A fusion molecule of CTLA4 and IL-15

Abstract

The present invention provides a soluble fusion protein complex containing domains from IL-15, the IL-15 receptor, and an αCTLA4 antibody for preventing, reducing the incidence of, and / or treating cancer or autoimmune diseases or disorders in a target population. [Solution] A soluble fusion protein complex is provided, comprising a first domain containing an IL-15 peptide or a variant thereof, a second domain containing a fusion polypeptide comprising an IL-15RαSushi peptide (IL15RαSu) and an αCTLA4 antibody heavy chain, and a third domain containing an αCTLA4 antibody light chain. The IL-15 peptide or variant binds to the IL15RαSu peptide to form a soluble fusion protein complex. The soluble fusion protein complex and its pharmaceutical composition modulate the immune response. A method for preventing or treating cancer in which the immune response is enhanced, and a method for preventing or treating autoimmune diseases or disorders in which the immune response is reduced are provided.

Claims

1. A soluble fusion protein complex, (a) A first domain comprising an interleukin-15 (IL-15) peptide having at least 85% sequence identity with SEQ ID NO: 17, (b) A second domain comprising a fusion polypeptide comprising an IL-15 receptor alpha-Sushi (IL15RαSu) peptide and an αCTLA4 antibody heavy chain, wherein the αCTLA4 antibody heavy chain has at least 85% sequence identity with SEQ ID NO: 10, (c) A third domain comprising an αCTLA4 antibody light chain having at least 85% sequence identity with SEQ ID NO: 3 A soluble fusion protein complex comprising the IL-15 peptide of the first domain, wherein the IL-15 peptide of the second domain binds to the IL-15RαSu peptide of the second domain to form a soluble fusion protein complex.

2. The soluble fusion protein complex according to claim 1, wherein the αCTLA4 antibody heavy chain has at least 90% sequence identity with SEQ ID NO: 10 and includes SEQ ID NOs: 11 to 13, and the αCTLA4 antibody light chain has at least 90% sequence identity with SEQ ID NO: 3 and includes SEQ ID NOs: 14 to 16.

3. The soluble fusion protein complex according to claim 1 or 2, wherein the αCTLA4 antibody heavy chain has at least 95% sequence identity with SEQ ID NO: 10 and includes SEQ ID NOs: 11 to 13, and the αCTLA4 antibody light chain has at least 95% sequence identity with SEQ ID NO: 3 and includes SEQ ID NOs: 14 to 16.

4. The soluble fusion protein complex according to claim 3, wherein the αCTLA4 antibody heavy chain comprises the sequence of SEQ ID NO: 10, and the αCTLA4 antibody light chain comprises the sequence of SEQ ID NO:

3.

5. The soluble fusion protein complex according to any one of claims 1 to 4, wherein the IL15RαSu peptide has at least 85% sequence identity with SEQ ID NO:

8.

6. The soluble fusion protein complex according to any one of claims 1 to 5, wherein the IL-15 peptide comprises SEQ ID NO:

17.

7. The soluble fusion protein complex according to any one of claims 1 to 6, wherein the IL-15 peptide comprises SEQ ID NO:

1.

8. The soluble fusion protein complex according to any one of claims 1 to 7, wherein the fusion polypeptide further comprises a peptide linker between the amino terminus of the IL15RαSu peptide and the carboxyl terminus of the αCTLA4 antibody heavy chain.

9. The soluble fusion protein complex according to any one of claims 1 to 8, wherein the fusion polypeptide has at least 85% sequence identity with SEQ ID NO:

5.

10. The soluble fusion protein complex according to claim 9, wherein the fusion polypeptide comprises SEQ ID NO:

5.

11. The soluble fusion protein complex according to any one of claims 1 to 10, wherein the fusion polypeptide further comprises a peptide linker between the carboxyl terminus of the IL15RαSu peptide and the amino terminus of the αCTLA4 antibody heavy chain.

12. The soluble fusion protein complex according to any one of claims 1 to 11, wherein the fusion polypeptide has at least 85% sequence identity with SEQ ID NO:

4.

13. The soluble fusion protein complex according to any one of claims 1 to 12, wherein the fusion polypeptide comprises SEQ ID NO:

4.

14. A pharmaceutical composition comprising a soluble fusion protein complex according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition according to claim 14, formulated for parenteral injection.

16. A pharmaceutical composition according to claim 14 or 15, formulated for subcutaneous, intravenous, intramuscular, intravesicular, intratumoral, or intraperitoneal injection.

17. A pharmaceutical composition according to any one of claims 14 to 16, formulated for intravenous injection.

18. A method for preventing or treating cancer in a subject in need thereof, comprising administering to the subject a soluble fusion protein complex according to any one of claims 1 to 13 or a pharmaceutical composition according to any one of claims 14 to 17.

19. The method according to claim 18, wherein the cancer is selected from the group consisting of acute leukemia, AIDS-related cancer, breast cancer, bone cancer, brain tumor, head and neck cancer, lymphoma, adenoma, squamous cell carcinoma, laryngeal cancer, gallbladder and bile duct cancer, retinal cancer, esophageal cancer, gastric cancer, multiple myeloma, ovarian cancer, uterine cancer, thyroid cancer, testicular cancer, endometrial cancer, melanoma, lung cancer, bladder cancer, prostate cancer, lung cancer, pancreatic cancer, sarcoma, Wilms' tumor, cervical cancer, skin cancer, nasopharyngeal cancer, liposarcoma, epithelial carcinoma, renal cell carcinoma, gallbladder adenocarcinoma, parotid gland cancer, endometrial sarcoma, and multidrug-resistant cancer.

20. A method for preventing or treating an autoimmune disease or disorder in a subject in need thereof, comprising administering to the subject a soluble fusion protein complex according to any one of claims 1 to 13 or a pharmaceutical composition according to any one of claims 14 to 17.

21. Use of a soluble fusion protein complex according to any one of claims 1 to 13 or a pharmaceutical composition according to any one of claims 14 to 17 for the prevention or treatment of cancer in a person in need thereof.

22. Use of a soluble fusion protein complex according to any one of claims 1 to 13 or a pharmaceutical composition according to any one of claims 14 to 17 for the prevention or treatment of an autoimmune disease or disorder in a person in need thereof.

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