Immunocytokines for the treatment of cancer
The present invention relates to new immunocytokines which are useful for the treatment of cancer. These fusion proteins comprise (i) an antibody or antigen-binding fragment thereof fused to (ii) a cleavable peptide linker, and (iii) cytokine, or functional fragments thereof. Methods of treatment using these immunocytokines are also disclosed.
1. A fusion protein comprising:
an antibody which binds a tumour-associated antigen (TAA) or a tumour-specific antigen (TSA), or antigen-binding fragment thereof, fused to
(ii) a cleavable peptide linker, wherein the cleavable peptide linker comprises a tumor-associated protease cleavage site and
(iii) a cytokine, or functional fragments thereof.
2. The fusion protein of claim 1 , wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanised antibodies, scFv, single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv.
3. The fusion protein of claim 1 , wherein the protease cleavage site is cleaved by a matrix metalloproteinase or by uPA.
4. The fusion protein of claim 3 , wherein the matrix metalloproteinase is MMP-2, MMP-9.
5. The fusion protein of claim 1 , wherein the cleavable peptide linker has a sequence selected from the group consisting of: GPLGIAGQ (SEQ ID NO: 38), GPLGLWAQ (SEQ ID NO: 40), GPLGMLSQ (SEQ ID NO: 42), PLGLAG (SEQ ID NO: 36), PVGLIG (SEQ ID NO: 44), SGRS (SEQ ID NO: 166), SGRSA (SEQ ID NO: 168), and PSSRRRVN (SEQ ID NO: 170).
6. The fusion protein of claim 1 , wherein the cytokine is a human cytokine or a functional fragment thereof.
7. The fusion protein of claim 1 , wherein the cytokine is selected in the group consisting of: IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-26, IL-28, IL-29, IL-33, IL-36, IL-37, IL-38, IFN-α (including IFN-α1/13, IFN-α2, IFN-α4, IFN-α5, IFN-α6, IFN-α7, IFN-α8, IFN-α10, IFN-α14, IFN-α16, IFN-α17, and IFN-α21), IFN-β, IFN-γ, IFN-λ, TNF-α, TNF-β, TGF-β1, M-CSF, G-CSF, GM-CSF, and CXL10.
8. The fusion protein of claim 1 , wherein the cytokine is selected in the group consisting of: IL-15, CXCL10, IL-36, and IFN-α.
9. The fusion protein of claim 1 , wherein:
(i) the cytokine, or functional fragment thereof is fused to the cleavable peptide linker, and
(ii) the cleavable peptide linker is used N-terminally or C-terminally to the light chain of the antibody or antigen-binding fragment thereof.
10. The fusion protein of claim 1 , wherein:
the cytokine, or functional fragment thereof is fused to the cleavable peptide linker, and
(ii) the cleavable peptide linker is fused N-terminally or C-terminally to the heavy chain of the antibody or antigen-binding fragment thereof.
11. A pharmaceutical composition comprising a fusion protein of claim 1 and a pharmaceutically acceptable excipient.