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1. WO2020159836 - ANTAGONISTES DE PSMP DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT D'UNE MALADIE FIBROTIQUE DU POUMON, DU REIN OU DU FOIE

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CLAIMS

What is claimed is:

1. A PC3-secreted microprotein (PSMP) antagonist for use in the treatment of liver, lung, or kidney fibrosis.

2. The PSMP antagonist of claim 1 , wherein the PSMP antagonist is for use in the treatment of liver fibrosis, optionally wherein the liver fibrosis has progressed to liver cirrhosis.

3. The PSMP antagonist of claim 2, wherein the liver fibrosis is hepatitis B virus (HBV) -induced, hepatitis C virus (HCV)-induced, or alcohol-induced liver fibrosis,

or wherein the liver fibrosis is associated with a disease selected from the group consisting of nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC), optionally wherein the nonalcoholic fatty liver disease is nonalcoholic steatohepatitis (NASH).

4. The PSMP antagonist of claim 1 , wherein the PSMP antagonist is for use in the treatment of lung fibrosis, optionally wherein the lung fibrosis is associated with a drug-induced lung injury.

5. The PSMP antagonist of claim 1, wherein the PSMP antagonist is for use in the treatment of kidney fibrosis,

optionally wherein the kidney fibrosis is associated with a disease or disorder selected from the group consisting of lupus nephritis, IgA nephropathy, and membranous glomerulonephritis .

6. A PC3-secreted microprotein (PSMP) antagonist for use in the treatment of a disease selected from the group consisting of nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC).

7. The PSMP antagonist of claim 6, wherein nonalcoholic fatty liver disease is nonalcoholic steatohepatitis (NASH).

8. A PC3-secreted microprotein (PSMP) antagonist for use in the treatment of acute kidney injury (AKI) or chronic kidney disease (CKD),

optionally wherein the AKI is rhabdomyolysis-induced,

optionally wherein the CKD is caused by a disease or disorder selected from the group consisting of lupus nephritis, IgA nephropathy, and membranous glomerulonephritis.

9. A PC3-secreted microprotein (PSMP) antagonist for use in the treatment of a disease or disorder selected from the group consisting of graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), and lupus nephritis.

10. The PSMP antagonist of any one of cl aims 1 to 9, wherein the PSMP antagonist is a soluble protein that specifically binds to PSMP.

11. The PSMP antagonist of claim 10, wherein the soluble protein competes for binding to PSMP with an antibody comprising a heavy chain variable domain (VH) having the amino acid sequence shown in SEQ ID NO:4 and a light chain variable domain (VL) having the amino acid sequence shown in SEQ ID NO:5.

12. The PSMP antagonist of claim 10, wherein the soluble protein is an antibody.

13. The PSMP antagonist of claim 12, wherein the antibody competes for binding to PSMP with a second antibody comprising a heavy chain variable domain (VH) having the amino acid sequence shown in SEQ ID NO:4 and a light chain variable domain (VL) having the amino acid sequence shown in SEQ ID NO:5.

14. The PSMP antagonist of claim 13, wherein the antibody comprises a VH domain comprising complementarity determining regions (CDRs) CDR-HlAb, CDR-H2AI>, and CDR-H3AI>, wherein said set of VH CDRs has three or fewer amino acid substitutions relative to a reference set of CDRs CDR-HlRef, CDR-H2Ref, and CDR-H3Ref in which

CDR-HlRef is a CDR-H1 of SEQ ID NO:4;

CDR-H2Ref is a CDR-H2 of SEQ ID NO:4; and

CDR-H3Ref is a CDR-H3 of SEQ ID NO:4.

15. The PSMP antagonist of claim 14, wherein

CDR-H b is a CDR-H1 of SEQ ID NO:4;

CDR-H2Ab is a CDR-H2 of SEQ ID NO:4; and

CDR-H3Ab is a CDR-H3 of SEQ ID NO: 4.

16. The PSMP antagonist of claim 14, wherein each VH CDR is defined according to the Chothia definition, the Rabat definition, the AbM definition, or the contact definition of CDR.

17. The PSMP antagonist of claim 15, wherein each VH CDR is defined according to the Chothia definition, the Rabat definition, the AbM definition, or the contact definition of CDR.

18. The PSMP antagonist of claim 16, wherein each VH CDR is defined according to the Chothia definition of CDR, whereby

CDR-HlRef has the amino acid sequence shown in residues 31-35 of SEQ ID NO:4; CDR-H2Ref has the amino acid sequence shown in residues 50-69 of SEQ ID NO:4; and

CDR-H3Ref has the amino acid sequence shown in residues 99-108 of SEQ ID NO:4.

19. The PSMP antagonist of claim 18, wherein

CDR-HlAb has the amino acid sequence shown in residues 31-35 of SEQ ID NO:4; CDR-H2Ab has the amino acid sequence shown in residues 50-69 of SEQ ID NO:4; and

CDR-H3Ab has the amino acid sequence shown in residues 99-108 of SEQ ID NO:4.

20. The PSMP antagonist of any one of cl aims 14 to 19, wherein the antibody comprises a VL domain comprising complementarity determining regions (CDRs) CDR-LlAb, CDR-L2Ab, and CDR-L3Ab, wherein said set of VL CDRs has three or fewer amino acid substitutions relative to a reference set of CDRs CDR-LlRef, CDR-L2Ref, and CDR-L3Ref in which

CDR-LlRef is a CDR-L1 of SEQ ID NO:5;

CDR-L2Ref is a CDR-L1 of SEQ ID NO:5; and

CDR-L3Ref is a CDR-L1 of SEQ ID NO:5.

21. The PSMP antagonist of claim 20, wherein

CDR-L b is a CDR-L1 of SEQ ID NO:5;

CDR-L2Ab is a CDR-L2 of SEQ ID NO:5; and

CDR-L3Ab is a CDR-L3 of SEQ ID NO:5.

22. The PSMP antagonist of claim 20, wherein each VL CDR is defined according to the Chothia definition, the Rabat definition, the AbM definition, or the contact definition of CDR.

23. The PSMP antagonist of claim 21, wherein each VL CDR is defined according to the Chothia definition, the Rabat definition, the AbM definition, or the contact definition of CDR.

24. The PSMP antagonist of claim 22, wherein each VL CDR is defined according to the Chothia definition of CDR, whereby

CDR-LlRef has the amino acid sequence shown in residues 24-34 of SEQ ID NO:5; CDR-L2Ref has the amino acid sequence shown in residues 50-56 of SEQ ID NO:5; and

CDR-L3Ref has the amino acid sequence shown in residues 89-97 of SEQ ID NO:5.

25. The PSMP antagonist of claim 24, wherein

CDR-LlAb has the amino acid sequence shown in residues 24-34 of SEQ ID NO:5; CDR-L2,\h has the amino acid sequence shown in residues 50-56 of SEQ ID NO:5; and

CDR-L3,\h has the amino acid sequence shown in residues 89-97 of SEQ ID NO:5.

26. The PSMP antagonist of claim 19, wherein the antibody comprises a VH domain having the amino acid sequence shown in SEQ ID NO:4.

27. The PSMP antagonist of claim 25, wherein the antibody comprises a VL domain having the amino acid sequence shown in SEQ ID NO:5.

28. The PSMP antagonist of any one of cl aims 12 to 25, wherein the antibody is a humanized antibody or a chimeric antibody.

29. The PSMP antagonist of claim 12 or 13, wherein the antibody is a human antibody.

30. The PSMP antagonist of any one of cl aims 12 to 27, wherein the antibody is a single chain antibody.