Agents that modulate immune cell activation and methods of use thereof
The present invention relates to compositions and methods for the immunomodulation mediated by the interaction of PD-L2 and RGMb.
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.