Coversin for the treatment of autoimmune blistering diseases

Abstract

The present invention relates to methods of treating or preventing AIBD.

1 . A method of treating or preventing an AIBD in a subject, which comprises administering to the subject a therapeutically or prophylactically effective amount of an agent which is a protein comprising amino acids 19 to 168 of the amino acid sequence in  FIG.  2    (SEQ ID NO: 2) or a functional equivalent of this protein. 
     
     
         2 . An agent which is a protein comprising amino acids 19 to 168 of the amino acid sequence in  FIG.  2    (SEQ ID NO: 2) or a functional equivalent of this protein for use in a method of treating or preventing an AIBD in a subject. 
     
     
         3 . A method of treating or preventing an AIBD in a subject, which comprises administering to the subject a therapeutically or prophylactically effective amount of an, agent which is a nucleic acid molecule encoding a protein comprising amino acids 19 to 168 of the amino acid sequence in  FIG.  2    (SEQ ID NO: 2) or a functional equivalent of this protein. 
     
     
         4 . An agent which is a nucleic acid molecule encoding a protein comprising amino acids 19 to 168 of the amino acid sequence in  FIG.  2    (SEQ ID NO: 2) or a functional equivalent of this protein for use in a method of treating or preventing an AIBD in a subject 
     
     
         5 . The method of any one of  claims 1  or  3  or the agent for use of any one of  claim 2 , or  4 , wherein the agent is, or encodes, a protein comprising a sequence having at least 90% sequence identity to the sequence of amino acids 19 to 168 of SEQ ID NO: 2, and said protein binds C5 to prevent the cleavage of complement C5 by convertase into complement C5a and complement C5b and/or binds to LTB4. 
     
     
         6 . The method of any one of  claims 1 ,  3  or  5  or the agent for use of any one of  claim 2 ,  4  or  5 , wherein the agent is, or encodes, a protein comprising a sequence having at least 95% sequence identity to the sequence of amino acids 19 to 168 of SEQ ID NO: 2,
 and said protein binds C5 to prevent the cleavage of complement C5 by convertase into complement C5a and complement C5b and/or binds to LTB4. 
 
     
     
         7 . The method of any one of  claims 1 ,  3  or  5  to  6 , or the agent for use of any one of  claims 2 ,  4  or  5  to  6 , wherein the agent is, or encodes, a protein comprising or consisting of the sequence of amino acids 19 to 168 of SEQ ID NO: 2. 
     
     
         8 . The method of any one of  claims 1  or  3 , or the agent for use of any one of  claim 2  or  4 , wherein agent is, or encodes, a protein comprising the sequence of amino acids 19 to 168 of SEQ ID NO: 2, in which up to 10 amino acid substitutions, insertions or deletions have been made,
 and the protein binds C5 to prevent the cleavage of complement C5 by convertase into complement C5a and complement C5b and/or binds to LTB4. 
 
     
     
         9 . The method of any one of  claims 1  or  3 , or the agent for use of any one of  claims 2  or  4 , wherein the agent is, or encodes, a fragment of the protein as defined in any of  claims 4  to  7 ,
 and the protein binds C5 to prevent the cleavage of complement C5 by convertase into complement C5a and complement C5b and/or binds to LTB4. 
 
     
     
         10 . The method or the agent for use of any preceding claim, wherein the agent is administered subcutaneously. 
     
     
         11 . The method or the agent for use of any preceding claim, wherein the subject is a human. 
     
     
         12 . The method or the agent for use of any preceding claim, wherein the agent is administered in a dose sufficient to bind as much available C5 and/or LTB4 as possible in the subject, preferably, all available C5. 
     
     
         13 . The method or the agent for use of any preceding claim, wherein the agent is administered in a dose 1.5 times the molar dose needed to bind all available C5 and/or LTB4 in the subject. 
     
     
         14 . The method or the agent for use of any preceding claim, wherein the method comprises administering to the subject an initial loading dose of the agent and then administering maintenance doses thereof. 
     
     
         15 . The method of  claim 14  wherein there in an initial maintenance dose and one or more further maintenance doses. 
     
     
         16 . The method or the agent for use of any preceding claim, wherein the method further comprises the administration of a second AIBD treatment. 
     
     
         17 . The method or the agent for use of  claim 16 , wherein the second AIBD treatment is selected from systemic corticosteroid therapy, topical corticosteroid therapy, immunosuppressive therapy and immunosuppressive biological therapy. 
     
     
         18 . The method or the agent for use of  claim 17  wherein corticosteroid is selected from prednisone and prednisolone, the immunosuppressive therapy is selected from methylprednisolone, mycophenolate, azathioprine, dapsone and cyclophosphamide and the immunosuppressive biological therapy is selected from rituximab and intravenous immunoglobulin G (IVIG). 
     
     
         19 . The method or the agent for use of any preceding claim wherein the AIBD is bullous pemphigoid or EBA, preferably bullous pemphigoid. 
     
     
         20 . The method or the agent for use of any preceding claim wherein the functional equivalent of the protein comprising amino acids 19 to 168 of SEQ ID NO:2 is a fusion protein comprising (a) a sequence having at least 90% sequence identity to the sequence of amino acids 19 to 168 of SEQ ID NO: 2, and (b) a second sequence
 and said fusion protein binds C5 to prevent the cleavage of complement C5 by convertase into complement C5a and complement C5b and/or binds LTB4.   
     
     
         21 . The method or agent for use of  claim 20  wherein said second sequence is a PAS sequence. 
     
     
         22 . The method or agent for use of  claims 20  or  21  wherein said fusion protein comprises (a) a PAS sequence consisting of 30 copies of SEQ ID NO:15 and (b) (i) amino acids 19-168 of SEQ ID NO:2, wherein (a) is fused to the N terminus of (b). 
     
     
         23 . The method or agent for use of any one of  claims 1  to  22 , wherein the protein or fusion protein binds C5 to prevent the cleavage of complement C5 by convertase into complement C5a and complement C5b and binds LTB4.