Multimeric IL-15 soluble fusion molecules and methods of treating neoplasia and HIV 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. A method for treating neoplasia or human immunodeficiency virus (HIV) infection in a subject, the method comprising administering to said subject an effective amount of a pharmaceutical composition comprising interleukin-15 N72D: IL-15 receptor alpha Sushi/IgG1 CH2-CH3 (IL-15N72D:IL-15RαSu/Fc complex (Alt-803) comprising a dimeric IL-15RαSu/Fc and two IL-15N72D molecules, thereby treating the neoplasia or virus infection.
2. The method of claim 1 , wherein the IL-15RaSu/Fc comprises the following sequences (“IL-15RaSu/Fc” (SEQ ID NO: 1): itcpppmsvehadiwvksyslysreryicnsgfkrkagtssltecvinkatnvahwttpslkcir [IL-15RαSu] (amino acids 1-65 of SEQ ID NO:1) and epkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeq ynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiav ewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk [IgG1 Ch2-CH3 (Fc domain)] (amino acids 66-297 of SEQ ID NO:1).
3. The method of claim 1 , wherein the IL-15N72D molecule comprises the following sequence (SEQ ID NO: 2): nwvnvisdlkkiedliqsmhidatlytesdvhpsckvtamkcfllelqvislesgdasihdtvenli ilandslssngnvtesgckeceeleeknikeflqsfvhivqmfints [IL-15N72D].
4. The method of claim 1 , wherein the neoplasia is selected from the group consisting of multiple myeloma, beta-cell lymphoma, urothelial/bladder carcinoma and melanoma.
5. The method of claim 1 , wherein the effective amount is between about 1 and 20 μg/kg.
6. The method of claim 5 , wherein the effective amount is about 1 μg/kg, 5 μg/kg, 10 μg/kg, 15 μg/kg, or 20 μg/kg.
7. The method of claim 6 , wherein the effective amount is 10 μg/week.
8. The method of claim 1 , wherein the effective amount is between about 20 μg and 100 μg/kg.
9. The method of claim 1 , wherein the effective amount is 30 μg/kg, 50 μg/kg, 75 μg/kg, or 100 μg/kg.
10. The method of claim 1 , wherein Alt-803 is administered once, twice, or three times per week.
11. The method of claim 1 , wherein the pharmaceutical composition is administered systemically, intravenously, or by instillation.
12. The method of claim 1 , wherein Alt-803
increases serum levels of IFN-γ;
increases the number of CD8 + CD44 high memory T cells,
causes CD8 + CD44 high memory T cells to acquire an innate-type phenotype and secrete IFN-γ independent of antigen requirement; and/or
induces a long lasting anti-myeloma immune memory response.
13. The method of claim 1 , wherein the effective amount is between about 1 and 100 μg/kg.
14. A method of treating neoplasia in a subject, the method comprising administering to said subject an effective amount of a pharmaceutical composition comprising an anti-CD20 single chain antibody (scAb) T2 molecule (T2M) complex or a CD20-targeted IL-15N72D:IL-15Rα/Fc fusion protein complex (2B8T2M), thereby treating the neoplasia.
15. The method of claim 14 , wherein anti-CD20 scAb T2M comprises a soluble anti-CD20 scAb/huIL-15N72D:anti-CD20 scAb/huIL-15RαSu/huIgG1 Fc complex, wherein anti-CD20 scAb/huIL-15RαSu/huIgG1 Fc has the sequence shown in SEQ ID NO: 51, and the anti-CD20 scAb/hIL-15N72D construct has the sequence shown in SEQ ID NO: 49.
16. The method of claim 14 , wherein the neoplasia is beta-cell lymphoma or Burkitt's lymphoma.