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.