Compositions, kits, and methods for the diagnosis prognosis, monitoring, treatment and modulation of post-transplant lymphoproliferative disorders and hypoxia associated angiogenesis disorders using galectin-1

Patent metadata

Field	Value
Publication number	US-10456465-B2
Application number	US-201514598405-A
Country	US
Kind code	B2
Filing date	Jan 16, 2015
Priority date	Nov 13, 2009
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

The present invention is based, in part, on the discovery that galectin-1 (Gal1) plays a role in viral-associated PTLD, e.g., EBV-associated PTLD and hypoxia associated angiogenesis disorders. Accordingly, the invention relates to compositions, kits, and method for diagnosing, prognosing, monitoring, treating and modulating viral-associated PTLD, e.g., EBV-associated PTLD and hypoxia associated angiogenesis disorders.

First claim

What is claimed is:

1. A method for treating a human subject afflicted with a post-transplant lymphoproliferative disorder (PTLD) in which lymphocytes are infected with a virus, are overproduced, and overexpress wild-type galectin 1 (Gal1) comprising administering an anti-Gal1 monoclonal antibody or antigen-binding fragment thereof comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein CDR-H1 consists of residues 31-35 of SEQ ID NO: 7, CDR-H2 consists of residues 50-66 of SEQ ID NO: 7, CDR-H3 consists of residues 99-107 of SEQ ID NO: 7, CDR-L1 consists of residues 23-36 of SEQ ID NO: 9, CDR-L2 consists of residues 52-58 of SEQ ID NO: 9, and CDR-L3 consists of residues 91-99 of SEQ ID NO: 9.

2. The method of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof, comprises the heavy chain variable domain sequence of SEQ ID NO: 7.

3. The method of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof, comprises the light chain variable domain sequence of SEQ ID NO: 9.

4. The method of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof, comprises the heavy chain variable domain sequence of SEQ ID NO: 7 and the light chain variable domain sequence of SEQ ID NO: 9.

5. The method of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof, inhibits Gal1-induced T cell apoptosis, stimulates IFN-γ production of lymph node cells in the presence of melanoma cells, stimulates IL-17 production of lymph node cells in the presence of melanoma cells, stimulates intratumoral CD8+ T cell influx in a melanoma tumor, inhibits endothelial cell proliferation induced by Gal1, inhibits endothelial cell migration induced by Gal1, inhibits capillary tube formation induced by Gal1, inhibits melanoma tumor hypoxia, inhibits angiogenesis, increases blood vessel pericyte coverage, or increases pericyte maturation.

6. The method of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof, is a humanized antibody, a chimeric antibody, a Fab fragment, a F(ab′) 2 fragment, or an Fv fragment.

7. The method of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof, is an IgG, IgG1, IgG2, IgG2A, IgG2B, IgG3, IgG4, IgA, IgM, or IgE.

8. The method of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof, is conjugated to an agent selected from the group consisting of a cytotoxic agent, a drug, and a radioactive material.

9. The method of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof, is in a pharmaceutically acceptable carrier.

10. The method of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof, is produced by the hybridoma 14-19 8F4-F8-G7 deposited under accession number PTA-10535.

11. The method of claim 1 , further comprising determining the progress, outcome, or efficacy of the administered monoclonal antibody, or antigen-binding fragment thereof, for treating the PTLD in the subject by measuring at least one criteria selected from the group consisting of survival until mortality, pathological complete response, clinical complete remission, clinical partial remission, clinical stable disease, recurrence-free survival, metastasis free survival, and disease free survival.

12. A method for upregulating an immune response in a human subject afflicted with a post-transplant lymphoproliferative disorder (PTLD) in which lymphocytes are infected with a virus, are overproduced, and overexpress wild-type galectin 1 (Gal1) comprising administering to the subject an anti-Gal1 monoclonal antibody or antigen-binding fragment thereof comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein CDR-H1 consists of residues 31-35 of SEQ ID NO: 7, CDR-H2 consists of residues 50-66 of SEQ ID NO: 7, CDR-H3 consists of residues 99-107 of SEQ ID NO: 7, CDR-L1 consists of residues 23-36 of SEQ ID NO: 9, CDR-L2 consists of residues 52-58 of SEQ ID NO: 9, and CDR-L3 consists of residues 91-99 of SEQ ID NO: 9.

13. The method of claim 12 , wherein the monoclonal antibody, or antigen-binding fragment thereof, comprises the heavy chain variable domain sequence of SEQ ID NO: 7.

14. The method of claim 12 , wherein the monoclonal antibody, or antigen-binding fragment thereof, comprises the light chain variable domain sequence of SEQ ID NO: 9.

15. The method of claim 12 , wherein the monoclonal antibody, or antigen-binding fragment thereof, comprises the heavy chain variable domain sequence of SEQ ID NO: 7 and the light chain variable domain sequence of SEQ ID NO: 9.

16. The method of claim 12 , wherein the monoclonal antibody, or antigen-binding fragment thereof, inhibits Gal1-induced T cell apoptosis, stimulates IFN-γ production of lymph node cells in the presence of melanoma cells, stimulates IL-17 production of lymph node cells in the presence of melanoma cells, stimulates intratumoral CD8+ T cell influx in a melanoma tumor, inhibits endothelial cell proliferation induced by Gal1, inhibits endothelial cell migration induced by Gal1, inhibits capillary tube formation induced by Gal1, inhibits melanoma tumor hypoxia, inhibits angiogenesis, increases blood vessel pericyte coverage, or increases pericyte maturation.

17. The method of claim 12 , wherein the monoclonal antibody, or antigen-binding fragment thereof, is a humanized antibody, a chimeric antibody, a Fab fragment, a F(ab′) 2 fragment, or an Fv fragment.

18. The method of claim 12 , wherein the monoclonal antibody, or antigen-binding fragment thereof, is an IgG, IgG1, IgG2, IgG2A, IgG2B, IgG3, IgG4, IgA, IgM, or IgE.

19. The method of claim 12 , wherein the monoclonal antibody, or antigen-binding fragment thereof, is conjugated to an agent selected from the group consisting of a cytotoxic agent, a drug, and a radioactive material.

20. The method of claim 12 , wherein the monoclonal antibody, or antigen-binding fragment thereof, is in a pharmaceutically acceptable carrier.

21. The method of claim 12 , wherein the monoclonal antibody, or antigen-binding fragment thereof, is produced by the hybridoma 14-19 8F4-F8-G7 deposited under accession number PTA-10535.

22. The method of claim 12 , further comprising contacting the immune cell with an additional agent that upregulates an immune response.

Assignees

• Dana Farber Cancer Inst Inc
• Brigham & Womens Hospital Inc
• Consejo Nacional De Investigaciones Cientificas Y Tecn Conicet
• Fund Sales

Inventors

• Shipp Margaret A
• Ouyang Jing
• Takeyama Kunihiko
• Kutok Jeffery L
• Rodig Scott J
• Rabinovich Gabriel
• Russo Diego Omar Croci
• Salatino Mariana

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title