Antibodies that immunospecifically bind to TRAIL receptors

• US 20060270837A1
• Filed: 03/29/2006
• Published: 11/30/2006
• Est. Priority Date: 05/25/2001
• Status: Active Grant

• Current Assignee: Human Genome Sciences Incorporated (GlaxoSmithKline PLC)
• Original Assignee: Human Genome Sciences Incorporated (GlaxoSmithKline PLC)
• Inventors: Rosen, Craig A., Ruben, Steven M., Albert, Vivian R., Salcedo, Theodora W.
• Granted Patent: US 7,361,341 B2
• Time in Patent Office: Days
• US Class Current: 530/388.800
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Abstract

The present invention relates to antibodies and related molecules that immunospecifically bind to TRAIL receptor, TR4. Such antibodies have uses, for example, in the prevention and treatment of cancers and other proliferative disorders. The invention also relates to nucleic acid molecules encoding anti-TR4 antibodies, vectors and host cells containing these nucleic acids, and methods for producing the same. The present invention relates to methods and compositions for preventing, detecting, diagnosing, treating or ameliorating a disease or disorder, especially cancer and other hyperproliferative disorders, comprising administering to an animal, preferably a human, an effective amount of one or more antibodies or fragments or variants thereof, or related molecules, that immunospecifically bind to TRAIL receptor TR4.

Claims

1. An isolated antibody or fragment thereof comprising:

(a) an amino acid sequence that is at least 90% identical to a VH domain of any one of SEQ ID NOS;

42-53;

(b) an amino acid sequence that is at least 90% identical to a VL domain of any one of SEQ ID NOS;

42-53;

or

(c) both (a) and (b);

wherein said antibody or fragment thereof immunospecifically binds TR4.

2. The antibody or fragment thereof of claim 1 comprising:

(a) the amino acid sequence of a VH domain of any one of SEQ ID NOS;

42-53;

(b) the amino acid sequence of a VL domain of any one of SEQ ID NOS;

42-53;

or

(c) both (a) and (b);

wherein said antibody or fragment thereof immunospecifically binds TR4.

3. The antibody or fragment thereof of claim 1 wherein the antibody or fragment thereof is selected from the group consisting of:

(a) a whole immunoglobulin molecule;

(b) an scFv;

(e) a monoclonal antibody;

(d) a human antibody;

(e) a chimeric antibody;

(f) a humanized antibody;

(g) a Fab fragment;

(h) an Fab′

fragment;

(i) an F(ab′

)2;

(j) an Fv; and

(k) a disulfide linked Fv.

4. The antibody or fragment thereof of claim 2, that binds TR4 expressed on the surface of a cell.

5. The antibody or fragment thereof of claim 1 wherein the antibody or fragment thereof has a dissociation constant (K_D) of less than or equal to 10⁻

9 M.

6. The antibody or fragment thereof of claim 1 wherein the antibody or fragment thereof is conjugated to a detectable label.

7. The antibody or fragment thereof of claim 1 wherein the antibody or fragment thereof is conjugated to a therapeutic or cytotoxic agent.

8. An isolated cell that produces the antibody or fragment thereof of claim 2.

9. The isolated cell of claim 8 selected from the group consisting of:

a) the cell line contained in ATCC Deposit No. PTA-3570;

b) the cell line contained in ATCC Deposit No. PTA-3571; and

c) the cell line contained in ATCC Deposit No. PTA-3675.

10. The antibody or fragment thereof of claim 1 wherein the antibody or fragment thereof is an agonist of TR4.

11. The antibody or fragment thereof of claim 1 wherein the antibody or fragment thereof is an antagonist of TR4.

12. A method of treating, preventing or ameliorating a cancer comprising administering to an animal the antibody or fragment thereof of claim 1 or a composition containing said antibody or fragment thereof.

13. The method of claim 12, wherein the antibody or fragment thereof is administered in combination with a chemotherapeutic agent.

14. The method of claim 13, wherein said chemotherapeutic agent is selected from the group consisting of:

(a) a Heat Shock Protein (HSP) inhibitor;

(b) a synthetic retinoid;

(c) a caseine kinase II inhibitor;

(d) a RAF kinase inhibitor;

(e) a VEGFR inhibitor;

(f) thapsigargin;

(g) a survivin inhibitor; and

(h) thalidomide or a thalidomide analogue.

15. A method of treating, preventing or ameliorating a premalignant condition comprising administering to an animal the antibody or fragment thereof of claim 1 or a composition containing said antibody or fragment thereof.

16. The method of claim 15, wherein the premalignant condition is selected from the group consisting of:

(a) a hyperplasia;

(b) a metaplasia; and

(c) a dysplasia.

17. The method of claim 15, wherein the antibody or fragment thereof is administered in combination with a chemotherapeutic agent.

18. The method of claim 17, wherein said chemotherapeutic agent is selected from the group consisting of:

(a) a Heat Shock Protein (HSP) inhibitor;

(b) a synthetic retinoid;

(c) a caseine kinase II inhibitor;

(d) a RAF kinase inhibitor;

(e) a VEGFR inhibitor;

(f) thapsigargin;

(g) a survivin inhibitor; and

(h) thalidomide or a thalidomide analogue.

19. A method of detecting, diagnosing, prognosing, or monitoring a premalignant condition comprising:

(a) assaying the expression of a TR4 polypeptide in a biological sample from an individual using the antibody or fragment thereof of claim 1;

and

(b) comparing the level of a TR4 polypeptide with a standard level of TR4 polypeptide.

20. A kit comprising the antibody or fragment thereof of claim 1.