Enhanced depletion of targeted cells with CD47 blockade and an immune costimulatory agonist
Methods are provided for targeting cells for depletion, including without limitation tumor cells, in a regimen comprising contacting the targeted cells with a combination of agents that modulate immunoregulatory signaling. Immunoregulatory modulating agents include (i) an agent that blockades CD47 activity; and (ii) an agent that agonizes an immune costimulatory molecule, e.g. CD137. The regimen may further comprise an agent that specifically binds to the target cell, e.g. an antibody or biologically active fragment or derivative thereof. The level of depletion of the targeted cell is enhanced relative to a regimen in which a single immunoregulatory modulating agent is used; and the effect may be synergistic relative to a regimen in which a single immunoregulatory modulating agent is used.
1. A method of targeting tumor cells for immunodepletion, the method comprising:
contacting a population of cells comprising the targeted tumor cells and a population of immune cells with (i) an agent that blockades CD47 activity; and (ii) an antibody that agonizes CD137; in a dose effective to increase depletion of the targeted cells.
2. The method of claim 1 , wherein the immune cells comprise one or both of NK cells and phagocytic cells.
3. The method of claim 2 , wherein the immune cells comprise NK cells and macrophages.
4. The method of claim 1 , wherein the contacting is performed on a mammal in vivo.
5. The method of claim 1 , wherein depletion of the target cells is enhanced relative to the depletion observed with a monotherapy of (i) an agent that blockades CD47 activity; or (ii) an agent that agonizes an immune costimulatory molecule.
6. The method of claim 1 , further comprising contacting the cell population with (iii) an agent that specifically binds to the targeted tumor cells.
7. The method of claim 6 , wherein the agent that specifically binds to the targeted tumor cells is a tumor-specific antibody.
8. The method of claim 1 wherein the agent that blockades CD47 activity comprises a soluble signal regulatory protein alpha (SIRPα) polypeptide.
9. The method of claim 8 , wherein the soluble SIRPα polypeptide is a high affinity SIRPα variant.
10. The method of claim 9 , wherein the soluble SIRPα polypeptide is consensus variant 1 (CV1).
11. The method of claim 8 , wherein the agent is a fusion protein comprising a SIRPα polypeptide.
12. The method of claim 11 , wherein the agent is a monomer or a dimer.
13. The method of claim 1 wherein the agent that agent that blockades CD47 activity is an anti-CD47 antibody.
14. The method of claim 1 wherein the agent that agent that blockades CD47 activity is an anti-SIRPα antibody.
15. The method of claim 13 , wherein the anti-CD47 antibody comprises an IgG4 Fc region.
16. The method of claim 13 wherein the antibody is 5F9-G4.
17. The method of claim 1 , wherein said mammal is a mouse.
18. The method of claim 1 , wherein said mammal is a human.