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-11230607-B2
Publication Date
2022-01-25
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 a subject infected with an intracellular pathogen by administering an agent that reduces the binding of CD47 on infected cells to SIRPα on host phagocytic cells. This reduces the "don't eat-me" signal presented by infected cells, thereby increasing the phagocytosis and removal of the infected cells. The agents include soluble high affinity SIRPα polypeptides, soluble CD47, anti-CD47 antibodies, and anti-SIRPα antibodies, which act effectively in increasing phagocytosis of infected cells.
The background identifies that healthy cells display CD47 as a "don't eat-me" signal binding to SIRPα on phagocytes to prevent their engulfment, while unwanted or dying cells display "eat-me" signals for removal. Infection with intracellular pathogens causes infected cells to increase CD47 expression, enabling them to evade phagocytic clearance by inhibiting engulfment. Thus, the problem being solved is the persistence of chronic intracellular infections due to pathogens exploiting the CD47-SIRPα interaction to avoid immune removal. The invention targets this immune evasion pathway by blocking CD47-SIRPα binding to promote the clearance of infected cells.
Claims Coverage
The patent includes one independent claim covering a method of treating a mammalian subject for intracellular bacterial infection using an anti-CD47 agent. This claim encompasses several main inventive features relating to the agent type and mechanism of action.
Anti-CD47 agent reducing CD47-SIRPα binding to increase phagocytosis in bacterial infection
A method of treating a mammalian subject infected with an intracellular bacterium by administering an anti-CD47 agent that reduces binding between CD47 on infected cells and SIRPα on phagocytic cells, at an effective dose which increases phagocytosis of infected cells.
Anti-CD47 agents that do not stimulate SIRPα signaling
The anti-CD47 agent is selected from: (a) an anti-CD47 antibody, (b) an anti-SIRPα antibody that does not stimulate SIRPα signaling, (c) a soluble SIRPα polypeptide specifically binding CD47, or (d) a soluble CD47 polypeptide specifically binding SIRPα, wherein none stimulate SIRPα signaling on phagocytic cells.
Use of specific anti-CD47 antibody forms
The anti-CD47 antibody can be fully human, humanized, or chimeric, including humanized 5F9-hIgG4 antibody and antibody fragments such as Fab, Fab′, F(ab′)₂, Fv, or diabodies.
Use of modified SIRPα polypeptides
Anti-CD47 agents may include modified SIRPα polypeptides with altered amino acids in the d1 domain to increase CD47 binding affinity, optionally fused to an immunoglobulin Fc region.
The independent claim covers treating intracellular bacterial infections in mammals by administering an anti-CD47 agent that blocks CD47-SIRPα binding without stimulating SIRPα signaling, using antibodies, modified polypeptides, or soluble forms, to promote phagocytic clearance of infected cells.
Stated Advantages
Increased phagocytosis of infected cells by reducing the CD47 "don't eat-me" signal, allowing effective removal of pathogen-infected cells.
Ability to treat chronic intracellular infections that persist due to immune evasion via CD47 overexpression.
Applicability to a broad range of intracellular pathogens including viruses, bacteria, and protozoa.
Use of high affinity agents and humanized antibodies improves specificity and therapeutic potential with reduced immunogenicity.
Documented Applications
Treatment of intracellular pathogen infections in mammalian subjects, including humans and companion animals such as dogs, cats, horses, and livestock.
Treatment of chronic intracellular infections by viruses (e.g., HIV), bacteria (e.g., Chlamydia trachomatis), and protozoan pathogens.
Ex vivo purging or depletion of infected cells from blood samples by contacting with anti-CD47 agents.
In vivo administration of anti-CD47 agents to target and eliminate pathogen-infected cells within the host.
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