CD47 targeted therapies for the treatment of infectious disease
Inventors
Weiskopf, Kipp Andrew • Hasenkrug, Kim J. • Stoddart, Cheryl A. • McCune, Joseph M. • Weissman, Irving L.
Assignees
University of California San Diego UCSD • Leland Stanford Junior University • US Department of Health and Human Services
Publication Number
US-9771428-B2
Publication Date
2017-09-26
Expiration Date
2034-02-05
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Abstract
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.
Core Innovation
The invention provides methods for treating subjects infected with intracellular pathogens by administering an agent that reduces the binding of CD47 on infected cells to SIRPα on host phagocytic cells. This treatment is effective in increasing the phagocytosis and thus removal of infected cells. Suitable agents include soluble high affinity SIRPα polypeptides, soluble CD47, anti-CD47 antibodies, anti-SIRPα antibodies, and variants thereof.
The problem being solved is that infectious agents induce upregulation of CD47 on infected cells, which acts as a “don't eat-me” signal by engaging SIRPα on phagocytic cells, thereby inhibiting phagocytosis and allowing infected cells to evade immune clearance. Thus, persistent infections overcome programmed cell death and phagocytic cell removal pathways, leading to chronic or latent infections. By blocking the CD47-SIRPα interaction, the invention seeks to disrupt this immune evasion mechanism and promote removal of infected cells.
Claims Coverage
There is one independent claim that broadly covers the method of treating HIV infection by administering an anti-CD47 agent to increase phagocytosis of infected cells. The inventive features encompass the specific targeting of the CD47-SIRPα interaction and the use of particular anti-CD47 agents.
Method of treating HIV infection by blocking CD47-SIRPα interaction
Administering to a human subject an anti-CD47 agent that reduces binding of CD47 on an infected cell to SIRPα on a phagocytic cell at an effective dose that increases phagocytosis of HIV-infected cells.
Use of anti-CD47 agents specifically binding CD47
Using anti-CD47 agents that specifically bind CD47, including antibodies such as humanized 5F9-hIgG4, and high affinity SIRPα reagents.
Use of anti-CD47 agents specifically binding SIRPα
Using anti-CD47 agents that specifically bind SIRPα, including anti-SIRPα antibodies that do not stimulate SIRPα signaling and soluble CD47 polypeptides that do not activate SIRPα signaling.
The independent claim covers methods for treating HIV by administering anti-CD47 agents that disrupt CD47-SIRPα binding, increasing phagocytosis of infected cells, and specifies agents including anti-CD47 antibodies, high affinity SIRPα reagents, anti-SIRPα antibodies, and soluble CD47 polypeptides that do not activate SIRPα.
Stated Advantages
Increased phagocytosis of infected cells by blocking the CD47-SIRPα 'don't eat-me' signal.
Enhanced clearance of infected cells that express higher levels of CD47, allowing immune system to overcome infection persistence.
Preferential targeting and removal of infected cells over non-infected cells due to differential CD47 expression.
Documented Applications
Treatment of intracellular pathogen infections, including viral, bacterial, and protozoan infections.
Treatment of chronic infections such as retrovirus, lentivirus, Hepatitis B virus, herpes viruses, and human papilloma viruses.
Treatment of intracellular bacterial infections including Mycobacterium, Chlamydophila, Ehrlichia, Rickettsia, Brucella, Legionella, Francisella, Listeria, Coxiella, Neisseria, Salmonella, and Yersinia species.
Treatment of intracellular protozoan infections including Plasmodium, Trypanosoma, Giardia, Toxoplasma, and Leishmania species.
Ex vivo depletion of infected cells from blood samples by contacting with anti-CD47 agents.
In vivo targeting and depletion of infected cells in subjects by administration of anti-CD47 agents.
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