JP2014511844A5

JP2014511844A5 -

Info

Publication number: JP2014511844A5
Application number: JP2014501659A
Authority: JP
Filing date: 2012-03-30
Publication date: 2015-04-23
Anticipated expiration: 2032-03-30

Claims

A pharmaceutical formulation comprising a polypeptide comprising two anti-tumor necrosis factor alpha (TNFα) SDAB and one anti-human serum albumin (HSA) SDAB , wherein multiple 30-400 mg doses of the polypeptide are administered to a human it makes wherein administration, Ru interval der least about every 4 weeks, for use in the treatment of a human in need of treatment for immune disorders, pharmaceutical formulation.

Each anti-TNFα SDAB contains three complementarity determining regions (CDR1, CDR2, and CDR3), where
(A) CDR1 is
(I) the amino acid sequence DYWMY (SEQ ID NO: 22);
(Ii) an amino acid sequence having at least 80% sequence identity with DYWMY (SEQ ID NO: 22); or (iii) an amino acid sequence having only one amino acid difference from DYWMY (SEQ ID NO: 22);
(B) CDR2 is
(I) amino acid sequence EINTNGLITKYPSVKG (SEQ ID NO: 23);
(Ii) an amino acid sequence having at least 80%, 90%, or 95% sequence identity with EINTNGLITKYPDSVKG (SEQ ID NO: 23); or And (c) CDR3 is
(I) the amino acid sequence SPSGFN (SEQ ID NO: 24);
2. (ii) an amino acid sequence having at least 80% sequence identity with SPSGFN (SEQ ID NO: 24); or (iii) an amino acid sequence having one amino acid difference from SPSGFN (SEQ ID NO: 24). Pharmaceutical formulation .

CDR1 comprises the amino acid sequence DYWMY (SEQ ID NO: 22), CDR2 has an amino acid sequence EINTNGLITKYPDSVKG (SEQ ID NO: 23), CDR3 comprises the amino acid sequence SPSGFN (SEQ ID NO: 24), wherein according to claim 1 or 2, wherein Formulation .

4. At least one of the anti-TNFα SDABs comprises an amino acid sequence having at least 80%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 2 (TNF30). Pharmaceutical formulation .

The pharmaceutical of any one of claims 1 to 4, wherein each anti-TNFα SDAB comprises an amino acid sequence having at least 80%, 90%, 95%, or 95% sequence identity with SEQ ID NO: 2 (TNF30). Formulation .

Anti-HSA SDAB contains three CDRs (CDR1, CDR2, and CDR3), where
(A) CDR1 is
(I) amino acid sequence SFGMS (SEQ ID NO: 25);
(Ii) an amino acid sequence having at least 80% sequence identity with SFGMS (SEQ ID NO: 25); or (iii) an amino acid sequence having only one amino acid difference from SFGMS (SEQ ID NO: 25);
(B) CDR2 is
(I) the amino acid sequence SISSGSSDTLLYADSVKG (SEQ ID NO: 26);
(Ii) an amino acid sequence having at least 80%, 90%, or 95% sequence identity with SISSGSGSDLYADSVKG (SEQ ID NO: 26); or (iii) an amino acid having 2 or 1 amino acid difference from SISGSGSDTLYADSVKG (SEQ ID NO: 26) Including a sequence;
(C) CDR3 is
(I) the amino acid sequence GGSLSR (SEQ ID NO: 27);
6. (ii) an amino acid sequence having at least 80% sequence identity with GGSLSR (SEQ ID NO: 27); or (iii) an amino acid sequence having one amino acid difference from GGSLSR (SEQ ID NO: 27). The pharmaceutical formulation of any one of these.

The pharmaceutical preparation according to claim 6, wherein CDR1 comprises the amino acid sequence SFGMS (SEQ ID NO: 25), CDR2 comprises the amino acid sequence SISSGSSDLYLYSVSVKG (SEQ ID NO: 26), and CDR3 comprises the amino acid sequence GGSLSR (SEQ ID NO: 27). .

