Anti-LAG-3 antibodies and uses thereof
The present disclosure provides antibodies that bind Lymphocyte Activation Gene-3 (LAG-3). Also provided are methods of stimulating an immune response, inhibiting growth of tumor cells, and treating an autoimmune, inflammatory, or viral disease.
1. A method of treating cancer in a patient in need thereof, comprising administering to the patient an antibody or fragment thereof, wherein the antibody or fragment thereof has specificity to a human Lymphocyte Activation Gene-3 (LAG-3) protein and comprises a heavy chain variable region comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region comprising light chain complementarity determining regions CDRL1, CDRL2, and CDRL3, and wherein
the CDRH1 comprises the amino acid sequence of SEQ ID NO:240;
the CDRH2 comprises the amino acid sequence of SEQ ID NO:241 or SEQ ID NO:347;
the CDRH3 comprises the amino acid sequence of SEQ ID NO:242 or SEQ ID NO:354;
the CDRL1 comprises the amino acid sequence of SEQ ID NO:243, SEQ ID NO:376 or amino acid residues 24-39 of SEQ ID NO:330;
the CDRL2 comprises the amino acid sequence of SEQ ID NO:244; and
the CDRL3 comprises the amino acid sequence of SEQ ID NO:245 or SEQ ID NO:374.
2. The method of claim 1 , wherein the cancer is selected from the group consisting of a leukemia, a lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer, rectal cancer, bladder cancer, urothelial cancer, lung cancer, bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, gall bladder cancer, bile duct cancer, esophageal cancer, renal cell carcinoma, thyroid cancer, squamous cell carcinoma of the head and neck, testicular cancer, cancer of the endocrine gland, cancer of the adrenal gland, cancer of the pituitary gland, cancer of the skin, cancer of soft tissues, cancer of blood vessels, cancer of brain, cancer of nerves, cancer of eyes, cancer of meninges, cancer of oropharynx, cancer of hypopharynx, cancer of cervix, and cancer of uterus, glioblastoma, meduloblastoma, astrocytoma, glioma, meningioma, gastrinoma, neuroblastoma, melanoma, myelodysplastic syndrome, and a sarcoma.
3. The method of claim 2 , wherein the leukemia is selected from the group consisting of systemic mastocytosis, acute lymphocytic leukemia (ALL), T cell ALL, acute myeloid leukemia (AML), myelogenous leukemia, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), chronic myeloid leukemia (CML), myeloproliferative disorder/neoplasm, myelodysplastic syndrome, monocytic cell leukemia, and plasma cell leukemia; wherein said lymphoma is selected from the group consisting of histiocytic lymphoma and T cell lymphoma, B cell lymphomas, including Hodgkin's lymphoma and non-Hodgkin's lymphoma, such as low grade/follicular non-Hodgkin's lymphoma (NHL), cell lymphoma (FCC), mantle cell lymphoma (MCL), diffuse large cell lymphoma (DLCL), small lymphocytic (SL) NHL, intermediate grade/follicular NHL, intermediate grade diffuse NHL, high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small non-cleaved cell NHL, bulky disease NHL, and Waldenstrom's Macroglobulinemia.
4. A method of treating cancer in a patient in need thereof, comprising:
(a) treating a T cell, in vitro, with an antibody or fragment thereof; and
(b) administering the treated T cell to the patient,
wherein the antibody or fragment thereof has specificity to a human Lymphocyte Activation Gene-3 (LAG-3) protein and comprises a heavy chain variable region comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region comprising light chain complementarity determining regions CDRL1, CDRL2, and CDRL3, and wherein
the CDRH1 comprises the amino acid sequence of SEQ ID NO:240;
the CDRH2 comprises the amino acid sequence of SEQ ID NO:241 or SEQ ID NO:347;
the CDRH3 comprises the amino acid sequence of SEQ ID NO:242 or SEQ ID NO:354;
the CDRL1 comprises the amino acid sequence of SEQ ID NO:243, SEQ ID NO:376 or amino acid residues 24-39 of SEQ ID NO:330;
the CDRL2 comprises the amino acid sequence of SEQ ID NO:244; and
the CDRL3 comprises the amino acid sequence of SEQ ID NO:245 or SEQ ID NO:374.
5. A method of treating cancer in a patient in need thereof, comprising administering to the patient an antibody or fragment thereof, wherein the antibody or fragment thereof has specificity to a human Lymphocyte Activation Gene-3 (LAG-3) protein and comprises
(a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:329 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:330, or
(b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:335 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:336.
6. The method of claim 1 , wherein
the CDRH1 comprises the amino acid sequence of SEQ ID NO:240;
the CDRH2 comprises the amino acid sequence of SEQ ID NO:241;
the CDRH3 comprises the amino acid sequence of SEQ ID NO:242;
the CDRL1 comprises the amino acid sequence of SEQ ID NO:243;
the CDRL2 comprises the amino acid sequence of SEQ ID NO:244; and
the CDRL3 comprises the amino acid sequence of SEQ ID NO:245.
7. The method of claim 6 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:238, and the light chain variable region comprises the amino acid sequences of SEQ ID NO:239.
8. The method of claim 6 , wherein the heavy chain variable region comprises an amino acid sequence of selected from the group consisting SEQ ID NO:251, 252, 258 and 259, and the light chain variable region comprises the amino acid sequences of SEQ ID NO:260.
9. The method of claim 1 , wherein
the CDRH1 comprises the amino acid sequence of SEQ ID NO:240;
the CDRH2 comprises the amino acid sequence of SEQ ID NO:347;
the CDRH3 comprises the amino acid sequence of SEQ ID NO:354;
the CDRL1 comprises the amino acid sequence of amino acid residues 24-39 of SEQ ID NO:330;
the CDRL2 comprises the amino acid sequence of SEQ ID NO:244; and
the CDRL3 comprises the amino acid sequence of SEQ ID NO:374.
10. The method of claim 9 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:329, and the light chain variable region comprises the amino acid sequences of SEQ ID NO:330.
11. The method of claim 1 , wherein
the CDRH1 comprises the amino acid sequence of SEQ ID NO:240;
the CDRH2 comprises the amino acid sequence of SEQ ID NO:347;
the CDRH3 comprises the amino acid sequence of SEQ ID NO:354;
the CDRL1 comprises the amino acid sequence of SEQ ID NO:376;
the CDRL2 comprises the amino acid sequence of SEQ ID NO:244; and
the CDRL3 comprises the amino acid sequence of SEQ ID NO:374.