Antibodies Specific to Heterodimers of Bcl-2 Family and Uses Thereof

• US 20120225794A1
• Filed: 03/23/2012
• Published: 09/06/2012
• Est. Priority Date: 05/07/2008
• Status: Abandoned Application

• Current Assignee: Eutropics Pharmaceuticals, Inc.
• Original Assignee: Eutropics Pharmaceuticals, Inc.
• Inventors: CARDONE, Michael H., LETAI, Anthony G.
• Application Number:
  US13/428,889
• Publication Number:
  US 20120225794A1
• Time in Patent Office: Days
• US Class Current: 506/9
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: G01N 33/57492 involving compounds localized on the membrane of tumor or cancer cells

Abstract

Isolated antibodies specifically binding to heterodimers of the Bcl-2 family and uses thereof for detecting presence of Bcl-2 heterodimers in a patient.

Claims

1. An isolated antibody specifically binding to a heterodimer of the Bcl-2 family.

2. The isolated antibody of claim 1, wherein the antibody is a whole immunoglobulin selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a chimeric antibody, and a humanized antibody,

3. The isolated antibody of claim 1, wherein the antibody is a fragment of an immunoglobulin, wherein the fragment is selected from the group consisting of F(ab′

)₂, Fab′

, F(ab)₂, and Fab.

4. The isolated antibody of claim 1, wherein the antibody is a single-chain antibody.

5. The isolated antibody of claim 1, wherein the heterodimer contains a first member of the Bcl-2 family selected from the group consisting of Bim, Bid, Bad, Puma, Noxa, Bak, Hrk, Bax, Bird, and Mule, and a second member of the Bcl-2 family selected from the group consisting of Mcl-1, Bcl-2, Bcl-XL, Bfl-1, and Bcl-w.

6. The isolated antibody of claim 5, wherein the first member of the Bcl-2 family is Bim and the second member of the Bcl-2 family is Mcl-1, Bcl-2, or Bcl-XL.

7. The isolated antibody of claim 6, wherein the antibody is a whole immunoglobulin selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a chimeric antibody, and a humanized antibody,

8. The isolated antibody of claim 7, wherein the antibody is a fragment of an immunoglobulin, wherein the fragment is selected from the group consisting of F(ab′

)₂, Fab′

, F(ab)₂, and Fab.

9. The isolated antibody of claim 6, wherein the antibody is a single-chain antibody.

10. A method for detecting the presence of a heterodimer of the Bcl-2 family in a tissue sample, comprising

providing a tissue sample suspected of having a heterodimer of the Bcl-2 family,

contacting an isolated antibody specifically binding to the heterodimer,

detecting a signal that indicates binding of the antibody to the heterodimer, and

determining the presence of the heterodimer in the biosample based on the intensity of the signal.

11. The method of claim 10, wherein the heterodimer of Bcl-2 family contains a first member of the Bcl-2 family selected from the group consisting of Bim, Bid, Bad, Puma, Noxa, Bak, Hrk, Bax, Bmf, and Mule, and a second member of the Bcl-2 family selected from the group consisting of Mcl-1, Bcl-2, Bcl-XL, Bfl-1, and Bcl-w.

12. The method of claim 11, wherein the first member of the Bcl-2 family is Bim and the second member of the Bcl-2 family is Mcl-1, Bcl-XL, or Bcl-2.

13. The method of claim 10, wherein the tissue sample is a peripheral blood sample, a lymph-node sample, a bone marrow sample, or an organ tissue sample.

14. The method of claim 10, wherein the tissue sample is a mitochondrial fraction.

16. The method of claim 14, wherein the heterodimer of Bcl-2 family contains a first member of the Bcl-2 family selected from the group consisting of Bim, Bid, Bad, Puma, Noxa, Bak, Hrk, Bax, and Mule, and a second member of the Bcl-2 family selected from the group consisting of Mcl-1, Bcl-2, Bcl-xL, Bfl-1, and Bcl-w.

17. The method of claim 16, wherein the first member of the Bcl-2 family is Bim and the second member of the Bcl-2 family is Mcl-1 or Bcl-2.

15. A method for assessing whether a patient is sensitive or resistant to a drug that interferes with formation of a heterodimer of the Bcl-2 family, comprising:

providing a tissue sample Obtained from a patient,

contacting the tissue sample with an isolated antibody specifically binding to a heterodimer of the Bcl-2 family,

detecting a signal that indicates binding of the antibody to the heterodimer,

determining the presence of the heterodimer based on the intensity of the signal, and

assessing sensitivity or resistance of the patient to a drug that interferes with formation of the heterodimer based on the presence of the heterodimer.

18. The method of claim 15, wherein the drug induces apoptosis, the patient suffers from a cancer, and the tissue sample contains cancer cells.

19. The method of claim 18, wherein the heterodimer is an anti-apoptotic heterodimer and its presence indicates that the patient is sensitive to the drug.

20. The method of claim 15, wherein the drug inhibits apoptosis and the patient suffers from a neurodegenerative disease or a cardiovascular disease.

21. The method of claim 20, wherein the heterodimer is a pro-apoptotic heterodimer and its presence indicates that the patient is responsive to the drug.