Method of treating cancer and/or cellular proliferative conditions and agents targeting hyaluronan anabolism useful for same
The present invention relates generally to the modulation of hyaluronan (HA) synthesis and degradation. The present invention further contemplates modulation of cellular proliferation, useful in the prophylaxis and/or treatment of inflammatory disorders including hyperproliferative conditions, such as but not limited to, cancer and psoriasis. The present invention is directed to compounds, agents, pharmaceutically active agents, medicaments, therapeutics, actives, drugs and the like which specifically target a portion of HAS which is accessible to the extracellular environment in malignant or inflammatory or proliferative cells but which portion is not accessible to the external environment in “normal” cells. A “normal” cell in this instance is a non-malignant, inflammatory or proliferative cell.
1. A method for the treatment of a cancer in a subject, said method comprising administering to said subject an effective amount of an isolated antibody, or an antigen-binding fragment thereof, which reduces the level of HAS, and/or the activity of HYAL1, and/or the activity of HYAL2 and wherein said antibody, or an antigen-binding fragment thereof, specifically binds SEQ ID NO:25 or SEQ ID NO:26 within HAS 1.
2. The method of claim 1 , wherein the subject is a human.
3. A method for reducing the level of hyaluronan synthase (HAS) or the extracellular release of hyaturanon (HA) in cancer cells comprising contacting said cells with an isolated antibody, or antigen binding fragment thereof, wherein said antibody, or antigen binding fragment thereof, reduces the level of HAS, and/or activity of HYAL1, and/or activity of HYAL2, and wherein said antibody, or antigen binding fragment thereof, specifically binds SEQ ID NO:25 or SEQ ID NO:26 within HAS1.
4. The method of claim 3 , wherein said antibody, or antigen binding fragment thereof, binds an epitope that is presented in cancer cells in the extracellular space and in normal cells in the intracellular space or plasma membrane.
5. The method of claim 3 , wherein the antibody is selected from the group consisting of a monoclonal antibody, polyclonal antibody, and a humanized antibody.
6. The method of claim 5 , wherein said antibody, or antigen-binding fragment thereof, specifically binds EX-1 (SEQ ID NO:25).
7. The method according to claim 5 , wherein said antibody, or antigen-binding fragment thereof, specifically binds the INT-2(SEQ ID NO:26).
8. A method of treatment of cancer cells comprising administering to said cells an isolated antibody, or antigen-binding fragment thereof, wherein. said antibody. or antigen-binding fragment thereof, reduces the level of hyaluronan synthase (HAS), or extracellular release of hyaluranon (HA), and wherein said antibody, or antigen-binding fragment thereof, specifically binds SEQ ID NO:25 or SEQ ID NO:26 within HAS 1,
9. The method according to claim 8 , wherein the antibody is selected from the group consisting of a monoclonal antibody, polyclonal antibody, and a humanized antibody.
10. The method of claim 8 , wherein said antibody, or antigen binding fragment thereof, binds an epitope that is present in the cancer cells in the extracellular space and in normal cells in the intracellular space or plasma membrane.
11. The method according to claim 9 , wherein the antibody, or antigen-binding fragment thereof, specifically binds INT-2 (SEQ ID NO:26).
12. The method according to claim 9 , wherein the antibody, or antigen-binding fragment thereof, specifically binds EX-1 (SEQ ID NO:25).
13. The method according to claim 8 , wherein the cancer cells are breast cancer cells.
14. The method of claim 8 , wherein the HAS is selected from the group consisting of isoforms HAS I, HAS II and HAS III.
15. The method of claim 14 , wherein the HAS is HAS II.
16. The method according to claim 3 , wherein the HAS is selected from the group consisting of isoforms HAS I, HAS II and HAS III.
17. The method according to claim 3 , wherein the HAS is HAS II.
18. The method according to according to claim 3 , wherein the cancer cells are breast cancer cells,
19. The method according to claim 1 or 3 , wherein said isolated antibody, or said antigen-binding fragment thereof, increases the level of HYAL3activity.