8. The pharmaceutical formulation of claim 6 or 7, wherein the anti-HSA SDAB comprises an amino acid sequence having at least 80%, 90%, 95%, or 95% sequence identity with SEQ ID NO: 5 (ALB8).

The pharmaceutical preparation according to any one of claims 1 to 8, which comprises the amino acid sequence represented by SEQ ID NO: 1 (ozoralizumab).

10. The pharmaceutical formulation according to any one of claims 1 to 9, wherein at least one SDAB is humanized.

The two anti-TNF SDABs and one anti-HSA SDAB are linked via a linker, and each linker is selected from the group consisting of the amino acid sequences shown in SEQ ID NO: 6 and SEQ ID NO: 7. The pharmaceutical formulation of any one of 1-10.

12. The pharmaceutical formulation according to any one of claims 1 to 11, wherein the administration is at a time interval of at least about 1 month.

13. The pharmaceutical formulation according to any one of claims 1 to 12, wherein the administration is at a time interval of at least about 6 weeks.

14. The pharmaceutical formulation according to any one of claims 1 to 13, wherein the administration is at a time interval of at least about 8 weeks.

The dose is selected from the group consisting of about 10, 30, 80, 100, 120, 140, 160, 180, 200, 250, 275, 300, 320, 350, 375 and 400 mg of SDAB molecule. 14. The pharmaceutical preparation according to any one of 14.

The pharmaceutical preparation according to any one of claims 1 to 15, which is administered subcutaneously or intravenously.

The pharmaceutical formulation according to any one of claims 1 to 16, wherein the human is co-treated with methotrexate.

The pharmaceutical preparation according to claim 1, which is formulated into a pharmaceutically acceptable preparation .

The formulation is
(A) the polypeptide according to claim 1 having a concentration of about 10 mg / ml to 250 mg / ml;
(B) a cryoprotectant selected from sucrose, sorbitol, or trehalose at a concentration of about 5% to about 10%;
(C) a surfactant selected from polysorbate 80 or poloxamer 188 at a concentration of about 0.01% to 0.6%; and (d) the pH of the formulation is about 5.0 to 7.5, 19. The pharmaceutical formulation of claim 18, comprising a buffer selected from a histidine buffer at a concentration of about 10-20 mM or a Tris buffer at a concentration of about 20 mM.

20. The pharmaceutical composition of claim 19, wherein the formulation comprises 100 mg / ml of the polypeptide of claim 1, 20 mM histidine, 7.5% (w / v) sucrose, and 0.01% polysorbate 80 at pH 6.0. Formulation .

Immune disorders: inflammation, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, arthritis including juvenile idiopathic arthritis and osteoarthritis, inflammatory bowel disease including COPD, asthma, Crohn's disease and ulcerative colitis, Multiple sclerosis, Addison's disease, autoimmune hepatitis, autoimmune parotitis, type I diabetes, epididymis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, whole body Systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, sweat abscess, rheumatic fever, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthritis, thyroiditis, and vasculitis 21. A pharmaceutical formulation according to any one of claims 1 to 20 selected from the group.

The pharmaceutical preparation according to claim 21, wherein the immune disorder is rheumatoid arthritis.

A pharmaceutical comprising a polypeptide comprising the amino acid sequence shown in SEQ ID NO: 1 for use in the treatment in a human by administering 80 mg of the polypeptide about 4 weeks to a human in need of treatment for rheumatoid arthritis formulation and a, the person is simultaneously treated with methotrexate, polypeptide.

A pharmaceutical comprising a polypeptide comprising the amino acid sequence shown in SEQ ID NO: 1 for use in the treatment in a human by administering 80 mg of the polypeptide to a human in need of rheumatoid arthritis about every 8 weeks formulation and a, the person is simultaneously treated with methotrexate, polypeptide.

A pharmaceutical formulation comprising a polypeptide for use in a treatment in humans in need of treatment of an immune disorder that competes with a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 1 (ozoralizumab) according to claim 9.