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 mammalian subject for intracellular pathogen infection, wherein the pathogen is a bacterium, the method comprising:
administering to the subject an anti-CD47 agent that reduces the binding of CD47 on an infected cell to SIRPα on a phagocytic cell, at an effective dose of from 1 mg/kg to 50 mg/kg for increasing the phagocytosis of the 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 modified 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.
2. The method of claim 1 , wherein the subject is a human.
3. The method of claim 1 , wherein the bacterium is selected from Chlamydia sp., Yersinia sp., franciscella sp.; Pasteurella sp.; Vibrio sp., Legionella sp., Listeria sp., Mycoplasma sp., Mycobacterium sp., Rickettsia sp., and Helicobacter sp.
4. The method of claim 1 , wherein the bacterium is selected from Chlamydia sp., Chlamydia trachomatis, Chlamydia pneumoniae , and Chlamydia psittaci.
5. The method of claim 1 , wherein the bacterium is Chlamydia trachomatis.
6. The method of claim 1 wherein the anti-CD47 agent is an anti-CD47 antibody.
7. The method of claim 6 , wherein the anti-CD47 antibody is a fully human, humanized or chimeric antibody.
8. The method of claim 7 , wherein the antibody is humanized 5F9-hIgG4.
9. The method of claim 6 , wherein the anti-CD47 antibody is an antibody fragment selected from (i) Fab, Fab′, Fab′-SH, F(ab′)2, and Fv fragment or (ii) diabody.
10. The method of claim 1 , wherein the anti-CD47 agent is an anti-SIRPα antibody that does not stimulate signaling through SIRPα.
11. The method of claim 10 , wherein the anti-SIRPα antibody is a humanized antibody.
12. The method of claim 10 , wherein the anti-SIRPα antibody is an antibody fragment selected from Fab, Fab′, Fab′-SH, F(ab′) 2 , and Fv fragment; or a diabody.
13. The method of claim 1 , wherein the anti-CD47 agent is a modified SIRPα polypeptide that specifically binds to CD47, comprising at least the d1 domain of SIRPα with modified amino acid residues to increase affinity.
14. The method of claim 13 , wherein the modified SIRPα polypeptide is fused in frame with an immunoglobulin Fc region.
15. 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.
16. The method of claim 1 , wherein the anti-CD47 agent that reduces the binding of CD47 on an infected cell to SIRPα on a phagocytic cell is administered in combination with an antibiotic or antiviral agent.
17. The method of claim 1 , further comprising a step of monitoring the subject after administration of the anti-CD47 agent that reduces the binding of CD47 on an infected cell to SIRPα on a phagocytic cell.
18. The method of claim 17 , wherein the monitoring step comprises measuring clinical indicia of infection.
19. The method of claim 17 , wherein the monitoring step comprises direct monitoring for presence of the pathogen.