B-lymphocyte stimulator binding polypeptides and methods based thereon

Abstract

Binding polypeptides that specifically bind B lymphocyte stimulator protein or B lymphocyte stimulator-like polypeptides can be used in methods of the invention for detecting, diagnosing, or prognosing a disease or disorder associated with aberrant B lymphocyte stimulator or B lymphocyte stimulator receptor expression or inappropriate function of B lymphocyte stimulator or B lymphocyte stimulator receptor, comprising B lymphocyte stimulator binding polypeptides or fragments or variants thereof, that specifically bind to B lymphocyte stimulator. The present invention further relates to methods and compositions for preventing, treating or ameliorating a disease or disorder associated with aberrant B lymphocyte stimulator or B lymphocyte stimulator receptor expression or inappropriate B lymphocyte stimulator function or B lymphocyte stimulator receptor function, comprising administering to an animal, preferably a human, an effective amount of one or more B lymphocyte stimulator binding polypeptides or fragments or variants thereof, that specifically bind to B lymphocyte stimulator.

1 . An isolated B lymphocyte stimulator binding polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of:
 (a) X 1 -X 2 -X 3 -Cys-X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -Cys-X 16 -X 17 -X 18  (SEQ ID NO:5), wherein
 X 1  is Arg, Asp, Gly, His, Leu, Phe, Pro, Ser, Trp, Tyr, or is absent; 
 X 2  is Ala, Arg, Asn, Asp, Gly, Pro, Ser, or is absent; 
 X 3  is Arg, Asn, Gln, Glu, Gly, Lys, Met, Pro, Trp or Val; 
 X 5  is Arg, Asn, Gln, Glu, His, Leu, Phe, Pro, Trp, Tyr, or Val; 
 X 6  is Arg, Asp, Gln, Gly, Ile, Lys, Phe, Thr, Trp or Tyr; 
 X 7  is Ala, Arg, Asp, Glu, Gly, Leu, Ser, or Tyr; 
 X 8  is Asp, Gln, Glu, Leu, Met, Phe, Pro, Ser, or Tyr; 
 X 9  is Asp, Leu, Pro, Thr, or Val; 
 X 10  is Arg, Gln, His, Ile, Leu, Lys, Met, Phe, Thr, Trp or Tyr; 
 X 11  is Ala, Arg, Asn, Gln, Glu, His, Leu, Lys, Met, or Thr; 
 X 12  is Ala, Asn, Gln, Gly, Leu, Lys, Phe, Pro, Thr, Trp, or Tyr; 
 X 13  is Ala, Arg, Gln, His, Lys, Met, Phe, Pro, Thr, Trp, or Tyr; 
 X 14  is Arg, Gln, Glu, Gly, His, Leu, Met, Phe, Pro, Ser, Thr, Tyr, or Val; 
 X 16  is Arg, Asp, Gly, His, Lys, Met, Phe, Pro, Ser, or Trp; 
 X 17  is Arg, Asn, Asp, Gly, His, Phe, Pro, Ser, Trp or Tyr; and 
 X 18  is Ala, Arg, Asn, Asp, His, Leu, Phe, or Trp; 
   (b) Cys-X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -Cys (SEQ ID NO: 12), wherein
 X 2  is Arg, Asn, Gln, Glu, His, Leu, Phe, Pro, Trp, Tyr, or Val; 
 X 3  is Arg, Asp, Gln, Gly, Ile, Lys, Phe, Thr, Trp or Tyr 
 X 4  is Ala, Arg, Asp, Glu, Gly, Leu, Ser, or Tyr; 
 X 5 , is Asp, Gln, Glu, Leu, Met, Phe, Pro, Ser, or Tyr; 
 X 6  is Asp, Leu, Pro, Thr, or Val; 
 X 7  is Arg, Gln, His, Ile, Leu, Lys, Met, Phe, Thr, Trp or Tyr; 
 X 8  is Ala, Arg, Asn, Gln, Glu, His, Leu, Lys, Met, or Thr; 
 X 9  is Ala, Asn, Gln, Gly, Leu, Lys, Phe, Pro, Thr, Trp, or Tyr; 
 X 10  is Ala, Arg, Gln, His, Lys, Met, Phe, Pro, Thr, Trp, or Tyr; and 
 X 11  is Arg, Gln, Glu, Gly, His, Leu, Met, Phe, Pro, Ser, Thr, Tyr, or Val; 
   (c) Asp-Xaa-Leu-Thr (SEQ ID NO: 446), wherein
 Xaa is Pro, Ser, Thr, Phe, Leu, Tyr, Cys, or Ala; 
   (d) His-Leu-Arg-Cys-Trp-Ser-Thr-Asn-Cys-Arg-Tyr-Asp (SEQ ID NO:20);   (e) Val-Met-Asp-Cys-Leu-Ile-Asn-Arg-Cys-Asp-Thr-Val (SEQ ID NO:21);   (f) Met-Ile-Ile-Val-Leu-Leu-Leu-Leu-Arg-Phe-Ala-Ile-Ser-Arg (SEQ ID NO:62);   (g) Ser-Leu-Leu-Val-Ile-Phe-Leu-Leu-Ile-Gly-Ala-Gly-Ser-Leu (SEQ ID NO:63)   (h) Cys-X 2 -Phe-X 4 -Trp-Glu-Cys (SEQ ID NO: 8), wherein
