Treating cancer by blocking the interaction of TIM-3 and its ligand
Provided herein are methods of activating immune response and/or treating cancer in a patient comprising administering to the patient a Gal3:TIM-3 inhibitor that interferes with the interaction between Gal3 and TIM-3, where said inhibitor is administered in an amount sufficient to activate immune response. Also provided are a humanized anti-Gal3 antibodies that can block the interaction between Gal3 and TIM3 and methods of using the anti-Gal3 antibody to treat cancer. Methods for determining if a patient's cancer is suitable for treatment with a Gal3:TIM-3 inhibitor and methods for selecting compounds that can block interaction between Gal3 and TIM-3, activating immune response and/or treating cancer are also provided.
1. A method of activating immune response in a patient with a cancer, comprising:
administering to the patient an effective amount of an anti-Gal3 antibody that interferes with the interaction between Gal3 and TIM-3, wherein the anti-Gal3 antibody comprises
(1) a light chain variable region comprising a complementary determining region (CDR) L1, a CDR L2, and a CDR L3 and
(2) a heavy chain variable region comprising a CDR H1, a CDR H2, and a CDR H3,
wherein
the CDR L1 comprises the amino acid sequence of SEQ ID NO:17,
the CDR L2 comprises the amino acid sequence of SEQ ID NO:18,
the CDR L3 comprises the amino acid sequence of SEQ ID NO:19,
the CDR H1 comprises the amino acid sequence of SEQ ID NO:9,
the CDR H2 comprises the amino acid of SEQ ID NO:10, and
the CDR H3 comprises the amino acid sequence of SEQ ID NO:11;
wherein the Gal3 is overexpressed on cells in a tumor microenvironment,
the TIM-3 is expressed on immune cells, and
the effective amount is sufficient to activate the immune response in the patient
wherein the anti-Gal3 antibody is a humanized antibody.
2. The method of claim 1 , wherein the interaction between Gal3 and TIM-3 occurs in a tumor microenvironment, and wherein the activation of the immune response decreases the cancer load of the patient.
3. The method of claim 1 , wherein the immune cells are T cells or NK cells and activating the immune response is through activating the T cells or NK cells.
4. The method of claim 1 , wherein the cancer is a metastatic cancer or a primary cancer.
5. The method of claim 1 , wherein the antibody is a single chain antibody or a Fab.
6. The method of claim 1 , wherein the anti-Gal3 antibody-is administered intravenously.
7. The method of claim 1 , wherein the anti-Gal3 antibody is administered in combination with at least one of a chemotherapy, radiotherapy, or a checkpoint inhibitor therapy.
8. The method of claim 7 , wherein the checkpoint inhibitor therapy is an anti-PD-1 therapy or an anti-CTLA-4 therapy.
9. The method of claim 1 , wherein the anti-Gal3 antibody-is administered at a dose of between 10 μg to 100 mg per kilogram of body weight of the patient every other week.
10. A method of activating immune response in a patient comprising administering to the patient an anti-Gal3 antibody that interferes with the interaction between Gal3 and TIM-3,
wherein said anti-Gal3 antibody is administered in an amount sufficient to activate immune response,
wherein the anti-Gal3 antibody is a humanized antibody; and
wherein the anti-Gal3 antibody comprises
(1) a light chain variable region comprising a complementary determining region (CDR) L1, a CDR L2, and a CDR L3 and
(2) a heavy chain variable region comprising a CDR H1, a CDR H2, and a CDR H3,
wherein
the CDR L1 comprises the amino acid sequence of SEQ ID NO:17,
the CDR L2 comprises the amino acid sequence of SEQ ID NO:18,
the CDR L3 comprises the amino acid sequence of SEQ ID NO:19,
the CDR H1 comprises the amino acid sequence of SEQ ID NO:9,
the CDR H2 comprises the amino acid of SEQ ID NO:10, and
the CDR H3 comprises the amino acid sequence of SEQ ID NO:11.
11. A method of activating immune response in a patient comprising administering to the patient an antibody, wherein the antibody includes a means for inhibiting the interaction between Gal3 and TIM-3, wherein the means for inhibiting the interaction comprises a light chain variable region comprising a CDR L1, a CDR L2, and a CDR L3, and a heavy chain variable region comprising a CDR H1, a CDR H2, and a CDR H3, wherein
the CDR L1 comprises the amino acid sequence of SEQ ID NO:17,
the CDR L2 comprises the amino acid sequence of SEQ ID NO:18,
the CDR L3 comprises the amino acid sequence of SEQ ID NO:19,
the CDR H1 comprises the amino acid sequence of SEQ ID NO:9,
the CDR H2 comprises the amino acid of SEQ ID NO:10, and
the CDR H3 comprises the amino acid sequence of SEQ ID NO:11.
12. The method of claim 10 , wherein the heavy chain variable region has a sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 25.
13. The method of claim 10 , wherein the light chain variable region has a sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 26.
14. The method of claim 1 , wherein the heavy chain variable region has a sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 25.
15. The method of claim 1 , wherein the light chain variable region has a sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 26.