INTERLEUKIN 18 (IL-18) VARIANTS AND FUSION PROTEINS COMPRISING SAME
Provided herein are variant human IL-18 (hIL-18) proteins and fusion proteins comprising the variant hIL-18 proteins. Such variant hIL-18 proteins exhibit biological IL-18 activity while having reduced or no detectable binding to inhibitory IL-18BP. Thus, in some embodiments, the variant hIL-18 proteins advantageously retain IL-18 biological activity in the presence of IL-18BP. Such variant hIL-18 and related fusion proteins find use, for example, in the treatment of cancer.
1 - 38 . (canceled)
39 . An IL-18/IL-12 albumin binding domain fusion protein comprising:
a) a variant hIL-18 protein that has an amino acid sequence as set forth in SEQ ID NO:3 or in SEQ ID NO:4;
b) a human IL-12 (hIL-12) comprising an amino acid sequence as set forth in SEQ ID NO: 14; and
c) a human albumin binding domain (hABD) comprising an antibody heavy chain variable domain (VH), an antibody light chain variable domain (VL), and an scFv linker that attaches the VH to the VL, wherein the VH comprises an amino acid sequence as set forth in SEQ ID NO:5, and the VL comprises an amino acid sequence as set forth in SEQ ID NO:9, and
wherein the hIL-18 is attached to the human albumin binding domain by a first peptide linker, and the hIL-12 is attached to the human albumin binding domain by a second peptide linker, wherein the first peptide linker and the second peptide linker is a (Gly4Ser) 5 linker having an amino acid sequence as set forth in SEQ ID NO: 19.
40 . The IL-18/IL-12 albumin binding domain fusion protein of claim 39 , wherein the IL-18/IL-12 albumin binding domain fusion protein comprises from N- to C-terminus: hIL-18-linker 1-hABD-linker 2-hIL-12.
41 . The IL-18/IL-12 albumin binding domain fusion protein of claim 39 , wherein the IL-18/IL-12 albumin binding domain fusion protein comprises from N- to C-terminus: hIL-12-linker 2-hABD-linker 1-hIL 18.
42 . A nucleic acid encoding the IL-18/IL-12 albumin binding domain fusion protein of claim 39 .
43 . An expression vector comprising the nucleic acid of claim 42 .
44 . A host cell comprising the expression vector of claim 43 .
45 . A method of making an IL-18/IL-12 albumin binding domain fusion protein comprising culturing the host cell of claim 44 under condition wherein the IL-18/IL-12 albumin binding domain fusion protein is expressed, and recovering the IL-18/IL-12 albumin binding domain fusion protein.