Multimeric IL-15-based molecules
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.
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 one of the first or second soluble protein further comprises a binding domain substantially identical to SEQ ID NO:2 or SEQ ID NO:6, 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 binding domain comprises an immunoglobulin light chain variable domain covalently linked to an immunoglobulin heavy chain variable domain by a polypeptide linker sequence.
5. The soluble fusion protein complex of claim 1 , wherein the binding domain specifically binds to one or more molecules comprising: programmed death ligand 1 (PD-L1), programmed death 1 (PD-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), cluster of differentiation 33 (CD33), cluster of differentiation 47 (CD47), glucocorticoid-induced tumor necrosis factor receptor (TNFR) family related gene (GITR), lymphocyte function-associated antigen 1 (LFA-1), tissue factor (TF), delta-like protein 4 (DLL4), single strand DNA or T-cell immunoglobulin and mucin-binding domain containing-3 (Tim-3).
6. 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.
7. The soluble fusion protein complex of claim 1 , wherein the second soluble protein comprises the amino acid sequence set forth in one of SEQ ID NOs: 4, 8, 12, 14, 16, 22, 26, 30, 34, 36, 40, 42, 44, 46, 51, 52, 53, or 54.
8. An isolated soluble fusion protein comprising an IL-15 peptide domain fused to a binding domain substantially identical SEQ ID NO:2 or SEQ ID NO:6.
9. An isolated soluble fusion protein comprising IL-15RαSu fused to both: (a) an immunoglobulin Fc domain; and (b) a binding domain substantially identical to SEQ ID NO:2 or SEQ ID NO:6.