Interferon-antibody fusion proteins demonstrating potent apoptotic and anti-tumor activities

• US 9,139,634 B2
• Filed: 09/19/2008
• Issued: 09/22/2015
• Est. Priority Date: 09/21/2007
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Morrison, Sherie L., Huang, Tzu-Hsuan, Xuan, Caiyun
• Primary Examiner(s): Landsman, Robert
• Assistant Examiner(s): Hissong, Bruce D
• Application Number:
  US12/678,981
• Publication Number:
  US 20100297076A1
• Time in Patent Office: 2,559 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/215 IFN-beta
• CPC Class Codes: A61K 47/6813 the drug being a peptidic cytokine, e.g. an interleukin or interferon
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6855 the tumour determinant being from breast cancer cell
• CPC Class Codes: A61K 47/6875 the antibody being a hybrid immunoglobulin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07K 14/555 Interferons [IFN]
• CPC Class Codes: C07K 14/56 IFN-alpha
• CPC Class Codes: C07K 14/565 IFN-beta
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2319/33 : fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Abstract

This invention provides novel chimeric moieties that show significant efficacy against cancers. 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).

Claims

1. A method of inhibiting growth and/or proliferation of a cancer cell, said method comprising contacting said cancer cell with a chimeric construct comprising a type I interferon attached to a full-length antibody that binds to a tumor-associated antigen, wherein said antibody is attached to said interferon by a peptide linker that is resistant to proteolysis, wherein the amino acid sequence of said peptide linker is SGGGGS (SEQ ID NO:

62) or AEAAAKEAAAKAGS (SEQ ID NO;

63).

2. The method of claim 1, wherein said cancer cell is selected from the group consisting of a cell in a solid tumor, a metastatic cell, a breast cancer cell, and a B cell lymphoma.

3. The method of claim 1, wherein said cancer cell is cell produced by a cancer selected from the group consisting of a B cell lymphoma, lung cancer, a bronchus cancer, a colorectal cancer, a prostate cancer, a breast cancer, a pancreas cancer, a stomach cancer, an ovarian cancer, a urinary bladder cancer, a brain or central nervous system cancer, a peripheral nervous system cancer, an esophageal cancer, a cervical cancer, a melanoma, a uterine or endometrial cancer, a cancer of the oral cavity or pharynx, a liver cancer, a kidney cancer, a biliary tract cancer, a small bowel or appendix cancer, a salivary gland cancer, a thyroid gland cancer, a adrenal gland cancer, an osteosarcoma, a chondrosarcoma, a liposarcoma, a testes cancer, and a malignant fibrous histiocytoma.

4. The method of claim 1, wherein said contacting comprises administration via a route selected from the group consisting of systemic administration, administration directly into a tumor site, and intravenous administration.

5. The method of claim 1, wherein said cancer cell is a cancer cell in a human.

6. The method of claim 1, wherein said cancer cell is a cancer cell in a non-human mammal.

7. The method of claim 1, wherein said antibody is attached to said interferon by a peptide linker wherein the amino acid sequence of said linker is SGGGGS (SEQ ID NO:

62).

8. The method of claim 1, wherein said antibody specifically binds a tumor associated antigen selected from the group consisting of CD20, HER3, HER2/neu, mucin 1 (MUC-1), G250, mesothelin, gp100, tyrosinase, and melanoma-associated antigen (MAGE).

9. The method of claim 1, wherein said antibody is an antibody that binds CD20.

10. The method of claim 1, wherein said antibody is an antibody that comprises the variable regions for anti-CD20 (Rituximab).

11. The method of claim 1, wherein said antibody is an antibody selected form the group consisting of rituximab, IF5, B1, 1H4, CD19, B4, B43, FVS191, hLL2, LL2, RFB4, M195, HuM195, AT13/5, trastuzumab, 4D5, HuCC49, HUCC39Δ

CH2 B72.3, 12C10, IG5, H23, BM-2, BM-7, 12H12, MAM-6, HMFG-1.

12. The method of claim 7, wherein said antibody is an antibody that binds to CD20.

13. The method of claim 7, wherein said antibody is an antibody that binds to HER2.

14. The method according to any one of claim 12 or 13, wherein said interferon is IFN-α

.

15. The method according to any one of claim 12 or 13, wherein said interferon is IFN-β

.

16. The method of claim 1, wherein said antibody is attached to said interferon by a peptide linker wherein the amino acid sequence of said linker is AEAAAKEAAAKAGS (SEQ ID NO:

63).