 X 2  is Phe, Trp, or Tyr; and 
 X 4  is Pro or Tyr; 
   (i) Cys-X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -Cys (SEQ ID NO: 9), wherein
 X 2  is Asp, Ile, Leu, or Tyr; 
 X 3  is Arg, Asp, Glu, His, Ile, Leu, Lys, Phe, Pro, Tyr, or Val; 
 X 4  is His, Leu, Lys, or Phe; 
 X 5  is Leu, Pro, or Thr; 
 X 6  is Arg, Asn, Gly, His, Ile, Lys, Met, or Trp; and 
 X 7  is Ala, Asn, Gln, Glu, Gly, His, Ile, Leu, Met, Phe, Ser, Trp, Tyr, or Val; 
   (j) Cys-X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -Cys (SEQ ID NO: 10), wherein
 X 2  is Asn, Asp, Pro, Ser, or Thr; 
 X 3  is Arg, Asp, Ile, Leu, Met, Pro, or Val; 
 X 4  is Ala, Ile, Leu, Pro, Thr, or Val; 
 X 5  is Asn, His, Ile, Leu, Lys, Phe, or Thr; 
 X 6  is Asn, Glu, Gly, His, Leu, Lys, Met, Pro, or Thr; 
 X 7  is Arg, Asn, Asp, Gln, Glu, Gly, Ile, Lys, Met, Pro, Ser, or Trp; and 
 X 8  is Arg, Glu, Gly, Lys, Phe, Ser, Trp, or Tyr; 
   (k) Cys-X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Cys (SEQ ID NO: 11), wherein
 X 2  is Asp, Gln, His, Ile, Leu, Lys, Met, Phe, or Thr; 
 X 3  is His, Ile, Leu, Met, Phe, Pro, Trp, or Tyr; 
 X 4  is Asp, His, Leu, or Ser; 
 X 5  is Ala, Arg, Asp, Glu, Leu, Phe, Pro, or Thr; 
 X 6  is Ala, Arg, Asn, or Leu; 
 X 7  is Ile, Leu, Met, Pro, Ser, or Thr; 
 X 8  is Ala, Arg, Asn, Gly, His, Lys, Ser, or Tyr; and 
 X 9  is Ala, Arg, Asn, Gln, Leu, Met, Ser, Trp, Tyr, or Val; 
   (l) X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12  (SEQ ID NO: 6), wherein
 X 1  is Ala, Arg, Gly, His, Leu, Lys, Met, Phe, Trp, Tyr, or Val; 
 X 2  is Ala, Arg, Gln, His, Ile, Leu, Phe, Thr, Trp, or Tyr; 
 X 3  is Ala, Asp, Lys, Phe, Thr, Trp or Tyr; 
 X 4  is Arg, Asp, Gln, Lys, Met, Phe, Pro, Ser, Tyr, or Val; 
 X 5  is Asp, Leu, Lys, Phe, Pro, Ser, or Val; 
 X 6  is His, Ile, Leu, Pro, Ser, or Thr; 
 X 7  is Arg, Gly, His, Leu, Lys, Met, or Thr; 
 X 8  is Ala, Arg, Asn, Ile, Leu, Lys, Met, or Thr; 
 X 9  is Ala, Asn, Arg, Asp, Glu, Gly, His, Leu, Met, Ser, Trp, Tyr, or Val; 
 X 10  is Ile, Leu, Phe, Ser, Thr, Trp, Tyr, or Val; 
 X 11  is Ala, Arg, Gly, His, Ile, Leu, Lys, Pro, Ser, Thr, Trp, Tyr, or Val; and 
 X 12  is Arg, Asp, His, Leu, Lys, Met, Phe, Pro, Ser, Trp, Tyr, or Val; and 
   (m) X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13  (SEQ ID NO: 7), wherein
 X 1  is Asp, Gln, Glu, Gly, His, Lys, Met, or Trp; 
 X 2  is Arg, Gln, His, Ile, Leu, or Pro; 
 X 3  is Asp, Gly, Ile, Lys, Thr, Tyr or Val; 
 X 4  is Asn, Asp, Gln, Glu, Met, Pro, Ser, or Tyr; 
 X 5  is Asn, Asp, His, Ile, Leu, Met, Pro, Thr or Val; 
 X 6  is Asp, Glu, His, Leu, Lys, Pro, or Val; 
 X 7  is Arg, Asn, Gln, His, Ile, Leu, Met, Pro, or Thr; 
 X 8  is Gln, Gly, His, Leu, Met, Ser, or Thr; 
 X 9  is Asn, Gln, Gly, His, Leu, Lys, Ser, or Thr; 
 X 10  is Ala, Gly, Ile, Leu, Lys, Met, or Phe; 
 X 11  is Ala, Glu, His, Ile, Leu, Met, Ser, Thr, Trp, Tyr, or Val; 
 X 12  is Arg, Gln, Glu, Gly, His, Ile, Lys, Tyr, or Val; and 
 X 13  is Arg, Asn, Glu, His, Ile, Ser, Thr, Trp, or Val; 
   wherein the B lymphocyte stimulator binding polypeptide binds a B lymphocyte stimulator protein selected from the group consisting of:
 (i) a protein whose amino acid sequence consists of amino acid residues 1-285 of SEQ ID NO: 173; 
 (ii) a protein whose amino acid sequence consists of amino acid residues 134-285 of SEQ ID NO:173; and 
 (iii) a trimer of the protein of (b). 
   
