Methods for treating cholestatic liver fibrosis
View Patent ↗Provided are methods of treating fibrotic conditions in a subject by the identification of specific subsets of fibrogenic myofibroblasts, such as portal fibroblasts expressing mesothelin, and diagnostic methods useful for determining fibrosis, and the prognosis of fibrosis.
1. A method for treating or attenuating cholestatic liver fibrosis in a subject in need thereof comprising administering to said subject a therapeutic amount of an anti-mesothelin antibody or antigen binding fragment thereof capable of inhibiting the activity of mesothelin, wherein the anti-mesothelin antibody or antigen binding fragment thereof comprises: a V H chain comprising CDRs 1, 2, and 3 having the amino acid sequence set forth in SEQ ID NOS: 1, 2 and 3, respectively and a V L chain comprising CDRs 1, 2, and 3 having the amino acid sequence set forth in SEQ ID NOS:4, 5 and 6, respectively; or a V H chain comprising CDRs 1, 2, and 3 having the amino acid sequence set forth in SEQ ID NOS: 7, 8, and 9, respectively and a V L chain comprising CDRs 1, 2, and 3 having the amino acid sequence set forth in SEQ ID NOS: 10, 11 and 12, respectively, wherein the antibody or antigen binding fragment thereof specifically binds to mesothelin, thereby treating or attenuating the cholestatic liver fibrosis.
2. The method of claim 1 , wherein the anti-mesothelin antibody or antigen binding fragment thereof is a conjugate.
3. The method of claim 2 , wherein the conjugate comprises an immunotoxin.
4. The method of claim 1 , wherein the anti-mesothelin antibody or antigen binding fragment thereof is given in combination with an additional active agent.
5. The method of claim 4 , wherein the additional active agent comprises tauroursodeoxycholic acid.
6. The method of claim 4 , wherein the additional active agent comprises a corticosteroid.
7. The method of claim 1 , wherein the anti-mesothelin antibody or antigen binding fragment thereof is a recombinant polypeptide.
8. The method of claim 1 , wherein the subject is a human.
9. The method of claim 1 , wherein the subject is a non-human primate.
10. The method of claim 1 , wherein the cholestatic liver fibrosis is partially inhibited or reduced.
11. The method of claim 1 , wherein the administering to said subject the therapeutic amount of the anti-mesothelin antibody or antigen binding fragment thereof reduces the severity of the cholestatic liver fibrosis.
12. The method of claim 1 , wherein the administering to said subject the therapeutic amount of the anti-mesothelin antibody or antigen binding fragment thereof retards or slows the progression of the cholestatic liver fibrosis.
13. The method of claim 4 , wherein the additional active agent comprises an antifibrotic.
14. The method of claim 4 , wherein the additional active agent comprises an anti-inflammatory.
15. The method of claim 4 , wherein the additional active agent comprises an immunosuppressant.
16. The method of claim 4 , wherein the additional active agent comprises a chemotherapeutic agent.
17. The method of claim 4 , wherein the additional active agent comprises an anti-metabolite.
18. The method of claim 4 , wherein the additional active agent comprises an immunomodulator.
19. The method of claim 9 , wherein the non-human primate is a dog, a cat, a horse or a mouse.
20. The method of claim 7 , wherein the recombinant antigen binding fragment comprises a humanized antibody.
21. The method of claim 1 , wherein the V H chain and the V L chain are linked by a peptide linker to form a scFv, or the V H chain and the V L chain have one or more cysteine residues engineered into a framework region to permit formation of a disulfide bond linking the V H chain and the V L chain together.