METHODS OF TREATMENT USING ANTIBODIES TO NEUTROKINE-ALPHA

• US 20090068201A1
• Filed: 07/09/2008
• Published: 03/12/2009
• Est. Priority Date: 10/25/1996
• Status: Active Grant

• Current Assignee: Human Genome Sciences Incorporated (GlaxoSmithKline PLC)
• Original Assignee: Human Genome Sciences Incorporated (GlaxoSmithKline PLC)
• Inventors: YU, GUO-LIANG, Ni, Jian, Rosen, Craig A., Ebner, Reinhard
• Granted Patent: US 8,173,122 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C07K 14/52 Cytokines; Lymphokines; Interferons
• CPC Class Codes: C07K 14/715 for cytokines; for lymphokines; for interferons
• CPC Class Codes: C07K 16/24 against cytokines, lymphokines or interferons
• CPC Class Codes: C07K 16/2875 against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: G01N 2333/52 Assays involving cytokines
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2500/02 Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
• CPC Class Codes: G01N 2800/245 : Transplantation related diseases, e.g. graft versus host disease
• CPC Class Codes: G01N 33/564 : for pre-existing immune complex or autoimmune disease , i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
• CPC Class Codes: G01N 33/6863 : Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to a novel Neutrokine-alpha, and a splice variant thereof designated Neutrokine-alphaSV, polynucleotides and polypeptides which are members of the TNF family. In particular, isolated nucleic acid molecules are provided encoding the human Neutrokine-alpha and/or Neutrokine-alphaSV polypeptides, including soluble forms of the extracellular domain. Neutrokine-alpha and/or Neutrokine-alphaSV polypeptides are also provided as are vectors, host cells and recombinant methods for producing the same. The invention further relates to screening methods for identifying agonists and antagonists of Neutrokine-alpha and/or Neutrokine-alphaSV activity. Also provided are diagnostic methods for detecting immune system-related disorders and therapeutic methods for treating immune system-related disorders.

Claims

1. A method of treating, preventing or ameliorating a cancer comprising administering to a patient in need thereof a Neutrokine-alpha antagonist in an amount effective to treat, prevent or ameliorate the cancer.

2. The method of claim 1 wherein the Neutrokine-alpha antagonist is selected from the group consisting of:

(a) an anti-Neutrokine-alpha antibody;

(b) a Neutrokine-alpha-binding peptide;

(c) a Neutrokine-alpha protein variant; and

(d) an anti-Neutrokine-alpha receptor antibody.

3. The method of claim 2 wherein the Neutrokine-alpha antagonist is an anti-Neutrokine-alpha antibody.

4. The method of claim 1 wherein the cancer is a B cell cancer.

5. The method of claim 4 wherein the B cell cancer is selected from the group consisting of:

(a) Waldenstrom'"'"'s Macroglobulinemia;

(b) acute lymphocytic leukemia;

(c) chronic lymphocytic leukemia;

(d) non-Hodgkin'"'"'s lymphoma; and

(e) multiple myeloma.

6. The method of claim 1, further comprising administration of one or more agents employed for treating, preventing or ameliorating cancer, to a patient in need thereof.

7. The method of claim 6 wherein the Neutrokine-alpha antagonist is selected from the group consisting of:

(a) an anti-Neutrokine-alpha antibody;

(b) a Neutrokine-alpha-binding peptide;

(c) a Neutrokine-alpha protein variant; and

(d) an anti-Neutrokine-alpha receptor antibody.

8. The method of claim 7 wherein the Neutrokine-alpha antagonist is an anti-Neutrokine-alpha antibody.

9. The method of claim 6 wherein the cancer is a B cell cancer.

10. The method of claim 9 wherein the B cell cancer is selected from the group consisting of:

(a) Waldenstrom'"'"'s Macroglobulinemia;

(b) acute lymphocytic leukemia;

(c) chronic lymphocytic leukemia;

(d) non-Hodgkin'"'"'s lymphoma; and

(e) multiple myeloma.

11. The method of claim 6 wherein the one or more agents for treating cancer is selected from the group consisting of:

(a) a chemotherapeutic agent;

(b) a steroid;

(c) a cytokine;

(d) a growth factor;

(e) an anti-angiogenic factor; and

(f) radiation therapy.

12. The method of claim 9 wherein the one or more agents for treating B cell cancer is selected from the group consisting of:

(a) an anti-CD20 antibody;

(b) an anti-CD22 antibody;

(c) an anti-HLA-DR antibody; and

(d) CHOP therapy.

13. A method of inhibiting the activation of nuclear factor KB in a cancer cell comprising administering a Neutrokine-alpha antagonist.

14. The method of claim 13 wherein the Neutrokine-alpha antagonist is selected from the group consisting of:

(a) an anti-Neutrokine-alpha antibody;

(b) a Neutrokine-alpha-binding peptide;

(c) a Neutrokine-alpha protein variant; and

(d) an anti-Neutrokine-alpha receptor antibody.

15. The method of claim 14 comprising the steps of treating the cell with a Neutrokine-alpha antagonist in an amount effective to induce radiation sensitivity therein, wherein the Neutrokine-alpha antagonist is an antibody that recognizes Neutrokine-alpha protein, and wherein the Neutrokine-alpha protein is defined by the amino acid sequence of SEQ ID NO:

2, activation of nuclear factor KB in a cancer cell is inhibited and radiation susceptibility is induced.

16. The method of claim 13 wherein the cancer cell is a B cell cancer cell.

17. The method of claim 16 wherein the B cell cancer cell is selected from the group consisting of:

(a) Waldenstrom'"'"'s Macroglobulinemia;

(b) acute lymphocytic leukemia;

(c) chronic lymphocytic leukemia;

(d) non-Hodgkin'"'"'s lymphoma; and

(e) multiple myeloma.

18. A method of inhibiting the activation of nuclear factor KB in cancer cells to thereby induce radiation susceptibility therein, comprising the steps of treating said cells with an inhibitor of THANK protein in an amount effective to induce radiation sensitivity therein, wherein the THANK inhibitor is an antibody that recognizes THANK protein, and wherein said THANK protein is defined by the amino acid sequence of SEQ ID NO:

1.

19. The method of claim 18 wherein the cancer cells are is selected from the group consisting of follicular lymphomas, carcinomas with p53 mutations, hormone-dependent tumors, colon cancer, cardiac tumors, pancreatic cancer, melanoma, retinoblastoma, glioblastoma, lung cancer, intestinal cancer, testicular cancer, stomach cancer, neuroblastoma, myxoma, myoma, lymphoma, endothelioma, osteoblastoma, osteoclastoma, osteosarcoma, chondrosarcoma, adenoma, breast cancer, prostate cancer, Kaposi'"'"'s sarcoma, ovarian cancer, and B cell cancers.

20. The method of claim 19 wherein the B cell cancers are selected from the group consisting of:

(a) Waldenstrom'"'"'s Macroglobulinemia;

(b) acute lymphocytic leukemia;

(c) chronic lymphocytic leukemia;

(d) non-Hodgkin'"'"'s lymphoma; and

(e) multiple myeloma.