Monoclonal antibodies for tumor treatment
The present invention relates to methods for inhibiting tumor growth, increasing survival of a subject having a tumor and inducing protection against tumor recurrence in a mammal. The methods comprise administering a humanized monoclonal antibody comprising CDR regions derived from the murine monoclonal antibody designated mBAT-1, in combination with at least one chemotherapeutic agent.
1. A method of treating a tumor or enhancing survival of a subject having a tumor, the method comprising (i) administering to a subject in need thereof an effective amount of a humanized monoclonal antibody BAT (mBAT-1) or a fragment thereof, wherein the antibody or the fragment thereof has all complementarity determining regions of mBAT-1 and a framework region (FR) from an acceptor human immunoglobulin, or modified therefrom; and (ii) administering to the subject an effective amount of at least one chemotherapeutic agent selected from the group consisting of 5-fluorouracil, cytarabine, oxaliplatin, paclitaxel and combinations thereof, and the humanized antibody is administered between 1 and 30 days prior to commencing chemotherapy; thereby treating the tumor or enhancing survival of the subject having the tumor.
2. The method according to claim 1 , wherein the humanized antibody comprises: a light chain variable region selected from the group consisting of: BATRκA (SEQ ID NO: 15), BATRκB (SEQ ID NO: 16), BATRκC (SEQ ID NO: 17), and BATRκD (SEQ ID NO: 18), and a heavy chain variable region selected from the group consisting of: BATRHA (SEQ ID NO: 20), BATRHB (SEQ ID NO: 21), BATRHC (SEQ ID NO: 22), BATRHD (SEQ ID NO: 23) and BATRHE (SEQ ID NO: 24).
3. The method according to claim 1 , wherein the humanized antibody comprises variable regions selected from the group consisting of: BATRHA/BATRκA (SEQ ID NO: 20/SEQ ID NO: 15), BATRHB/BATRκA (SEQ ID NO: 21/SEQ ID NO: 15), BATRHB/BATRκB (SEQ ID NO: 21/SEQ ID NO: 16), BATRHC/BATRκB (SEQ ID NO: 22/SEQ ID NO: 16), BATRHB/BATRκD (SEQ ID NO: 21/SEQ ID NO: 18), and BATRHC/BATRκD (SEQ ID NO: 22/SEQ ID NO: 18).
4. The method according to claim 3 , wherein the humanized monoclonal antibody has variable regions corresponding to BATRHC/BATRκD (SEQ ID NO: 22/SEQ ID NO: 18).
5. The method according to claim 1 , wherein the fragment of the humanized antibody is selected from the group consisting of: Fv, Fab′, F(ab′) 2 , and a single chain antibody; or wherein the humanized antibody or the fragment thereof retains the antitumor activity of mBAT-1.
6. The method according to claim 1 , wherein the administering of the humanized antibody is carried out prior to initial administration of the at least one chemotherapeutic agent.
7. The method according to claim 1 , wherein the administering of either or both of the humanized antibody and the at least one chemotherapeutic agent is carried out by a route selected from the group consisting of intravenous, oral, intraperitoneal, subcutaneous, isolated limb perfusion, infusion into an organ and combinations thereof.
8. The method according to claim 1 , further comprising treating the subject with radiation; or further comprising assessing at least one parameter selected from the group consisting of: rate of tumor growth, tumor volume, number of metastases, tumor recurrence and combinations thereof.
9. The method according to claim 1 , wherein the tumor is selected from the group consisting of colorectal carcinoma; lung carcinoma; breast carcinoma; melanoma; ovarian carcinoma; cervical carcinoma, pancreatic cancer; multiple myeloma; renal cell carcinoma; non-Hodgkin's lymphoma; Hodgkin's disease; mantle cell lymphoma; Kaposi's sarcoma; squamous cell carcinoma; basal cell carcinoma; acute myeloid leukemia (AML); chronic myelocytic leukemia (CML); acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL).
10. A method of improving tolerability to at least one chemotherapeutic agent, the method comprising administering to a subject in need thereof an effective amount of a humanized monoclonal antibody BAT (mBAT-1) or a fragment thereof, wherein the antibody or the fragment thereof has all complementarity determining regions of mBAT-1 and a framework region (FR) from an acceptor human immunoglobulin, or modified therefrom; wherein the subject is undergoing chemotherapy with at least one chemotherapeutic agent; thereby improving tolerability to said at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is selected from the group consisting of 5-fluorouracil, cytarabine, oxaliplatin, paclitaxel and combinations thereof, and the humanized antibody is administered between 1 and 30 days prior to commencing chemotherapy.
11. The method according to claim 10 , wherein the humanized antibody comprises: a light chain variable region selected from the group consisting of: BATRκA (SEQ ID NO: 15), BATRκB (SEQ ID NO: 16), BATRκC (SEQ ID NO: 17), and BATRκD (SEQ ID NO: 18), and a heavy chain variable region selected from the group consisting of: BATRHA (SEQ ID NO: 20), BATRHB (SEQ ID NO: 21), BATRHC (SEQ ID NO: 22), BATRHD (SEQ ID NO: 23) and BATRHE (SEQ ID NO: 24).
