CD47 targeted therapies for the treatment of infectious disease
Methods are provided for treating a subject with for an intracellular pathogen infection, by administering an agent that reduces the binding of CD47 on a infected cell to SIRPα on a host phagocytic cell, in an effective dose for increasing the phagocytosis of infected cells.
1. A method of treating a human subject infected with a retrovirus or lentivirus, the method comprising:
administering to the subject infected with a retrovirus or lentivirus, an anti-CD47 agent that reduces the binding of CD47 on a virus-infected cell to signal-regulatory protein alpha (SIRPα) on a phagocytic cell, at an effective dose for increasing the phagocytosis of the virus-infected cell, wherein the anti-CD47 agent is: (a) an anti-CD47 antibody, (b) an anti-SIRPα antibody that does not stimulate signaling through SIRPα, (c) a SIRPα polypeptide that specifically binds to CD47, or (d) a soluble CD47 polypeptide that specifically binds to SIRPα and does not stimulate signaling through SIRPα;
wherein phagocytosis of the virus-infected cells is increased.
2. The method of claim 1 , wherein the virus is selected from HIV-1, HIV-2, HTLV, FIV, and SIV.
3. The method of claim 1 , wherein the anti-CD47 agent is an anti-CD47 antibody.
4. The method of claim 3 , wherein the anti-CD47 antibody is a fully human, humanized or chimeric antibody.
5. The method of claim 3 wherein the anti-CD47 antibody is an antibody fragment.
6. The method of claim 5 , wherein the antibody fragment is: (a) Fab, Fab', Fab'-SH, F(ab')2 or Fv fragment or (b) a diabody.
7. The method of claim 1 , wherein the anti-CD47 agent is an anti-SIRPα antibody that does not stimulate signaling through SIRPα.
8. The method of claim 7 , wherein the anti-SIRPα antibody is a fully human, humanized or chimeric antibody.
9. The method of claim 1 , wherein the anti-CD47 agent is a SIRPα-derived polypeptide that specifically binds to CD47.
10. The method of claim 9 , wherein the SIRPα-derived polypeptide comprises at least the d1 domain of SIRPα with modified amino acid residues to increase affinity.
11. The method of claim 10 , wherein the SIRPα-derived polypeptide is a fusion protein, optionally wherein the SIRPα-derived polypeptide is fused in frame with an immunoglobulin Fc region.
12. The method of claim 1 , wherein the anti-CD47 agent is a soluble CD47 polypeptide that specifically binds to SIRPα and does not stimulate signaling through SIRPα.
13. A method of treating a human subject infected with a retrovirus or lentivirus, the method comprising:
administering to the subject infected with a retrovirus or lentivirus, a combination of (i) an anti-CD47 agent that reduces the binding of CD47 on a virus-infected cell to signal-regulatory protein alpha (SIRPα) on a phagocytic cell, at an effective dose for increasing the phagocytosis of the virus-infected cell; and (ii) an antiviral agent, wherein the anti-CD47 agent is: (a) an anti-CD47 antibody, (b) an anti-SIRPα antibody that does not stimulate signaling through SIRPα, (c) a SIRPα polypeptide that specifically binds to CD47, or (d) a soluble CD47 polypeptide that specifically binds to SIRPα and does not stimulate signaling through SIRPα;
wherein phagocytosis of the virus-infected cell is increased.
14. The method of claim 13 , wherein the virus is selected from HIV-1, HIV-2, HTLV, FIV, and SIV.
15. The method of claim 13 , wherein the antiviral agent is a cytokine.
16. The method of claim 15 , wherein the cytokine is one or more of interferon γ, tumor necrosis factor α, and interleukin 12.
17. The method of claim 13 , wherein the antiviral agent is acyclovir or gancyclovir.
18. The method of claim 13 , wherein the virus is selected from HIV-1, HIV-2, HTLV, FIV, and SIV.
19. The method of claim 13 , wherein the anti-CD47 agent is an anti-CD47 antibody.
20. The method of claim 19 , wherein the anti-CD47 antibody is a fully human, humanized or chimeric antibody.
21. The method of claim 19 wherein the anti-CD47 antibody is an antibody fragment.
22. The method of claim 21 , wherein the antibody fragment is: (a) Fab, Fab', Fab'-SH, F(ab')2 or Fv fragment or (b) a diabody.
23. The method of claim 13 , wherein the anti-CD47 agent is an anti-SIRPα antibody that does not stimulate signaling through SIRPα.
24. The method of claim 23 , wherein the anti-SIRPα antibody is a fully human, humanized or chimeric antibody.
25. The method of claim 13 , wherein the anti-CD47 agent is a SIRPα-derived polypeptide that specifically binds to CD47.
26. The method of claim 25 , wherein the SIRPα-derived polypeptide comprises at least the d1 domain of SIRPα with modified amino acid residues to increase affinity.
27. The method of claim 26 , wherein the SIRPα-derived polypeptide is a fusion protein, optionally wherein the SIRPα-derived polypeptide is fused in frame with an immunoglobulin Fc region.
28. The method of claim 13 , wherein the anti-CD47 agent is a soluble CD47 polypeptide that specifically binds to SIRPα and does not stimulate signaling through SIRPα.