Targeted interferons 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 chimeric construct comprising a mutant interferon attached to an antibody that binds to a tumor-associated antigen, wherein:
said antibody is a full-length antibody that binds a tumor-associated antigen;
said antibody is attached to said mutant interferon by a peptide linker, the amino acid sequence of said linker consisting of the sequence SGGGGS (SEQ ID NO:81) or AEAAAKEAAAKAGS (SEQ ID NO:82);
said mutant interferon is a mutant interferon alpha where the mutations in said mutant interferon consist of one or more mutations selected from the group consisting of H57Y, E58N, and Q61S wherein the position is relative to the human wildtype interferon α2; and
wherein the construct when contacted to a tumor cell results in the killing or the inhibition of the growth or proliferation of the tumor cell.
2. The chimeric construct of claim 1 , wherein said antibody is an anti-CD20 antibody.
3. The chimeric construct of claim 1 , wherein said antibody is an anti-HER2 antibody.
4. The chimeric construct of claim 1 , wherein said antibody is an anti-CD33 antibody.
5. The chimeric construct of claim 2 , wherein the mutant interferon comprises mutations H57Y, E58N, and Q61S.
6. The chimeric construct of claim 3 , wherein the mutant interferon comprises mutations H57Y, E58N, and Q61S.
7. The chimeric construct of claim 4 , wherein the mutant interferon comprises mutations H57Y, E58N, and Q61S.
8. The chimeric construct of claim 1 , wherein the chimeric construct has reduced anti-proliferative activity against cells lacking expression of said tumor-associated antigen compared to the mutant interferon not attached to an antibody that binds the tumor-associated antigen.
9. The chimeric construct of claim 1 , wherein the chimeric construct has enhanced anti-proliferative activity against cells expressing said tumor-associated antigen compared to the mutant interferon not attached to an antibody that binds the tumor-associated antigen.
10. The chimeric construct of claim 1 , wherein the mutant interferon retains at least 80% biological activity of the wildtype interferon.
11. The chimeric construct of claim 1 , wherein the antibody is an antibody that specifically binds to tumor-associated antigen selected from the group consisting of CD20, HER3, HER2/neu, mucin 1 (MUC-1), G250, CD33, mesothelin, gp100, tyrosinase, and melanoma-associated antigen (MAGE).