Agents that modulate immune cell activation and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10457733-B2
Application number	US-201314418548-A
Country	US
Kind code	B2
Filing date	Aug 2, 2013
Priority date	Aug 3, 2012
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

The present invention relates to compositions and methods for the immunomodulation mediated by the interaction of PD-L2 and RGMb.

First claim

What is claimed is:

1. A method for upregulating an immune response comprising contacting a cell expressing RGMb with an agent that inhibits the interaction of PD-L2 with RGMb to thereby upregulate the immune response, wherein the agent is a blocking monoclonal antibody that binds RGMb, or an antigen-binding fragment thereof, comprising six CDRs: CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3, wherein the CDR-L1 sequence consists of amino acid residues 44-54 of SEQ ID NO:12, CDR-L2 sequence consists of amino acid residues 70-76 of SEQ ID NO:12, the CDR-L3 sequence consists of amino acid residues 109-116 of SEQ ID NO:12, the CDR-H1 sequence consists of amino acid residues 50-54 of SEQ ID NO:14, the CDR-H2 sequence consists of amino acid residues 69-85 of SEQ ID NO:14, and the CDR-H3 sequence consists of amino acid residues 118-125 of SEQ ID NO:14.

2. A method of treating a subject having a condition that would benefit from upregulation of an immune response comprising administering to the subject an agent that inhibits the interaction between RGMb and PD-L2 such that the condition that would benefit from upregulation of an immune response is treated, wherein the agent is a blocking monoclonal antibody that binds RGMb, or an antigen-binding fragment thereof, comprising six CDRs: CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3, wherein the CDR-L1 sequence consists of amino acid residues 44-54 of SEQ ID NO:12, CDR-L2 sequence consists of amino acid residues 70-76 of SEQ ID NO:12, the CDR-L3 sequence consists of amino acid residues 109-116 of SEQ ID NO:12, the CDR-H1 sequence consists of amino acid residues 50-54 of SEQ ID NO:14, the CDR-H2 sequence consists of amino acid residues 69-85 of SEQ ID NO:14, and the CDR-H3 sequence consists of amino acid residues 118-125 of SEQ ID NO:14.

3. The method of claim 2 , wherein the condition that would benefit from upregulation of an immune response is selected from the group consisting of cancer, a viral infection, a bacterial infection, a protozoan infection, a helminth infection, asthma associated with impaired airway tolerance, a neurological disease, multiple sclerosis, and an immunosuppressive disease.

4. The method of claim 1 , wherein the cell expressing RGMb is an immune cell.

5. The method of claim 4 , wherein the immune cell is selected from the group consisting of a T cell, a B cell, and a myeloid cell.

6. The method of claim 1 , wherein anergy, exhaustion, and/or clonal deletion is reduced in the cell by upregulating the immune response.

7. The method of claim 1 , further comprising contacting the cell with one or more additional agents that upregulates an immune response.

8. The method of claim 1 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable sequence with at least about 97% identity to SEQ ID NO:14 and a light chain sequence with at least about 97% identity to SEQ ID NO:12.

9. The method of claim 8 , wherein the antigen-binding fragment thereof is selected from the group consisting of Fv, Fav, F(ab′)2, Fab′, dsFv, scFv, sc(Fv)2, and diabodies fragments.

10. The method of claim 8 , wherein the blocking antibody that binds RGMb inhibits the interaction of RGMb with BMP-2/4.

11. The method of claim 8 , wherein the blocking antibody that binds RGMb comprises the heavy chain variable sequence of SEQ ID NO:14 and the light chain sequence of SEQ ID NO:12.

12. The method of claim 2 , further comprising administering the subject one or more additional agents that upregulates an immune response.

13. The method of claim 2 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable sequence with at least about 97% identity to SEQ ID NO:14 and a light chain sequence with at least about 97% identity to SEQ ID NO:12.

14. The method of claim 13 , wherein the antigen-binding fragment thereof is selected from the group consisting of Fv, Fav, F(ab′) 2 , Fab′, dsFv, scFv, sc(Fv)2, and diabodies fragments.

15. The method of claim 13 , wherein the blocking antibody that binds RGMb inhibits the interaction of RGMb with BMP-2/4.

16. The method of claim 13 , wherein the blocking antibody that binds RGMb
i) inhibits induction of respiratory tolerance;
ii) promotes T cell proliferation;
iii) promotes IL-4 production; and/or
iv) impairs T cell expansion to antigen in the subject.

17. The method of claim 16 , wherein PD-1:PD-L2 signaling is not needed.

18. The method of claim 13 , wherein the blocking antibody that binds RGMb comprises the heavy chain variable sequence of SEQ ID NO:14 and the light chain sequence of SEQ ID NO:12.

Assignees

• Dana Farber Cancer Inst Inc
• Boston Childrens Hospital
• Harvard College

Inventors

• Freeman Gordon J
• Sharpe Arlene H
• Xiao Yanping
• Francisco Loise
• Dekruyff Rosemarie
• Umetsu Dale

Classifications

• C07K16/28

  against receptors, cell surface antigens or cell surface determinants · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• G01N33/5047

  Cells of the immune system · CPC title

• G01N33/5041

  involving analysis of members of signalling pathways · CPC title