Engineered antibody-interferon mutant fusion molecules
The field of the present invention relates to genetically engineered fusion molecules, methods of making said fusion molecules, and uses thereof in anti-tumor immunotherapies. More specifically, the present invention relates to fusion molecule constructs wherein a tumor associated antigen (TAA) antibody (Ab) serves as a targeting moiety to selectively deliver a cytokine to a tumor cell for purposes of killing or inhibiting the growth or proliferation of said tumor cell. In various embodiments, the engineered fusion molecules comprise a TAA Ab fused to an interferon-alpha (IFN-α) mutant molecule. The engineered Ab-IFN-α mutant fusion molecules of the present invention demonstrate improved therapeutic index and preserved or increased efficacy as compared to Ab-wildtype IFN-α fusion molecules, and/or demonstrate improved PK properties as compared to Ab-wildtype IFN-α fusion molecules.
1. A genetically engineered fusion molecule comprising a tumor associated antigen (TAA) antibody (Ab) attached to an interferon alpha (IFN-α) mutant molecule, the IFN-α mutant molecule consisting of the amino acid sequence set forth in SEQ ID NO: 13, said amino acid sequence consisting of the two mutations R149A and R162A, and wherein said antibody is attached directed to said IFN-α mutant molecule.
2. A fusion molecule of claim 1 , wherein said fusion molecule demonstrates improved pharmacokinetics (PK) properties as compared to a TAA Ab-wildtypelFN-α fusion molecule.
3. A fusion molecule of claim 1 , wherein said fusion molecule when contacted to a tumor cell results in the killing or inhibition of growth or proliferation of said tumor cell.
4. A fusion molecule of claim 1 , wherein said TAA antibody is an antibody selected from the group consisting of anti-HER2/neu, anti-HER3, anti-HER4, anti-CD4, anti-CD19, anti-CD20, anti-CD22, anti-CD25, anti-CD33, anti-CD138, anti-CD200, anti-CD276, anti-CXCR3, anti-CXCR5, anti-CCR3, anti-CCR4, anti-CCR9, anti-chemoattractant receptor-homologous molecule expressed on T H 2 cells (CRTH2), anti-pro-melanin-concentrating hormone (PMCH), and anti-endoplasmin antibody.
5. A fusion molecule of claim 1 , wherein said TAA antibody is an anti-HER2/neu antibody.
6. A fusion molecule of claim 1 , wherein said TAA antibody is an anti-CD20antibody.
7. A fusion molecule of claim 1 , wherein said TAA antibody is an anti-CD138antibody.
8. A fusion molecule of claim 1 , wherein said TAA antibody is an anti-endoplasmin antibody.
9. A fusion molecule of claim 1 , wherein said TAA antibody is an anti-CD33antibody.
10. A fusion molecule of claim 1 , wherein said TAA antibody is an anti-CD276antibody.
11. A fusion molecule of claim 1 , wherein said antibody is directly joined to said interferon mutant molecule with a peptide linker, wherein said peptide linker is selected from the group consisting of SGGGGS (SEQ ID NO: 14) and AEAAAKEAAAKAGS (SEQ ID NO: 15).
12. A pharmaceutical composition comprising a fusion molecule of claim 1 in a pharmaceutically acceptable carrier.