Heparanase-neutralizing monoclonal antibodies
The present invention relates to heparanase-neutralizing monoclonal antibodies (m Abs), pharmaceutical composition comprising same, and use thereof for treating a disease or disorder associated with heparanase activity, including but not limited to cancer, inflammation, diabetes and related complications. The present invention further provides combined therapies comprising the heparanase-neutralizing m Ab and an anti-cancer treatment such as chemotherapy or radiation, for treating a proliferative disease in a subject.
1. An isolated monoclonal antibody (mAb) directed to the Lys158-Asp171 domain of human heparanase, wherein the mAb comprises a heavy-chain CDR1 comprising a sequence set forth in SEQ ID NO: 1, a heavy-chain CDR2 comprising a sequence set forth in SEQ ID NO: 2, a heavy-chain CDR3 comprising a sequence set forth in SEQ ID NO: 3, a light-chain CDR1 comprising a sequence set forth in SEQ ID NO: 4, a light-chain CDR2 comprising a sequence set forth in SEQ ID NO: 5 and a light-chain CDR3 comprising a sequence set forth in SEQ ID NO: 6.
2. The mAb of claim 1 , comprising a heavy chain variable domain having a sequence set forth in SEQ ID NO: 7 and a light chain variable domain having a sequence set forth in SEQ ID NO: 8.
3. The mAb of claim 1 , wherein the antibody is attached to a functional moiety.
4. The mAb of claim 3 , wherein the functional moiety is a marker, detectable tag, cytotoxic molecule or therapeutic agent.
5. The mAb of claim 1 , wherein the monoclonal antibody is of an immunoglobulin class including IgG, IgM, IgE, or IgA.
6. The mAb of claim 5 , wherein said IgA is IgA1 or IgA2 said IgG is IgG1, IgG2, IgG3, or IgG4.
7. The mAb of claim 1 , wherein the heavy chain variable domain is joined to the constant heavy region of a human IgG antibody subtype.
8. The mAb of claim 1 , wherein the mAb has a heparanase neutralizing effect.
9. The mAb of claim 1 , wherein the Lys158-Asp171 domain of human heparanase has the amino acid sequence set forth in SEQ ID NO: 11.
10. A pharmaceutical composition comprising the mAb of claim 1 and a pharmaceutically acceptable carrier.
11. A method for treating lymphoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the mAb of claim 1 , thereby treating the lymphoma in said subject.
12. The method of claim 11 , wherein the lymphoma is a B-cell lymphoma.
13. The method of claim 12 , wherein the B-cell lymphoma is selected from the group consisting of Burkitt lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, follicular lymphoma, small lymphocytic lymphoma, diffuse B-cell lymphoma, mantle cell lymphoma, and marginal zone lymphoma.
14. A method for treating multiple myeloma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the mAb of claim 1 .
15. The method of claim 10 , wherein said mAb is administered in combination with an anti-cancer treatment.