Anti-CTLA-4 antibodies and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11267889-B2
Application number	US-202016858195-A
Country	US
Kind code	B2
Filing date	Apr 24, 2020
Priority date	May 29, 2015
Publication date	Mar 8, 2022
Grant date	Mar 8, 2022

Abstract

The instant disclosure provides antibodies that specifically bind to human CTLA-4 and antagonize CTLA-4 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

First claim

What is claimed:

1. An isolated polynucleotide encoding:
(a) a heavy and a light chain variable region of an antibody that specifically binds to human CTLA-4, wherein the antibody comprises a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; and a light chain variable region comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; or
(b) a heavy chain variable region of an antibody that specifically binds to human CTLA-4, wherein the antibody comprises a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively.

2. The isolated polynucleotide of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7; and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8.

3. The isolated polynucleotide of claim 1 , wherein the polynucleotide encodes:
(a) an antibody heavy chain and an antibody light chain comprising the amino acid sequences of SEQ ID NO: 93 and 13, respectively; or
(b) an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 93.

4. A vector comprising the isolated polynucleotide of claim 1 .

5. A recombinant host cell comprising the isolated polynucleotide of claim 1 .

6. A method of producing an antibody that binds to human CTLA-4, the method comprising culturing the host cell of claim 5 so that the polynucleotide is expressed and the antibody is produced.

7. A method of increasing T cell activation in response to an antigen in a subject, the method comprising administering to the subject an effective amount of an antibody that specifically binds to human CTLA-4, the antibody comprising a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; and a light chain variable region comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively.

8. The method of claim 7 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

9. The method of claim 7 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 93; and a light chain comprising the amino acid sequence of SEQ ID NO: 13, respectively.

10. A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of an antibody that specifically binds to human CTLA-4, the antibody comprising a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; and a light chain variable region comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively.

11. The method of claim 10 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

12. The method of claim 10 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 93; and a light chain comprising the amino acid sequence of SEQ ID NO: 13, respectively.

13. The method of claim 10 , wherein the cancer is selected from the group consisting of acoustic neuroma, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, adenocarcinoma of the gastroesophageal junction, adrenal gland cancer, adult soft tissue sarcoma, anal cancer, anaplastic large cell lymphoma, angiosarcoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct carcinoma, biliary tract cancer, bladder cancer, blastoma, brain metastasis, brain or central nervous system cancer, breast cancer, HER2+ breast cancer, relapsed refractory HER2+ breast cancer, bronchial cancer, bronchogenic carcinoma, Burkitt lymphoma, cancer of the oral cavity or pharynx, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, colon cancer, craniopharyngioma, cystadenocarcinoma, desmoplastic melanoma, DIPG, embryonal carcinoma, endometrial carcinoma, endometrial stromal sarcoma, endotheliosarcoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing sarcoma, fibrosarcoma, follicular lymphoma, gastric cancer, gastroesophageal cancer, gastroesophageal junction carcinoma, gastrointestinal cancer, gastrointestinal stromal tumors, glioblastoma multiforme, glioblastoma multiforme that is refractory to bevacizumab therapy, hairy cell leukemia, head and neck cancer, head and neck squamous cell carcinoma, relapsed/refractory head and neck squamous cell carcinoma, heavy chain disease, hemangioblastoma, hepatic metastasis, hepatoma, hepatic carcinoma, Hodgkin's lymphoma, inflammatory breast cancer, intraocular lymphoma, kidney cancer, laryngeal cancer, squamous cell carcinoma of the hypopharynx, squamous cell carcinoma of the larynx, carcinoma of the oropharynx, verrucous carcinoma of the larynx, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, lymphoblastic lymphoma, lymphoma, mantle cell lymphoma, mast cell sarcoma, medullary carcinoma, medulloblastoma, melanoma, stage III melanoma, stage IV melanoma, melanoma with brain metastases, melanoma that is refractory to nivolumab or pembrolizumab, meningioma, Merkel cell carcinoma, mesothelioma, metastatic brain tumor, metastatic cancer, metastatic hormone refractory cancer, multiple myeloma, myelodysplastic syndrome, myeloma, myxosarcoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, ocular melanoma, oligodendroglioma, omyelodysplastic syndrome, surgically treatable or non-surgically treatable brain stem glioma, oropharyngeal cancer, orsplenic marginal zone lymphoma, osteocarcinoma, osteogenic sarcoma, ovarian cancer, metastatic ovarian cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, papillary adenocarcinomas, peripheral nervous system cancer, pinealoma, prostate cancer, hormone refractory prostate cancer, metastatic hormone refractory prostate cancer, progressive metastatic prostate cancer, rectal cancer, renal cell carcinoma, metastatic renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, sebaceous gland carcinoma, seminoma, serous adenocarcinoma, skin cancer, small bowel or appendix cancer, small cell lung cancer, small intestine lymphoma, soft tissue sarcoma, solid cancer, squamous cell cancer, stomach cancer, sweat gland carcinoma, synovia sarcoma, synovioma, T-cell lymphoma, testicular cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell cancer, urothelial cancer, uterine sarcoma, uveal melanoma, uveal melanoma with liver metastases, verrucous carcinoma, vulval cancer, Waldenstrom macroglobulinemia, and Wilms' tumor.

14. The method of claim 10 , wherein the antibody is administered subcutaneously,

Assignees

• Agenus Inc
• Ludwig Inst For Cancer Res Ltd
• Memorial Sloan Kettering Cancer Center

Inventors

• Van Dijk Marc
• Mundt Cornelia Anne
• Ritter Gerd
• Schaer David
• Wolchok Jedd David
• Merghoub Taha
• Savitsky David Adam
• Wilson Nicholas Stuart

Classifications

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• C07K2317/41

  Glycosylation, sialylation, or fucosylation · CPC title

• C07K16/283

  against Fc-receptors, e.g. CD16, CD32, CD64 (CD23 C07K16/2851) · CPC title