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 virus, the method comprising:
administering to the subject 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 cell is infected with a virus that integrates pathogen genetic elements into the host genome, and 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.
2. The method of claim 1 , wherein the virus is a retrovirus, lentivirus or Hepatitis B virus.
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 1 , wherein the anti-CD47 agent is an anti-SIRPα antibody that does not stimulate signaling through SIRPα.
6. The method of claim 5 , wherein the anti-SIRPα antibody is a humanized antibody.
7. The method of claim 3 wherein the anti-CD47 antibody is a monoclonal antibody.
8. The method of claim 3 wherein the anti-CD47 antibody is an antibody fragment.
9. The method of claim 8 , wherein the antibody fragment is:
(a) Fab, Fab′, Fab′-SH, F(ab′)2 or Fv fragment or
(b) a diabody.
10. The method of claim 1 , wherein the anti-CD47 agent is a SIRPα-derived polypeptide that specifically binds to CD47.
11. The method of claim 10 , wherein the SIRPα-derived polypeptide comprises at least the d 1 domain of SIRPα with modified amino acid residues to increase affinity.
12. 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.
13. 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.