CD47 targeted therapies for the treatment of infectious disease
Inventors
Weiskopf, Kipp Andrew • Hasenkrug, Kim J. • Stoddart, Cheryl A. • McCune, Joseph McCrary • Weissman, Irving L.
Assignees
University of California San Diego UCSD • Leland Stanford Junior University • US Department of Health and Human Services
Publication Number
US-10723803-B2
Publication Date
2020-07-28
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, thereby increasing the phagocytosis of those infected cells. Suitable agents include soluble high affinity SIRPα polypeptides, soluble CD47, anti-CD47 antibodies, anti-SIRPα antibodies, and variants thereof. These methods are applicable to mammalian subjects and can be used against a broad range of intracellular pathogen infections, including chronic infections caused by viruses, bacteria, and protozoan pathogens.
The problem addressed by the invention arises from the cellular mechanism where CD47, a "don't eat-me" signal expressed on healthy cells, engages SIRPα on phagocytic cells to inhibit phagocytosis. Infectious agents cause infected cells to upregulate CD47, thereby evading removal by host phagocytes and allowing persistent infection. Blocking the CD47-SIRPα interaction restores the ability of phagocytes to engulf and remove infected cells, overcoming the pathogen's evasion strategy.
Claims Coverage
The patent includes one independent claim that describes a method of treating viral infection by employing an anti-CD47 agent that inhibits CD47 binding to SIRPα to increase phagocytosis of infected cells. The claim outlines four types of anti-CD47 agents that can be used.
Use of an anti-CD47 agent to increase phagocytosis of virus-infected cells
Administering an anti-CD47 agent at an effective dose to reduce CD47 binding to SIRPα on phagocytes, thereby increasing the phagocytosis of virus-infected cells infected with a virus integrating genetic elements into the host genome.
Anti-CD47 agent comprising an anti-CD47 antibody
Using an anti-CD47 antibody that reduces CD47-SIRPα binding; this antibody may be fully human, humanized, chimeric, monoclonal, or an antibody fragment such as Fab, Fab′, or diabodies.
Anti-SIRPα antibodies that do not stimulate SIRPα signaling
Using anti-SIRPα antibodies that specifically bind SIRPα but do not activate SIRPα signaling, thereby facilitating increased phagocytosis of infected cells.
Use of SIRPα polypeptides with specific CD47 binding
Administering SIRPα-derived polypeptides, including those comprising at least the d1 domain with amino acid modifications to increase affinity or fusion proteins with immunoglobulin Fc regions, that specifically bind CD47 and block the CD47-SIRPα interaction.
Use of soluble CD47 polypeptides that bind SIRPα
Administering soluble CD47 polypeptides that specifically bind SIRPα without stimulating SIRPα signaling to block the CD47-SIRPα interaction.
The claims collectively cover the method of treating viral infections involving intracellular pathogens that integrate into host genomes by employing anti-CD47 agents of various types to block CD47-SIRPα binding and thereby enhance phagocytosis of infected cells.
Stated Advantages
Administration of anti-CD47 agents increases the phagocytosis of infected cells by blocking the CD47 "don't eat-me" signal, overcoming pathogen evasion of immune clearance.
The method enables preferential targeting and removal of infected cells without affecting non-infected cells, due to differential CD47 expression.
The approach enhances host immune response to chronic and latent intracellular infections that persist despite normal immune function.
Documented Applications
Treatment of intracellular pathogen infections in mammalian subjects, including humans, and domestic and farm animals.
Use in the treatment of chronic infections caused by retroviruses, lentiviruses, Hepatitis B virus, herpes viruses, pox viruses, and human papilloma virus.
Use in the treatment of intracellular bacterial infections such as Mycobacterium, Chlamydophila, Ehrlichia, Rickettsia, Brucella, Legionella, Francisella, Listeria, Coxiella, Neisseria, Salmonella, and Yersinia species.
Use in the treatment of intracellular protozoan infections such as Plasmodium, Trypanosoma, Giardia, Toxoplasma, and Leishmania species.
In vivo and ex vivo targeting or depletion of infected cells, including purging infected cells from blood samples.
Use in combination with other anti-infection agents, antibiotics, antiviral drugs, or cytokine therapies to treat infections.
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