Multimeric IL-15 soluble fusion molecules and methods of making and using same
View Patent ↗The present invention features compositions and methods featuring ALT-803, a complex of an interleukin-15 (IL-15) superagonist mutant and a dimeric IL-15 receptor α/Fc fusion protein useful for enhancing an immune response against a neoplasia (e.g., multiple myeloma, melanoma, lymphoma) or a viral infection (e.g., human immunodeficiency virus).
1. An IL-15 receptor fusion polypeptide comprising an IL-15 receptor alpha sushi-binding domain fused to an Fc domain (IL-15RaSu/Fc) and a variant interleukin-15 polypeptide comprising an N72D mutation (IL-15N72D) complex (IL-15N72D:IL-15RaSu/Fc; Alt-803) comprising a dimeric IL-15RaSu/Fc and two IL-15N72D molecules.
2. The polypeptide of claim 1 , wherein the IL-15RaSu/Fc comprises SEQ ID NO: 1.
3. The polypeptide of claim 2 , wherein amino acids 1-65 of SEQ ID NO: 1 comprise IL-15RaSu.
4. The polypeptide of claim 3 , wherein amino acids 66-297 of SEQ ID NO: 1 comprise IgG1 CH2-CH3 (Fc domain).
5. The polypeptide of claim 2 , wherein amino acids 20-84 of SEQ ID NO: 4 comprise IL-15RaSu.
6. The polypeptide of claim 5 , wherein amino acids 85-316 comprise IgG1 CH2-CH3 (Fc domain).
7. The polypeptide of claim 1 , wherein the IL-15N72D comprises SEQ ID NO: 2.
8. A nucleic acid sequence encoding the polypeptide of claim 1 .
9. A nucleic acid sequence encoding an IL-15 receptor fusion polypeptide comprising an IL-15RaSu/Fc and an IL-15N72D complex (IL-15N72D:IL-15RaSu/Fc; Alt-803), wherein the nucleic acid sequence encoding IL-15RaSu/Fc comprises SEQ ID NO: 57, and wherein the nucleic acid sequence encoding IL-15N72D comprises SEQ ID NO: 56.
10. The polypeptide of claim 1 , wherein the IL-15RaSu/Fc comprises SEQ ID NO: 4.
11. The polypeptide of claim 1 , wherein the IL-15N72D comprises SEQ ID NO: 3.
12. A nucleic acid sequence encoding the polypeptide of claim 2 .
13. A nucleic acid sequence encoding the polypeptide of claim 3 .
14. A nucleic acid sequence encoding the polypeptide of claim 4 .
15. A nucleic acid sequence encoding the polypeptide of claim 5 .
16. A nucleic acid sequence encoding the polypeptide of claim 10 .
17. A nucleic acid sequence encoding the polypeptide of claim 11 .
18. The nucleic acid sequence of claim 9 , wherein the nucleic acid sequence encoding IL-15N72D comprises nucleic acids 61 to 402 of SEQ ID NO: 56.
19. The nucleic acid sequence of claim 9 , wherein the nucleic acid sequence encoding the IL-15RaSu/Fc comprises nucleic acids 58 to 948 SEQ ID NO: 57.
20. The polypeptide of claim 11 , wherein the IL-15N72D comprises amino acids 21 to 134 of SEQ ID NO: 3.