12. The method according to claim 11 , wherein the humanized antibody comprises variable regions selected from the group consisting of: BATRHA/BATRκA (SEQ ID NO: 20/SEQ ID NO: 15), BATRHB/BATRκA (SEQ ID NO: 21/SEQ ID NO: 15), BATRHB/BATRκB (SEQ ID NO: 21/SEQ ID NO: 16), BATRHC/BATRκB (SEQ ID NO: 22/SEQ ID NO: 16), BATRHB/BATRκD (SEQ ID NO: 21/SEQ ID NO: 18), and BATRHC/BATRκD (SEQ ID NO: 22/SEQ ID NO: 18).
13. The method according to claim 12 , wherein the humanized monoclonal has variable regions corresponding to BATRHC/BATRκD (SEQ ID NO: 22/SEQ ID NO: 18).
14. The method according to claim 10 , wherein the fragment of the humanized antibody is selected from the group consisting of: Fv, Fab′, F(ab′) 2 , and a single chain antibody; or wherein the humanized antibody or the fragment thereof retains the antitumor activity of mBAT-1.
15. The method according to claim 10 , wherein the administering of the humanized antibody and of the at least one chemotherapeutic agent is carried out substantially simultaneously, concurrently, alternately, sequentially, successively or according to an overlapping schedule; and optionally wherein the administering of the humanized antibody is carried out prior to initial administration of the at least one chemotherapeutic agent.
16. The method according to claim 10 , wherein the administering of either or both of the humanized antibody and the at least one chemotherapeutic agent is carried out by a route selected from the group consisting of intravenous, oral, intraperitoneal, subcutaneous, isolated limb perfusion, infusion into an organ and combinations thereof; or wherein the chemotherapy is for treatment of a tumor selected from the group consisting of colorectal carcinoma; lung carcinoma; breast carcinoma; melanoma; ovarian carcinoma; cervical carcinoma, pancreatic cancer; multiple myeloma; renal cell carcinoma; non-Hodgkin's lymphoma; Hodgkin's disease; mantle cell lymphoma; Kaposi's sarcoma; squamous cell carcinoma; basal cell carcinoma; acute myeloid leukemia (AML); chronic myelocytic leukemia (CML); acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL).
17. The method of claim 1 , wherein the humanized antibody comprises: a light chain variable region selected from the group consisting of: BATRκA (SEQ ID NO: 15), BATRκB (SEQ ID NO: 16), BATRκC (SEQ ID NO: 17), and BATRκD (SEQ ID NO: 18), and a heavy chain variable region selected from the group consisting of: BATRHA (SEQ ID NO: 20), BATRHB (SEQ ID NO: 21), BATRHC (SEQ ID NO: 22), BATRHD (SEQ ID NO: 23) and BATRHE (SEQ ID NO: 24); thereby reducing or preventing tumor recurrence.
18. The method according to claim 17 , wherein the humanized antibody comprises variable regions selected from the group consisting of: BATRHA/BATRκA (SEQ ID NO: 20/SEQ ID NO: 15), BATRHB/BATRκA (SEQ ID NO: 21/SEQ ID NO: 15), BATRHB/BATRκB (SEQ ID NO: 21/SEQ ID NO: 16), BATRHC/BATRκB (SEQ ID NO: 22/SEQ ID NO: 16), BATRHB/BATRκD (SEQ ID NO: 21/SEQ ID NO: 18), and BATRHC/BATRκD (SEQ ID NO: 22/SEQ ID NO: 18).
19. The method according to claim 17 , wherein the administering of the humanized antibody and of the at least one chemotherapeutic agent is carried out substantially simultaneously, concurrently, alternately, sequentially, successively or according to a overlapping schedule; and optionally wherein the administering of the humanized antibody is carried out prior to initial administration of the at least one chemotherapeutic agent.
20. The method according to claim 1 , wherein the light chain variable region of the humanized monoclonal antibody is SEQ ID NO. 18 , the heavy chain variable region of the humanized monoclonal antibody is SEQ ID NO. 22, the chemotherapeutic agent is an antimetabolite such as 5-fluorouacil, the tumor is melanoma and the treatment is carried out sequentially.
21. The method according to claim 10 , wherein the light chain variable region of the humanized monoclonal antibody is SEQ ID NO. 18, the heavy chain variable region of the humanized monoclonal antibody is SEQ ID NO. 22, the chemotherapeutic agent is an antimetabolite such as 5-fluorouacil, the tumor is melanoma and the treatment is carried out sequentially.
22. The method according to claim 17 , wherein the light chain variable region of the humanized monoclonal antibody is SEQ ID NO. 18, the heavy chain variable region of the humanized monoclonal antibody is SEQ ID NO. 22, the chemotherapeutic agent is an antimetabolite such as 5-fluorouacil, the tumor is melanoma and the treatment is carried out sequentially.