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-10184004-B2
Publication Date
2019-01-22
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 agents that reduce the binding of CD47 on infected cells to SIRPα on host phagocytic cells. This reduction increases the phagocytosis of infected cells, enabling the host immune system to more effectively remove these cells. The agents can 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 increased expression of CD47 on infected cells, which serves as a "don't eat-me" signal by engaging SIRPα on phagocytic cells, thereby inhibiting phagocytosis and allowing infected cells to evade immune clearance. Persistent infections overcome programmed cell death and phagocytic removal, which complicates treatment. The invention addresses this by disrupting the CD47-SIRPα interaction to restore phagocytic clearance of infected cells.
Claims Coverage
The patent includes one independent claim focusing on a method of treating a subject infected with a hepadna virus using anti-CD47 agents. This claim introduces several inventive features related to the composition and use of the anti-CD47 agents.
Method of treating intracellular hepadna virus infection
Administering an anti-CD47 agent to a subject infected with a hepadna virus at an effective dose that reduces the binding of CD47 on infected cells to SIRPα on phagocytic cells, thereby increasing phagocytosis of infected cells.
Use of specific anti-CD47 agents
The anti-CD47 agent specifically binds either CD47 or SIRPα, and the agents include anti-CD47 antibodies (such as humanized 5F9-hIgG4), high affinity SIRPα reagents, anti-SIRPα antibodies that do not stimulate SIRPα signaling, and soluble CD47 polypeptides that do not stimulate SIRPα signaling.
Monitoring treatment efficacy
The method further comprises monitoring the subject for clinical signs of infection or for the presence of hepadna virus following administration of the anti-CD47 agent.
The claims collectively cover a therapeutic method targeting the CD47-SIRPα interaction to treat hepadna virus infections using specific anti-CD47 agents that increase phagocytosis of infected cells, with provisions for subject selection and monitoring treatment responses.
Stated Advantages
Increased phagocytosis of infected cells by disrupting the CD47-SIRPα mediated 'don't eat-me' signal.
Enhanced removal of infected cells that express elevated CD47, addressing persistent infections.
Potential specificity for infected cells due to their higher CD47 expression, reducing impact on healthy cells.
Documented Applications
Treatment of intracellular pathogen infections including viral infections such as retroviruses, lentiviruses, hepadna viruses (e.g., hepatitis B virus), herpes viruses, pox 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 such as Plasmodium, Trypanosoma, Giardia, Toxoplasma, and Leishmania species.
Ex vivo targeting or depletion of infected cells from blood samples using anti-CD47 agents conjugated to cytotoxic agents.
In vivo administration of anti-CD47 agents to increase phagocytosis and clearance of infected cells in subjects with chronic or latent intracellular infections.
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