Methods for upregulating immune responses using combinations of anti-RGMb and anti-PD-1 agents

1. A method of treating a subject having a cancer or an infection comprising administering to the subject a therapeutically effective amount of at least one agent that selectively inhibits or blocks the expression or activity of both RGMb and PD-1, wherein the at least one agent is a bispecific or multispecific antibody, or antigen binding fragment thereof, selective for both RGMb and PD-1, or

wherein the at least one agent is a combination of agents comprising a first antibody, or an antigen binding fragment thereof, that specifically binds to RGMb, and a second antibody, or an antigen binding fragment thereof, that specifically binds to PD-1,

wherein the antibody that specifically binds to RGMb is selected from the group consisting of 1) anti-RGMb antibodies that block the interaction between a BMP and RGMb without blocking the interaction between PD-L2 and RGMb, 2) anti-RGMb antibodies that block the interaction between NEO1 and RGMb without blocking the interaction between PD-L2 and RGMb, 3) anti-RGMb antibodies that block both the BMP/RGMb interaction and NEO1/RGMb interaction and without blocking the interaction between PD-L2 and RGMb, 4) anti-RGMb antibodies that block the interaction between a BMP and RGMb and block the interaction between PD-L2 and RGMb, 5) anti-RGMb antibodies that block the interaction between NEO1 and RGMb and block the interaction between PD-L2 and RGMb, and 6) anti-RGMb antibodies that block both the BMP/RGMb interaction and NEO1/RGMb interaction and further block the interaction between PD-L2 and RGMb.

2. The method of claim 1 , wherein the antibody that specifically binds PD-1 is selected from the group consisting of anti-PD-1 antibodies that block the interaction between PD-1 and PD- L1 without blocking the interaction between PD-1 and PD-L2; anti-PD-1 antibodies that block the interaction between PD-1 and PD-L2 without blocking the interaction between PD-1 and PD-L1; and anti-PD-1 antibodies that block both the interaction between PD-1 and PD-L1 and the interaction between PD-1 and PD-L2.

3. The method of claim 1 or 2 , wherein said antibody, or antigen binding fragment thereof, is murine, chimeric, humanized, composite, or human.

4. The method of claim 1 or 2 , wherein said antibody, or antigen binding fragment thereof, is detectably labeled, comprises an effector domain, comprises an Fc domain, and/or is selected from the group consisting of Fv, F(ab′)2, Fab′, dsFv, scFv, sc(Fv)2, and diabodies fragments.

5. The method of claim 1 or 2 , wherein said antibody, or antigen binding fragment thereof, is conjugated to a cytotoxic agent.

6. The method of claim 5 , wherein said cytotoxic agent is selected from the group consisting of a chemotherapeutic agent, a biologic agent, a toxin, and a radioactive isotope.

7. The method of claim 1 or 2 , wherein said at least one agent is administered in a pharmaceutically acceptable formulation.

8. The method of claim 1 or 2 , wherein anergy, exhaustion, and/or clonal deletion of immune cells in the subject is reduced.

9. The method of claim 1 or 2 , further comprising administering one or more additional agents or therapies that upregulates an immune response or treats the cancer or infection.

10. The method of claim 9 , wherein the one or more additional agents or therapies is selected from the group consisting of immunotherapy, immune checkpoint inhibition, a vaccine, chemotherapy, radiation, epigenetic modifiers, and targeted therapy.

11. The method of claim 1 or 2 , wherein the subject is a mammal.

12. The method of claim 11 , wherein the mammal is an animal model of the cancer or infection or is a human.

13. The method of claim 11 , wherein the mammal is a human.