Methods of treating disease with fusion molecules comprising IL-15 variants
View Patent ↗The instant invention provides soluble fusion protein complexes and IL-15 variants that have therapeutic and diagnostic use, and methods for making such proteins. The instant invention additionally provides methods of stimulating or suppressing immune responses in a mammal using the fusion protein complexes and IL-15 variants of the invention.
1. A method for treating disease, wherein said disease comprises cancer or human immunodeficiency virus (HIV), in a patient, the method comprising:
a) administering to the patient a soluble fusion protein complex comprising at least two soluble fusion proteins, wherein the first fusion protein comprises (a) a first single chain T-cell receptor (scTCR) covalently linked to (b) interleukin-15 (IL-15) polypeptide; and the second fusion protein comprises (c) a second scTCR covalently linked to (d) soluble interleukin-15 receptor alpha (IL-15Ra) polypeptide; wherein the IL-15 polypeptide of the first fusion protein binds to the soluble IL-15Ra polypeptide of the second fusion protein to form a soluble fusion protein complex, and wherein the first scTCR and the second scTCR comprise a TCR V-α chain covalently linked to a TCR V-β chain by a peptide linker sequence;
b) forming a specific binding complex (bridge) between antigen-expressing diseased cells and IL-15R-expressing immune cells sufficient to localize the immune cells; and
c) damaging or killing the disease cells sufficient to prevent or treat the disease in the patient.
2. A method for treating disease, wherein said disease comprises cancer or HIV), in a patient, the method comprising:
a) mixing immune cells bearing the IL-15R chains with a soluble fusion protein complex comprising at least two soluble fusion proteins, wherein the first fusion protein comprises (a) a first single chain T-cell receptor (scTCR) covalently linked to (b) interleukin-15 (IL-15) polypeptide; and the second fusion protein comprises (c) a second scTCR covalently linked to (d) soluble interleukin-15 receptor alpha (IL-15Ra) polypeptide; wherein the IL-15 polypeptide of the first fusion protein binds to the soluble IL-15Ra polypeptide of the second fusion protein to form a soluble fusion protein complex, and wherein the first scTCR and the second scTCR comprise a TCR V-α chain covalently linked to a TCR V-β chain by a peptide linker sequence,
b) administering to the patient the immune cell-fusion protein complex mixture;
c) forming a specific binding complex (bridge) between antigen-expressing diseased cells and IL-15R-expressing immune cells sufficient to localize the immune cells; and
d) damaging or killing the disease cells sufficient to prevent or treat the disease in the patient.
3. The method of claim 1 , wherein the diseased cells express a disease associated antigen.
4. The method of claim 1 , wherein the fusion protein complex recognizes a disease-associated antigen.
5. The method of claim 4 , wherein the disease associated antigen is a peptide/MHC complex.