Gain-of-function ADAMTS13 variants resistant to auto antibody inhibition and methods of use thereof

摘要

Compositions and methods for the treatment of thrombotic thrombocytopenic purpura are disclosed.

主权项

1. An isolated, recombinantly produced gain-of-function a disintegrin and metalloprotease with thromboppondin type 1 repeats-13 (ADAMTS13) human variant protein comprising at least one amino acid change in a spacer domain of the full-length ADAMTS13 comprising amino acids 1-2050, said variant having increased proteolytic activity of multimeric von Willebrand factor (VWF) and exhibiting resistance to anti-ADAMTS13 autoantibody inhibition relative to wild typc the human ADAMTS13 lacking said at least one amino acid change, wherein said variant is selected from the group consisting of:
i) an M4 variant, wherein an arginine at position 660 is replaced with a lysine, a phenylalanine at position 592 is replaced with a tyrosine, an arginine at position 568 is replaced with a lysine and an arginine at position 661 is replaced with a phenylalanine; and ii) an M5 variant, wherein an arginine at position 660 is replaced with a lysine, a phenylalanine at position 592 is replaced with a tyrosine, an arginine at position 568 is replaced with a lysine, an arginine at position 661 is replaced with a phenylalanine and a tyrosine at position 665 is replaced with a phenylalanine.