Interferon-antibody fusion proteins demonstrating potent apoptotic and anti-tumor activities
View Patent ↗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 chimeric construct comprising an interferon attached to an antibody that binds to a tumor associated antigen, wherein the antibody is attached to the interferon by a proteolysis resistant peptide linker, wherein the amino acid sequence of the linker is AEAAAKEAAAKAGS (SEQ ID NO:82), and wherein the construct when contacted to a tumor cell results in the killing, or the inhibition of growth or proliferation of the tumor cell.
2. The construct of claim 1 , wherein said interferon is a type 1 interferon.
3. The construct of claim 1 , wherein said interferon is a type 2 interferon.
4. The construct of claim 1 , wherein said interferon is an interferon alpha.
5. The construct of claim 1 , wherein said interferon is an interferon beta.
6. The construct of claim 1 , wherein said construct comprises a recombinantly expressed fusion protein.
7. The construct of claim 1 , wherein said antibody is an antibody selected from the group consisting of a single chain Fv (scFv), a FAB, a (Fab′) 2 , an (ScFv) 2 , and a full immunoglobulin.
8. The construct of claim 1 , wherein said antibody is an antibody that specifically binds a marker selected from the group consisting of CD20, HER3, HER2/neu, MUC-1, G250, CD33, mesothelin, gp100, tyrosinase, and MAGE.
9. The construct of claim 1 , wherein said antibody is an antibody that binds CD20.
10. The construct of claim 9 , wherein said antibody is an antibody that comprises the complementarity determining regions (CDRs) of anti-CD20 (rituximab).
11. The construct of claim 9 , wherein said antibody is an antibody that comprises the variable regions of anti-CD20 (rituximab).
12. The construct of claim 11 , wherein said interferon is interferon alpha.
13. The construct of claim 11 , wherein said interferon is interferon beta.
14. The construct of claim 9 , wherein said antibody is rituximab.
15. The construct of claim 14 , wherein said interferon is interferon alpha.
16. The construct of claim 14 , wherein said interferon is interferon beta.
17. The construct of claim 1 , wherein, wherein said antibody is an antibody that binds a member of the EGF receptor family.
18. The construct of claim 17 , wherein said antibody is an antibody that binds HER2.
19. The construct of claim 18 , wherein said antibody is a C6 antibody.
20. The construct of claim 19 , wherein said antibody is selected from the group consisting of C6.5, C6ML3-9, C6MH3-B1, and C6-B1D2.
21. The construct of claim 17 , wherein said antibody is selected from the group consisting of F5, HER3.F4, HER3.H1, HER3.H3, HER3.E12, HER3.B12, EGFR.E12, EGFR.C10, EGFR.B11, and EGFR.E8.
22. The construct of claim 1 wherein said antibody is an antibody selected from the group consisting of IF5, B1, 1H4, CD19, B4, B43, FVS191, hLL2, LL2, RFB4, M195, HuM195, AT13/5, Herceptin, 4D5, HuCC49, HUCC39ΔCH2 B72.3, 12C10, IG5, H23, BM-2, BM-7, 12H12, MAM-6, HMFG-1.
23. The construct of claim 1 , wherein said antibody is M195 or HuM195.
24. The construct 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.
25. A pharmaceutical formulation comprising a construct according to any one of claims 1 - 24 in a pharmaceutically acceptable excipient.
26. The pharmaceutical formulation according to claim 25 , wherein said formulation is a unit dosage formulation.
27. The pharmaceutical formulation according to claim 25 , wherein said formulation is a formulated for parenteral administration.
28. The pharmaceutical formulation according to claim 25 , wherein said formulation is a formulated for administration via a route selected from the group consisting of oral administration, intravenous administration, intramuscular administration, direct tumor administration, inhalation, rectal administration, vaginal administration, transdermal administration, and subcutaneous depot administration.