Therapeutic compositions for neutralizing type I interferons, and methods of use
Inventors
Assignees
US Army Medical Research Institute of Infectious Diseases • United States Department of the Army
Publication Number
US-9861681-B2
Publication Date
2018-01-09
Expiration Date
2034-04-15
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 that neutralize Type I interferons (IFNs) in mammals by using a soluble Orthopoxvirus IFN-binding protein modified to remove the cell-binding region. This modified protein specifically binds to Type I IFNs, neutralizing their activity and thereby reducing or controlling their amounts in the subject. The compositions include this isolated modified IFN-binding protein alongside a pharmaceutically acceptable carrier or excipient.
The problem addressed by the invention arises from the pathological effects caused by excessive amounts of Type I IFNs in mammals, which can result from viral infections, bacterial sepsis, autoimmune disorders, or medicinal IFN administration. Excessive Type I IFNs can drive acute inflammation leading to severe pathologies such as organ failure and death. Existing therapeutics lack broad neutralization encompassing all Type I IFN subtypes and do not provide efficient systemic neutralization without adverse effects. Moreover, natural IFN-binding proteins from Orthopoxviruses bind cells and do not diffuse systemically, limiting their therapeutic usefulness.
Claims Coverage
The patent discloses two main independent claims covering therapeutic compositions and methods for neutralizing Type I interferons with modified Orthopoxvirus IFN-binding proteins. These claims emphasize key inventive features regarding protein modification, solubility, systemic diffusion, and inclusion of native secretion signals.
Therapeutic composition with modified soluble IFN-binding protein containing native secretion signal
The composition comprises an isolated Orthopoxvirus IFN-binding protein modified by removing the cell-binding region, rendering it soluble to move through mammalian tissues without immobilization by cell surfaces. This protein retains the native secretion signal enabling expression in mammalian cells, and it specifically binds to and neutralizes Type I IFNs. The composition also contains a pharmaceutically acceptable carrier or excipient.
Method to reduce harmful effects of excessive Type I IFNs by systemic administration of modified IFN-binding protein
This method involves administering to a mammal a composition comprising the isolated Orthopoxvirus IFN-binding protein as described above, wherein the modified protein diffuses systemically and neutralizes both local and systemic Type I IFNs. Administration can be parenteral, aerosol or oral, targeting conditions caused by elevated Type I IFNs, including systemic inflammatory response syndrome, autoimmune diseases, inflammation, sepsis, ischemic reperfusion injuries, or medicaments containing Type I IFNs.
The claims cover a novel therapeutic composition comprising a modified soluble Orthopoxvirus IFN-binding protein with the native secretion signal, and methods of administering such compositions to systemically neutralize harmful excess Type I IFNs in mammals, thereby addressing inflammation-related pathologies.
Stated Advantages
The modified IFN-binding protein is soluble, enabling systemic diffusion throughout the mammal rather than localizing at the injection site due to cell binding.
Rapid and controlled neutralization of Type I IFNs is permitted, with the protein clearing from the host more easily, allowing regulated treatment of IFN levels.
Broad efficacy is achieved by neutralizing multiple Type I IFN subtypes across species due to the conserved binding region.
Use of a viral protein reduces the likelihood of inducing autoimmunity compared to host-derived molecules.
Documented Applications
Treatment or alleviation of systemic inflammatory response syndrome (SIRS), including sepsis and viral hemorrhagic fever.
Reduction of harmful effects of excessive Type I IFNs caused by autoimmune diseases, inflammation, infectious agents, ischemic reperfusion injuries, and pathological inflammation.
Control and regulation of IFN responses in mammals administered Type I IFN-containing medicines such as for Hepatitis C or multiple sclerosis.
Creation of transient interferon alpha/beta deficient animals as models for studying viral and pathogen infections.
Interested in licensing this patent?