Pidilizumab monoclonal antibody therapy following stem cell transplantation

• US 9,580,504 B1
• Filed: 11/07/2014
• Issued: 02/28/2017
• Est. Priority Date: 11/07/2013
• Status: Active Grant

• Current Assignee: CureTech Ltd. (Clal Biotechnology Industries Ltd.)
• Original Assignee: CureTech Ltd. (Clal Biotechnology Industries Ltd.)
• Inventors: Rotem-Yehudar, Rinat, Schickler, Michael
• Primary Examiner(s): Reddig, Peter J
• Application Number:
  US14/536,343
• Time in Patent Office: 844 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2035/122 for inducing tolerance or supression of immune responses
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 35/51 Umbilical cord; Umbilical cord blood; Umbilical stem cells
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]

Abstract

Methods for treating specific populations of cancer patients, specifically patients suffering from cancer who undergo stem cell transplantation and were classified as positive by a pre-transplant metabolic imaging, by administering to the subject a therapeutically effective amount of a pidilizumab monoclonal antibody.

Claims

1. An immunotherapy method of treating non-Hodgkin'"'"'s lymphoma in a human subject suffering from non-Hodgkin'"'"'s lymphoma and requiring stem cell transplantation, comprising the steps of:

performing a pre-transplant metabolic imaging;

classifying the subject as positive by the metabolic imaging;

administering following stem cell transplantation to the subject a therapeutically effective amount of a pidilizumab monoclonal antibody or a fragment thereof comprising a light chain variable region comprising CDRs having the sequences SEQ. ID NO. 13, SEQ. ID NO. 14 and SEQ. ID NO. 15 and a heavy chain variable region comprising CDRs having the sequences;

SEQ. ID NO. 16, SEQ. ID NO. 17 and SEQ. ID NO. 18, so as to thereby treat non-Hodgkin'"'"'s lymphoma or extend progression-free or overall survival in the subject, wherein said subject is classified as positive by a pre-transplant metabolic imaging; and

wherein the first administration of the antibody is within 2-12 weeks after the stem cell transplantation.

2. The method of claim 1, wherein said fragment of pidilizumab monoclonal antibody is selected from the group consisting of:

Fab, Fab′

, F(ab′

)₂, Fv;

single-chain antibody molecules and multi-specific antibodies formed from antibody fragments.

3. The method of claim 1, wherein the pidilizumab monoclonal antibody comprises a light chain variable region as set forth in SEQ ID NO:

22 (BATRκ

_D) and a heavy chain variable region as set forth in SEQ ID NO;

25 (BATRH_C).

4. The method of claim 1, wherein the pidilizumab monoclonal antibody comprises a light chain variable region selected from the group consisting of:

BATRκ

a (SEQ. ID NO.

     19), BATRκ

b (SEQ. ID NO.

     20), BATRκ

c (SEQ. ID NO.

     21), BATRκ

d (SEQ. ID NO.

     22), and the heavy chain variable region is selected from the group consisting of;

BATRH_A (SEQ. ID NO.

     23), BATRH_B (SEQ. ID NO.

     24), BATRH_C (SEQ. ID NO.

     25), BATRH_D (SEQ. ID NO.

     26) and BATRH_E (SEQ. ID NO.

     27).

5. The method of claim 1, wherein the pidilizumab monoclonal antibody comprises a variable region selected from the group consisting of:

BATRHA/BATRκ

a (SEQ. ID NO. 23/SEQ. ID NO.

     19), BATRH_B/BATRκ

a (SEQ. ID NO. 24/SEQ. ID NO.

     19), BATRH_B/BATRκ

b (SEQ. ID NO. 24/SEQ. ID NO.

     20), BATRH_C/BATRκ

b (SEQ. ID NO. 25/SEQ. ID NO.

     20), BATRH_B/BATRκ

d (SEQ. ID NO. 24/SEQ. ID NO.

     22), and BATRH_C/BATRκ

d (SEQ. ID NO. 25/SEQ. ID NO.

     22).

6. The method of claim 1, wherein the stem cell transplantation is autologous stem cell transplantation.

7. The method of claim 1, wherein the stem cell transplantation is allogeneic stem cell transplantation.

8. The method of claim 1, wherein stem cells for said stem cell transplantation are derived from umbilical cord.

9. The method of claim 1, wherein the metabolic imaging is selected from PET imaging and Ga imaging.

10. The method of claim 1, wherein the non-Hodgkin'"'"'s lymphoma is selected from the group consisting of:

Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, mycosis fungoides, anaplastic large cell lymphoma, precursor T-lymphoblastic lymphoma, AIDS-Related Lymphomas, Angioimmunoblastic Lymphoma, Blastic NK-Cell Lymphoma, Cutaneous T-Cell Lymphoma, Enteropathy-Type T-Cell Lymphoma, Hepatosplenic Gamma-Delta T-Cell Lymphoma, Lymphoblastic Lymphoma, Marginal Zone Lymphoma, Nasal T-Cell Lymphoma, Pediatric Lymphoma, Peripheral T-Cell Lymphomas, Primary Central Nervous System Lymphoma, T-Cell Leukemias, Transformed Lymphomas, Treatment-Related T-Cell Lymphomas and Waldenstrom'"'"'s Macroglobulinemia.

11. The method of claim 1, wherein the non-Hodgkin'"'"'s lymphoma is selected from the group consisting of:

diffuse large B cell lymphoma, primary mediastinal B-cell lymphoma and transformed indolent B cell non-Hodgkin'"'"'s lymphoma.

12. The method of claim 1, wherein the pidilizumab monoclonal antibody or fragment thereof is administered via intravenous infusion.

13. The method of claim 1, wherein the pidilizumab monoclonal antibody is administered periodically.

14. The method of claim 13, wherein the antibody is periodically administered according to an administration regime selected from the group consisting of:

between 1-30 times within a period of 24 months following the stem cell transplantation;

administration between 1-30 times within a period of 18 months following the stem cell transplantation;

between 1-12 times within a period of 18 months following the stem cell transplantation;

at least 3 times within a period of 18 months following the stem cell transplantation;

3 times within a period of 18 weeks;

3 times within a period of 12 weeks;

6 times within a period of 24 weeks;

12 times within a period of 24 weeks;

12 times within a period of 48 weeks; and

27 times within a period of 54 weeks.

15. The method of claim 13, wherein the periodic administration is every two-six weeks.

16. The method of claim 1, wherein the therapeutically effective amount is 1-6 mg/kg.

17. The method of claim 1, wherein the subject is diagnosed as having a measurable disease after the stem cell therapy.

18. The method of claim 1, further comprising administering at least one additional anti-cancer agent selected from the group consisting of:

an anti-metabolic agent, an anti-angiogenic agent, a cytotoxic agent, anti-tumor therapeutic antibodies and cell based therapies and combinations thereof.

19. The method of claim 18, wherein the anti-tumor therapeutic antibody is Rituximab.

20. The method of claim 18, wherein said therapeutically effective amount of pidilizumab monoclonal antibody and said at least one therapeutic agent are administered together or sequentially.

21. The method of claim 1, wherein said treating or enhancing survival is associated with an increase in the level of circulating lymphocytes selected from the group consisting of:

CD14+PD-L1+, CD14+PD-L2+ and a combination thereof.

22. The method of claim 1, wherein a first administration of the antibody is within 4-12 weeks after the stem cell transplantation.

23. The method of claim 22, wherein second and third administrations of the antibody are carried out in 6-weeks intervals.