Neutrokine-alpha and neutrokine-alpha splice variant

• US 20050186637A1
• Filed: 02/10/2005
• Published: 08/25/2005
• Est. Priority Date: 03/02/1999
• Status: Active Grant

• Current Assignee: Human Genome Sciences Incorporated (GSK plc)
• Original Assignee: Human Genome Sciences Incorporated (GSK plc)
• Inventors: Yu, Guo-Liang, Ni, Jian, Rosen, Craig A., Ebner, Reinhard, Ullrich, Stephen
• Granted Patent: US 8,212,004 B2
• Time in Patent Office: Days
• US Class Current: 435/7.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• 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 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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 14/70575 NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154 NGF C07K14/48, TNF C07K14/525
• 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 2317/21 from primates, e.g. man
• 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 2800/24 : Immunology or allergic disorders
• 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 33/56972 : White blood cells

Abstract

The present invention relates to nucleic acid molecules encoding 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 antibodies or portions thereof that specifically bind Neutrokine-alpha and/or Neutrokine-alphaSV and diagnostic and therapeutic methods using these antibodies. Also provided are diagnostic methods for detecting immune system-related disorders and therapeutic methods for treating immune system-related disorders using the compositions of the invention.

Claims

1. The hybridoma of ATCC Deposit Number PTA-1158 or PTA-3794.

2. The antibody secreted by the hybridoma of claim 1.

3. An antibody or portion thereof comprising an amino acid sequence of that is at least 90% identical to the amino acid sequence of the VH domain of the antibody of claim 2 (SEQ ID NO:

58) and an amino acid sequence of that is at least 90% identical to the amino acid sequence of the VL domain of the antibody of claim 2 (SEQ ID NO;

59) wherein said antibody or portion thereof specifically binds a Neutrokine-alpha protein wherein said Neutrokine-alpha protein is selected from the group consisting of;

a protein whose amino acid sequence consists of amino acid residues 1-285 of SEQ ID NO;

3228;

a protein whose amino acid sequence consists of amino acid residues 134-285 of SEQ ID NO;

3228; and

a trimer of the protein of (b).

4. The antibody of claim 3 which comprises the amino acid sequence of SEQ ID NO:

58 and the amino acid sequence SEQ ID NO;

59.

5. The antibody or portion thereof of claim 3 which is a monoclonal antibody.

6. The antibody or portion thereof of claim 3 which is a chimeric antibody, a humanized antibody, a single chain antibody, a Fab fragment, or an F(ab′

)2 fragment.

7. The antibody or portion thereof of claim 3 which is labeled.

8. The antibody or portion thereof of claim 7 which is labeled with an enzyme label, a radioisotope, a fluorescent label, or biotin.

9. An isolated cell that produces the antibody of claim 3.

10. A method of detecting Neutrokine-alpha protein in a biological sample comprising:

contacting the biological sample with the antibody or portion thereof of claim 3;

and

detecting the Neutrokine-alpha protein.

15. A method of treating a B cell cancer or an autoimmune disease comprising administering a therapeutically effective amount of the antibody or portion thereof of claim 3 to a patient in need thereof.

16. The method of claim 15 wherein the B cell cancer is selected from the group consisting of Non-Hodgkin'"'"'s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and plasmacytoma.

17. The method of claim 15 wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus multiple sclerosis, myasthenia gravis, Sjogren'"'"'s syndrome, type I diabetes, idiopathic thrombocytopenia purpura, Gullian-Barre syndrome, Hashimoto'"'"'s thyroiditis, or Graves'"'"' disease.

11. An isolated protein comprising a Neutrokine-alpha protein fused to a toxin protein, wherein said Neutrokine-alpha protein comprises an amino acid sequence selected from the group consisting of:

(a) the amino acid sequence of amino acid residues 134-285 of SEQ ID NO;

2;

(b) an amino acid sequence that is at least 90% identical to amino acid residues 134-285 of SEQ ID NO;

2; and

(c) the amino acid sequence of a portion of the polypeptide of SEQ ID NO;

2;

wherein said portion is at least 30 amino acids in length and wherein said portion is capable of stimulating B cell proliferation, differentiation, or survival.

12. The protein of claim 11, wherein said toxin protein is thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, pokeweed antiviral protein, alpha-sarcin, or cholera toxin.

13. An in vitro method of killing a B lymphocyte comprising contacting said B lymphocyte with the protein of claim 11.

14. Use of the protein of claim 11 for the preparation of a medicament for killing B lymphocytes.

18. A method of treating a B cell cancer or an autoimmune disease comprising administering a therapeutically effective amount of the protein of claim 11 to a patient in need thereof.

19. The method of claim 18 wherein the B cell cancer is selected from the group consisting of Non-Hodgkin'"'"'s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and plasmacytoma.

20. The method of claim 18 wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus multiple sclerosis, myasthenia gravis, Sjogren'"'"'s syndrome, type I diabetes, idiopathic thrombocytopenia purpura, Gullian-Barre syndrome, Hashimoto'"'"'s thyroiditis, or Graves'"'"' disease.