Therapy using a factor xii inhibitor in a neurotraumatic disorder

Abstract

The present invention relates to the use of a direct Factor XII (FXII) inhibitor in the treatment of a neurotraumatic disorder resulting from a traumatic injury of the brain (traumatic brain injury, TBI) or the spinal cord (spinal cord injury, SCI).

1 . A method of treating a neurotraumatic disorder in a human or animal subject, comprising administering to the subject a direct inhibitor of FXII in an amount sufficient to treat the neurotraumatic disorder, wherein the neurotraumatic disorder resulted from a traumatic injury of the brain or the spinal cord of the subject, and wherein the inhibitor of FXII is not C1 esterase inhibitor. 
     
     
         2 . The method of  claim 1 , wherein the FXII inhibitor comprises
 (i) a wild type Infestin-4 polypeptide sequence (SEQ ID NO: 1), or a variant thereof, wherein the variant comprises:
 (a) at least one and up to five amino acid mutations outside of N-terminal amino acids 2-13 of the wild type Infestin-4 polypeptide sequence (SEQ ID NO: 1); and/or 
 (b) six conserved cysteine residues from the wild type Infestin-4 polypeptide sequence (SEQ ID NO: 1), and a homology of at least 70%, 80%, 85%, 90%, 95%, 98%, or 99% to SEQ ID NO: 1; 
   (ii) a wild-type SPINK-1 polypeptide sequence (SEQ ID NO: 2), or a variant thereof, wherein the variant comprises:
 (a) N-terminal amino acids 2-13 of the wild type Infestin-4 polypeptide sequence (SEQ ID NO: 1) replacing N terminal amino acid positions 2-13 of the wild type SPINK-1 polypeptide sequence (SEQ ID NO: 2); wherein the variant optionally further comprises at least one and up to five additional amino acid mutations that increase the homology of the polypeptide sequence to the wild type Infestin-4 polypeptide sequence of SEQ ID NO: 1; and/or 
 (b) six conserved cysteine residues from the wild type SPINK-1 polypeptide sequence (SEQ ID NO: 2), and a homology of at least 70%, 80%, 85%, 90%, 95%, 98%, or 99% to the wild type SPINK-1 polypeptide sequence; 
   (iii) any one of SPINK-1 mutants K1 (SEQ ID NO: 3), K2 (SEQ ID NO: 4), or K3 (SEQ ID NO: 5); and/or   (iv) an anti-FXII antibody.   
     
     
         3 . The method of  claim 2 , wherein the anti-FXII antibody comprises
 (i) (a) a VH region comprising a heavy chain CDR1 sequence of SEQ ID NO: 8, a heavy chain CDR2 sequence of SEQ ID NO: 10, and a heavy chain CDR3 sequence of SEQ ID NO: 12; and/or
 (b) a VL region comprising a light chain CDR1 sequence of SEQ ID NO: 13, a light chain CDR2 sequence of SEQ ID NO: 14, and a light chain CDR3 sequence of SEQ ID NO: 16; or 
   (ii) (a) a VH region comprising a heavy chain CDR1 sequence of SEQ ID NO: 8, a heavy chain CDR2 sequence of SEQ ID NO: 9, and a heavy chain CDR3 sequence of SEQ ID NO: 11; and/or
 (b) a VL region comprising a light chain CDR1 sequence of SEQ ID NO: 13, a light chain CDR2 sequence of SEQ ID NO: 14, and a light chain CDR3 sequence of as set forth in SEQ ID NO: 15; or 
   (iii) a VH region comprising SEQ ID NO: 6 and a VL region comprising SEQ ID NO: 7.   
     
     
         4 . The method of  claim 2 , wherein the anti-FXII antibody is an IgG antibody. 
     
     
         5 . The method of  claim 1 , wherein the at least one FXII inhibitor is linked to a fusion partner comprising PEG or a half-life enhancing polypeptide selected from albumin, afamin, alpha-fetoprotein, vitamin D binding protein, human albumin, an immunoglobulin, and an Fc of an IgG. 
     
     
         6 . The method of  claim 5 , wherein the half-life enhancing polypeptide is linked to the FXII inhibitor via a linker. 
     
     
         7 . The method of  claim 5 , wherein the FXII inhibitor is a fusion protein comprising human albumin joined to a FXII inhibitor via a linker peptide. 
     
     
         8 . The method of  claim 1 , wherein the FXII inhibitor is administered intravenously, subcutaneously, or intrathecal. 
     
     
         9 . The method of  claim 1 , wherein the FXII inhibitor is administered (i) in a single dose as an injection or an infusion, (ii) in multiple doses, each as an injection or an infusion, or (iii) as a continuous infusion or application. 
     
     
         10 . The method of  claim 1 , wherein the FXII inhibitor is administered at a concentration ranging from about 0.01 mq/kq body weight to about 1000 mg/kg body weight. 
     
     
         11 . The method of  claim 1 , wherein the FXII inhibitor is administered after the traumatic injury. 
     
     
         12 . The method of  claim 11 , wherein the FXII inhibitor is first administered immediately after the traumatic injury or up to 24 hours after the traumatic injury. 
     
     
         13 . The method of  claim 1 , wherein the FXII inhibitor is administered at least once, at least twice, at least three times, at least four times, or at least five times. 
     
     
         14 . A kit for use in the treatment of a neurotraumatic disorder selected from a spinal cord injury and a traumatic brain injury, comprising:
 (a) at least one direct FXII inhibitor;   (b) instructions for using the kit in the treatment of a neurotraumatic disorder resulting from a traumatic injury of the brain or the spinal cord; and   (c) optionally, at least one further therapeutically active compound or drug;   wherein neither the FXII inhibitor nor the further therapeutically active compound or drug is C1 esterase inhibitor.   
     
     
         15 . The kit according to  claim 14 , wherein the further therapeutically active compound or drug is a steroid. 
     
     
         16 . The method of  claim 1 , wherein the FXII inhibitor is administered at a concentration ranging from about 1 mg/kg body weight to about 500 mg/kg body weight. 
     
     
         17 . The method of  claim 11 , wherein the FXII inhibitor is first administered up to 12 hours after the traumatic injury. 
     
     
         18 . The method of  claim 11 , wherein the FXII inhibitor is first administered up to 6 hours after the traumatic injury. 
     
     
         19 . The method of  claim 15 , wherein the steroid is cortisone.