IL-15 and IL-15RAPLHA sushi domain based immunocytokines
The present invention relates to an immunocytokine comprising (a) a conjugate, and (b) an immunomodulatory antibody or a fragment thereof directly or indirectly linked by covalence to said conjugate, wherein said conjugate comprises (i) a polypeptide comprising the amino acid sequence of the interleukin 15 or derivatives thereof, and a polypeptide comprising the amino acid sequence of the sushi domain of the IL-15Rα or derivatives thereof; and uses thereof.
1. An immunocytokine comprising of:
a polypeptide conjugate and an immunomodulatory antibody or an antigen binding fragment thereof, which are covalently linked as a fusion protein,
wherein said immunomodulatory antibody or antigen binding fragment thereof binds to a PD-1 receptor; and
wherein said polypeptide conjugate comprises:
(i) an interleukin 15 comprising a) the amino acid sequence of SEQ ID NO: 3, or b) a variant thereof of a) comprising at least one amino acid substitution selected from L45D, L45E, S51D, L52D, N72D, N72E, N72A, N72S, N72Y and N72P according to SEQ ID NO: 3, wherein the variant has the IL-15 activity;
(ii) an IL-15Rα fragment comprising the sushi domain and the hinge domain of an IL-15Ra, and comprising the amino acid sequence of SEQ ID NO: 12; and
(iii) a flexible peptide linker joining the IL-15Ra fragment and the IL-15 to form a fusion protein.
2. The immunocytokine of claim 1 , comprising, from N- to C-terminal, the immunomodulatory antibody or antigen binding fragment thereof, the IL-15Ra fragment, and the IL-15.
3. The immunocytokine of claim 1 , wherein the linker consists of 18-22 amino acids.
4. The immunocytokine of claim 1 , wherein the linker consists of 20 amino acids.
5. The immunocytokine of claim 1 , wherein the linker consists of the amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 14 or SEQ ID NO: 15.
6. The immunocytokine of claim 1 , wherein the polypeptide conjugate comprises the amino acid sequence of SEQ ID NO:18 or SEQ ID NO: 19.
7. A pharmaceutical composition comprising the immunocytokine of claim 1 and a pharmaceutically acceptable carrier.