Interferon-antibody fusion proteins demonstrating potent apoptotic and anti-tumor activities
Novel chimeric moieties that show significant efficacy against cancers are provided. In certain embodiments the chimeric moieties comprise a targeting moiety attached to an interferon. In certain embodiments, the chimeric moieties comprise fusion proteins where an antibody that specifically binds to a cancer marker is fused to interferon alpha (IFN-α) or interferon beta (IFN-β).
1. A composition comprising an interferon attached to a full-length antibody that binds to an antigen expressed in or associated with a cell, wherein the antibody is attached to the interferon by a proteolysis resistant peptide linker, wherein the amino acid sequence of the linker is SGGGGS (SEQ ID NO: 81), and wherein the antibody attached to an interferon, when contacted to a tumor cell, results in the killing or inhibition of growth or proliferation of the tumor cell.
2. The composition of claim 1 , wherein said interferon is a type 1 interferon.
3. The composition of claim 1 , wherein said interferon is an interferon alpha.
4. The composition of claim 1 , wherein said interferon is an interferon beta.
5. The composition of claim 1 , wherein said interferon is a type 2 interferon.
6. The composition of claim 1 , wherein said linker joins said interferon to the C terminus of the full-length heavy chain of said antibody.
7. The composition of claim 1 , wherein the killing or inhibition of growth or proliferation activity of said construct is at least 2-fold greater in vitro against a cell expressing the target marker than the same interferon not attached to a targeting moiety.
8. The composition of claim 1 , wherein the antigen is a cancer marker.
9. The composition of claim 1 , wherein said antibody specifically binds a marker selected from the group consisting of CD20, HER3, HER2/neu, MUC-1, G250, mesothelin, gp100, tyrosinase, and MAGE.
10. The composition of claim 1 , wherein said antibody is an antibody that binds CD20.
11. The composition of claim 1 , wherein the antibody is an anti-CD20 antibody, and the interferon is IFNα or IFNβ.
12. The composition of claim 1 , wherein said antibody is an antibody that comprises the complementarity determining regions (CDRs) of anti-CD20 rituximab.
13. The composition of claim 12 , wherein said antibody is an antibody that comprises the variable regions of anti-CD20 rituximab.
14. The composition of claim 1 , wherein the antibody is selected from the group consisting of rituximab, IF5, B1, 1H4, CD19, B4, B43, FVS191, hLL2, LL2, RFB4, M195, HuM195, AT13/5, trastuzumab, 4D5, HuCC49, HUCC39ΔCH2 B72.3, 12C10, IG5, H23, BM-2, BM-7, 12H12, MAM-6, HMFG-1, of C6.5, C6ML3-9, C6 MH3-B1, C6-B1D2, F5, HER3.A5, HER3.F4, HER3.H1, HER3.H3, HER3.E12, HER3.B12, EGFR.E12, EGFR.C10, EGFR.B11, EGFR.E8, HER4.B4, HER4.G4, HER4.F4, HER4.A8, HER4.B6, HER4.D4, HER4.D7, HER4.D11, HER4.D12, HER4.E3, HER4.E7, HER4.F8 and HER4.C7.
15. The composition of claim 14 , wherein the antibody is rituximab.
16. A kit comprising the composition of claim 1 .
17. An isolated nucleic acid encoding the full-length heavy chain of an antibody attached through the C terminus of said antibody by a linker to an interferon wherein the amino acid sequence of said linker is SGGGGS (SEQ ID NO: 81).
18. A plasmid comprising the isolated nucleic acid of claim 17 .
19. An isolated host cell comprising the isolated nucleic acid of claim 17 .