Therapeutic compositions for neutralizing type I interferons, and methods of use
Inventors
Assignees
United States Department of the Army
Publication Number
US-10548946-B2
Publication Date
2020-02-04
Expiration Date
2034-04-15
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Abstract
The inventions describe here cover therapeutic compositions, and methods of use, for neutralizing Type I interferons in a mammal. The compositions contain a soluble Orthopoxvirus IFN-binding protein that is modified to remove the cell-binding region, and that specifically binds to Type I IFNs, and a pharmaceutically acceptable carrier or excipient. Another variation of the invention entails a novel IFN-binding protein that is modified to remove the cell-binding region and the signal sequence.
Core Innovation
The invention provides therapeutic compositions and methods for neutralizing Type I interferons (IFNs) in mammals by using a modified Orthopoxvirus Type I IFN-binding protein that lacks the cell-binding region but retains the IFN-binding region and the signal sequence. This modified protein specifically binds to Type I IFNs, neutralizing their activity and thereby reducing or controlling the levels of Type I IFNs in vivo and in vitro.
The problem addressed is that excessive production of Type I IFNs, often observed in viral infections, bacterial sepsis, and certain autoimmune and inflammatory diseases, leads to harmful acute inflammation and pathology including systemic inflammatory response syndrome (SIRS), organ failure, and death. Existing therapeutic molecules, including antibodies, often have limited ability to broadly neutralize the diverse family of Type I IFNs or suffer from species specificity, and the naturally occurring Orthopoxvirus IFN-binding protein binds to cell surfaces which limits its systemic diffusion and controllability.
The innovation resides in removing the cell-binding region from the native Orthopoxvirus IFN-binding protein to create a soluble, systemically diffusible protein that selectively and effectively neutralizes Type I IFNs broadly across multiple species. This soluble modified protein avoids binding to cell surfaces, which enables rapid systemic dissemination and controlled clearance from the host. The invention includes compositions containing this modified protein and nucleic acids encoding it, expressed preferably in mammalian cells to ensure proper folding and activity, as well as methods of use for neutralizing harmful elevated Type I IFNs in various pathological conditions.
Claims Coverage
The patent includes two independent claims addressing different modifications of Orthopoxvirus Type I IFN-binding proteins that confer solubility and IFN neutralization properties. The main inventive features cover protein modification for solubility and specific IFN binding, sequence identity criteria, species specificity, nucleic acid encoding, and expression system adaptability.
Soluble Orthopoxvirus Type I IFN-binding protein lacking the cell-binding region
An isolated, soluble Orthopoxvirus Type I IFN-binding protein modified from the native form by removal of the cell-binding region, rendering it mobile through cell tissues and matrices without immobilization by cell surface binding, capable of systemic diffusion in a mammal, and specifically binding to and neutralizing Type I IFNs.
Modified IFN-binding protein with defined amino acid sequence and homologs
The modified IFN-binding protein having the amino acid sequence of SEQ ID NO:1 or a homolog with at least 90% identity, ensuring effective IFN binding and neutralization.
Encoding nucleic acid and species-specific orthopoxvirus origin
Nucleic acid sequences encoding the modified IFN-binding protein (e.g., SEQ ID NO:4), from Orthopoxviruses such as Vaccinia virus, camelpox virus, and others with at least 80% homology to ensure broad species applicability.
Protein further modified to remove the signal sequence
A modified Orthopoxvirus Type I IFN-binding protein variant that lacks both the cell-binding region and the signal sequence, represented by SEQ ID NO:2 or homologs with at least 90% identity, enabling expression in non-mammalian systems.
Use of foreign mammalian secretion signal sequences
Inclusion of foreign mammalian secretion signal sequences (e.g., tPA or Ig kappa chain leader) to replace the native signal sequence for improved expression and secretion in heterologous systems.
The claims cover isolated Orthopoxvirus IFN-binding proteins modified to remove cell-binding and optionally signal sequences, rendering them soluble, systemically diffusable, and capable of neutralizing Type I IFNs broadly. The claims define specific sequences and nucleic acids encoding these proteins, their orthopoxvirus origins, and modifications enhancing expression and functionality across diverse production systems.
Stated Advantages
Enables broad systemic diffusion of the IFN-binding protein due to removal of the cell-binding domain, allowing effective neutralization of Type I IFNs throughout the host.
Permits controlled and rapid clearance from the host, allowing regulation of IFN neutralization and reducing undesired prolonged inhibition of IFN responses.
Broadly neutralizes multiple Type I IFN subtypes across a variety of species, which is superior to antibody therapies that target single IFN subtypes and suffer from species specificity.
Can be expressed in mammalian cells to ensure proper folding and high potency, or in non-mammalian systems with modified sequences, enabling scalable and cost-effective production.
Provides therapeutic benefits in treating inflammatory and autoimmune diseases, SIRS, and conditions caused or exacerbated by excessive Type I IFN, such as sepsis and viral hemorrhagic fevers.
Documented Applications
Treatment and modulation of diseases characterized by harmful elevated Type I IFN levels, including systemic inflammatory response syndrome (SIRS), sepsis, viral hemorrhagic fevers, autoimmune diseases (e.g., lupus), and inflammation resulting from infectious agents.
Therapeutic neutralization of Type I IFNs in patients receiving IFN therapy (e.g., recombinant IFN-alpha for hepatitis C or IFN-beta for multiple sclerosis) to control adverse side effects caused by high levels of IFNs.
Development of animal models with transient Type I IFN deficiencies by administering soluble modified IFN-binding protein, facilitating research on viral pathogenesis and immune function.
Use in pharmaceutical compositions administered via parenteral injection, aerosol, infusion, or orally to achieve systemic IFN neutralization in mammals, including humans and domestic animals.
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