Multimeric IL-15-based molecules

Patent metadata

Field	Value
Publication number	US-11369679-B2
Application number	US-202016752606-A
Country	US
Kind code	B2
Filing date	Jan 24, 2020
Priority date	Oct 21, 2016
Publication date	Jun 28, 2022
Grant date	Jun 28, 2022

Abstract

The invention features multi-specific protein complexes with one domain comprising IL-15 or a functional variant and a binding domain specific to a disease antigen, immune checkpoint or signaling molecule.

First claim

What is claimed is:

1. An isolated soluble fusion protein complex comprising at least two soluble proteins, wherein
a first soluble protein comprises an interleukin-15 (IL-15) polypeptide domain and a second

soluble protein comprises a soluble IL-15 receptor alpha sushi-binding domain (IL-15RαSu) fused to
an immunoglobulin Fc domain,
wherein the second soluble protein is substantially identical to SEQ ID NO:14 or SEQ ID NO:16, and
wherein the IL-15 domain of the first soluble protein binds to the IL-15RαSu domain of the second soluble protein to form a soluble fusion protein complex.

2. The soluble fusion protein complex of claim 1 , wherein one of the first or second soluble protein further comprises a second binding domain that specifically binds to a disease antigen, immune checkpoint molecule, or immune signaling molecule.

3. The soluble fusion protein complex of claim 1 , wherein the IL-15 polypeptide is an IL-15 variant comprising an N72D mutation (IL-15N72D).

4. The soluble fusion protein complex of claim 1 , wherein the first soluble protein comprises the amino acid sequence set forth in one of SEQ ID NOs: 2, 6, 10, 18, 20, 24, 28, 32, or 38 and wherein the second soluble protein is substantially identical to SEQ ID NO:14 or SEQ ID NO:16.

5. A method for treating a neoplasia in a subject in need thereof comprising administering to the subject an effective amount of the soluble fusion protein complex of claim 1 .

6. The method of claim 5 , wherein the subject is suffering a neoplasia selected from the group consisting of a glioblastoma, prostate cancer, hematological cancer, B-cell neoplasms, multiple myeloma, B-cell lymphoma, B cell non-Hodgkin lymphoma, Hodgkin's lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, cutaneous T-cell lymphoma, T-cell lymphoma, a solid tumor, urothelial/bladder carcinoma, melanoma, lung cancer, renal cell carcinoma, breast cancer, gastric and esophageal cancer, prostate cancer, pancreatic cancer, colorectal cancer, ovarian cancer, non-small cell lung carcinoma, and squamous cell head and neck carcinoma.

7. The method of claim 5 , wherein the effective amount is between about 1 and 100 μg/kg said fusion protein complex.

8. The method of claim 5 , wherein the fusion protein complex is administered at least one time per week.

9. The method of claim 5 , wherein the fusion protein complex is administered systemically, locally, intravenously, subcutaneously or intratumorally.

10. The method of claim 5 , wherein said fusion protein complex increases immune cell proliferation.

11. The method of claim 5 , wherein the fusion protein complex stimulates immune cell responses against cells associated with the neoplasia.

12. An isolated soluble fusion protein complex comprising at least:
a first soluble protein having at least 85% sequence identity to SEQ ID NO:2; and
a second soluble protein comprising an interleukin-15 (IL-15) receptor alpha sushi-binding

domain (IL-15RαSu) fused to an immunoglobulin Fc domain,
wherein the first soluble protein is bound to the second soluble protein to form a soluble fusion protein complex.

13. The soluble fusion protein complex of claim 12 , wherein the first soluble protein lacks the signal peptide of amino acids 1-18 of SEQ ID NO:2.

14. The soluble fusion protein complex of claim 13 , wherein the second soluble protein has at least 85% sequence identity to SEQ ID NO:4, and wherein the second soluble protein lacks the signal peptide of amino acids 1-18 of SEQ ID NO:4.

15. An isolated soluble fusion protein complex comprising at least:
a first soluble protein comprising an interleukin-15 (IL-15) polypeptide domain; and
a second soluble protein having at least 85% sequence identity to SEQ ID NO:4,
wherein the first soluble protein is bound to the second soluble protein to form a soluble fusion protein complex.

16. The soluble fusion protein complex of claim 15 , wherein the second soluble protein lacks the signal peptide of amino acids 1-18 of SEQ ID NO:4.

Assignees

• Altor Bioscience Llc

Inventors

• Wong Hing C
• Marcus Warren
• Liu Bai
• Xu Wenxin
• Newman Robert
• Kage Karen
• You Lijing
• Rhode Peter
• Soon-Shiong Patrick

Classifications

• C07K16/114

  Lentivirus (G), e.g. human immunodeficiency virus [HIV], feline immunodeficiency virus [FIV] or simian immunodeficiency virus [SIV] · CPC title

• C07K2319/70

  containing domain for protein-protein interaction · CPC title

• C07K2319/035

  containing a signal for targeting to the external surface of a cell, e.g. to the outer membrane of Gram negative bacteria, GPI- anchored eukaryote proteins · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K2317/60

  characterized by non-natural combinations of immunoglobulin fragments · CPC title