METHODS FOR THE TREATMENT OF CANCER AND INFLAMMATORY DISEASES USING CEREBLON AS A PREDICTOR

• US 20120322073A1
• Filed: 04/27/2012
• Published: 12/20/2012
• Est. Priority Date: 04/29/2011
• Status: Active Grant

• Current Assignee: Celgene Corporation (Bristol-Myers Squibb Company)
• Original Assignee: Celgene Corporation (Bristol-Myers Squibb Company)
• Inventors: Lopez-Girona, Antonia, Schafer, Peter H., Gandhi, Anita, Daniel, Thomas O., Mendy, Derek
• Granted Patent: US 9,365,640 B2
• Time in Patent Office: Days
• US Class Current: 435/6.12
• CPC Class Codes: C07K 16/18 against material from animals or humans
• 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 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 Complete light chain, i.e. VL + CL
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 21/6428 Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" in vivo A61B5/00; immunoassay G01N33/53
• CPC Class Codes: G01N 2333/47 Assays involving proteins of known structure or function as defined in the subgroups
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 2800/60 Complex ways of combining multiple protein biomarkers for diagnosis
• CPC Class Codes: G01N 33/57426 leukemia
• CPC Class Codes: G01N 33/5743 of skin, e.g. melanoma
• CPC Class Codes: G01N 33/57484 involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites

Abstract

Uses of the protein cereblon as a predictor of clinical sensitivity to cancer, inflammatory diseases, and patient response to drug treatment.

Claims

1. A method of selecting a group of cancer patients based on the level of CRBN expression, or the levels of DDB1, DDB2, GSK3B, CUL4A, CUL4B, XBP-1, FAS1, RANBP6, DUS3L, PHGDH, AMPK, IRF4 or NFκ

B expression within the cancer, for the purposes of predicting clinical response, monitoring clinical response, or monitoring patient compliance to dosing by thalidomide, lenalidomide, pomalidomide or 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof;

wherein the cancer patients are multiple myeloma, non-Hodgkin'"'"'s lymphoma, diffuse large B-cell lymphoma, melanoma or solid tumor patients.

2. The method of claim 1, wherein the cancer patients are multiple myeloma patients.

3. The method of claim 1, wherein the cancer patients are non-Hodgkin'"'"'s lymphoma patients.

4. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of DDB1 expression within the cancer.

5. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of DDB2 expression within the cancer.

6. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of GSK3B expression within the cancer.

7. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of CUL4A expression within the cancer.

8. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of CUL4B expression within the cancer.

9. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of XBP-1 expression within the cancer.

10. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of FAS1 expression within the cancer.

11. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of RANBP6 expression within the cancer.

12. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of DUS3L expression within the cancer.

13. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of PHGDH expression within the cancer.

14. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of AMPK expression within the cancer.

15. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of IRF4 expression within the cancer.

16. The method of claim 1, wherein the method of selecting a group of cancer patients is based on the level of NFκ

B expression within the cancer.

17. A method of identifying or monitoring multiple myeloma patient resistance to thalidomide, lenalidomide, pomalidomide or 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione therapy, based on the presence or appearance of mutations within a CRBN gene.

18. The method of claim 17, wherein the mutation with the CRBN gene is a single-nucleotide polymorphism in the coding region c.745C>

CA causing an amino acid change 249D>

YD in the protein within the DDB1 binding domain of CRBN.

19. A method of selecting a group of cancer patients responsive to treatment with thalidomide, lenalidomide, pomalidomide or 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof;

based on the level of CRBN expression, or the levels of DDB1, DDB2, GSK3B, CUL4A, CUL4B, XBP-1, FAS1, RANBP6, DUS3L, PHGDH, AMPK, IRF4 or NFκ

B expression within the patient'"'"'s T cells, B cells, or plasma cells, for the purposes of predicting clinical response, monitoring clinical response, or monitoring patient compliance to dosing by thalidomide, lenalidomide, pomalidomide or 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

20. The method of claim 19, wherein the cancer patients are multiple myeloma, non-Hodgkin'"'"'s lymphoma, diffuse large B-cell lymphoma, melanoma or solid tumor patients.

21. The method of claim 20, wherein the cancer patients are multiple myeloma patients.

22. The method of claim 20, wherein the cancer patients are diffuse large B-cell lymphoma patients.

23. The method of claim 22, wherein the diffuse large B-cell lymphoma is of the activated B-cell-like subtype.

24. The method of claim 21, wherein the method of selecting the group of cancer patients is based on the level of CRBN or IRF4 expression within the patient'"'"'s T cells, B cells, or plasma cells.

25. An isolated antibody that immunospecifically binds to an epitope in CRBN, wherein the epitope has the amino acid sequence SEQ ID NO:

1.

26. The isolated antibody of claim 25, wherein the antibody is polyclonal.

31. A method of utilizing the antibody according to claim 25 to measure expression levels of CRBN in patient tumor or host cells, to predict clinical response, monitor clinical response, monitor patient compliance to dosing, or monitor development of resistance to therapy with thalidomide, lenalidomide, pomalidomide, or 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

27. An antibody that immunospecifically binds CRBN, wherein the antibody comprises:

a heavy chain having the amino acid sequence depicted in SEQ ID NO;

5 or 9.

28. An antibody that immunospecifically binds CRBN, wherein the antibody comprises a light chain having the amino acid sequence depicted in SEQ ID NO:

7 or 11.

29. An isolated antibody that comprises a heavy chain having the amino acid sequence depicted in SEQ ID NO:

5 and a light chain having the amino acid sequence depicted in SEQ ID NO;

7.

30. An isolated antibody, comprising a heavy chain having the amino acid sequence depicted in SEQ ID NO:

9 and a light chain having the amino acid sequence depicted in SEQ ID NO;

11.