two weeks after the initial administration of the anti-BDCA2 antibody or BDCA2-binding fragment, and optionally, the loading dose is 450 mg. Pharmaceutical composition.

22. The pharmaceutical composition is (i) Below: (a) 50mg / ml to 225mg / ml; (b) 75mg / ml to 225mg / ml; (c) 125 mg / ml to 175 mg / ml; or (d) 150mg / ml The anti-BDCA2 antibody or its BDCA2-binding fragment in the concentration of; and / or (ii) Below: (a) 0.05% to 10%; (b) 1% to 5%; or (c) 3% Sucrose at a concentration of; and / or (iii) Below: (a) 50mM to 250mM; (b) 75 mM to 125 mM; or (c) 100 mM Arg. of HCl concentration A pharmaceutical composition according to claim 21, comprising:

23. The pharmaceutical composition is (i) Polysorbate 80 (PS80) at any concentration of 0.01% to 0.1%, 0.03% to 0.08%, or 0.05%; (ii) Histidine in concentrations of 5 mM to 50 mM, 15 mM to 25 mM, or 20 mM, at any choice; and / or (iii) Thiol-containing antioxidants at concentrations of 0.02 mM to 2 mM, A pharmaceutical composition according to claim 21 or 22, comprising:

24. The pharmaceutical composition according to claim 21, wherein the pharmaceutical composition has a pH of 5.3 to 6.0, 5.3 to 5.7, 5.5, 5.7, or 6.

0.

25. The pharmaceutical composition is The anti-BDCA2 antibody at a concentration of 150 mg / ml; 3% sucrose concentration; Histidine at a concentration of 20 mM; Thiol-containing antioxidant at a concentration of 0.4 mM; Arg. HCl at a concentration of 100 mM; and 0.05% concentration of PS80 The pharmaceutical composition according to claim 21, comprising, wherein the pharmaceutical composition has a pH of 5.

7.

26. The pharmaceutical composition according to claim 21, wherein the pharmaceutical composition is for the administration of at least four, seven, or ten doses of the anti-BDCA2 antibody or its BDCA2-binding fragment.

27. ​​The pharmaceutical composition according to claim 21, wherein the anti-BDCA2 antibody or its BDCA2-conjugated fragment is for subcutaneous administration to a human subject at a dose of 50 mg every four weeks.

28. The pharmaceutical composition according to claim 21, wherein the anti-BDCA2 antibody or its BDCA2-conjugated fragment is for subcutaneous administration to a human subject at a dose of 150 mg every four weeks.

29. The pharmaceutical composition according to claim 21, wherein the anti-BDCA2 antibody or its BDCA2-conjugated fragment is for subcutaneous administration to a human subject at a dose of 450 mg every four weeks.

30. The pharmaceutical composition according to claim 29, wherein the pharmaceutical composition is for administering a loading dose of 450 mg of the anti-BDCA2 antibody or BDCA2-conjugated fragment two weeks after the initial administration of the anti-BDCA2 antibody or BDCA2-conjugated fragment.

31. The pharmaceutical composition according to claim 28, wherein the pharmaceutical composition is for administering a loading dose of 150 mg of the anti-BDCA2 antibody or BDCA2-conjugated fragment two weeks after the initial administration of the anti-BDCA2 antibody or BDCA2-conjugated fragment.

32. The pharmaceutical composition according to any one of claims 21 to 31, wherein VH has a sequence that is at least 80% identical to sequence number 7, and VL has a sequence that is at least 80% identical to sequence number 8.

33. The pharmaceutical composition according to any one of claims 21 to 31, wherein VH has a sequence that is at least 90% identical to sequence number 7, and VL has a sequence that is at least 90% identical to sequence number 8.

34. The pharmaceutical composition according to any one of claims 21 to 31, wherein VH consists of the amino acid sequence described in SEQ ID NO: 7, and VL consists of the amino acid sequence described in SEQ ID NO:

8.

35. The pharmaceutical composition according to any one of claims 21 to 31, wherein the anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, the immunoglobulin heavy chain having a sequence that is at least 80% identical to SEQ ID NO: 9, and the immunoglobulin light chain having a sequence that is at least 80% identical to SEQ ID NO:

10.

36. The pharmaceutical composition according to any one of claims 21 to 31, wherein the anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, the immunoglobulin heavy chain having a sequence that is at least 90% identical to SEQ ID NO: 9, and the immunoglobulin light chain having a sequence that is at least 90% identical to SEQ ID NO:

10.

37. The pharmaceutical composition according to any one of claims 21 to 31, wherein the anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, the immunoglobulin heavy chain consists of the amino acid sequence described in SEQ ID NO: 9, and the immunoglobulin light chain consists of the amino acid sequence described in SEQ ID NO:

10.

38. The use according to any one of claims 21 to 37, wherein the pharmaceutical composition is administered as a sterile preparation using a syringe, injection device, or pump, and the sterile preparation is adapted for subcutaneous administration of the anti-BDCA2 antibody or its BDCA2-conjugated fragment in fixed doses of 18 mg, 22 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, 150 mg, or 450 mg.

39. The pharmaceutical composition according to claim 38, wherein the pharmaceutical composition is administered as a sterile preparation using a syringe, injection device, or pump, and the sterile preparation is adapted for subcutaneous administration of the anti-BDCA2 antibody or its BDCA2-conjugated fragment at a fixed dose of 450 mg.

40. The pharmaceutical composition according to claim 38, wherein the pharmaceutical composition is administered as a sterile preparation using a syringe, injection device, or pump, and the sterile preparation is adapted for subcutaneous administration of the anti-BDCA2 antibody or its BDCA2-conjugated fragment at a fixed dose of 150 mg.

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