     
     
         2 . A fusion protein comprising the B lymphocyte stimulator binding polypeptide of  claim 1  fused to a heterologous polypeptide. 
     
     
         3 . The fusion protein of  claim 3 , wherein the heterologous polypeptide comprises an Fc region of an immunoglobulin. 
     
     
         4 . A method of isolating a B lymphocyte stimulator or B lymphocyte stimulator-like polypeptide comprising
 (a) contacting a solid support that comprises the B lymphocyte stimulator binding polypeptide of  claim 1  immobilized thereon with a solution containing a B lymphocyte stimulator or B lymphocyte stimulator-like polypeptide, and   (b) separating the solution from the support.   
     
     
         5 . A method for detecting a B lymphocyte stimulator or B lymphocyte stimulator-like polypeptide in a solution comprising
 (a) contacting the solution with the B lymphocyte stimulator binding polypeptide of  claim 1 , and   (b) detecting binding of B lymphocyte stimulator or B lymphocyte stimulator-like polypeptide to the B lymphocyte stimulator binding polypeptide, thereby detecting the presence of a B lymphocyte stimulator or B lymphocyte stimulator-like polypeptide in the solution.   
     
     
         6 . A method for treating an autoimmune disease comprising administering to a mammal the B lymphocyte stimulator binding polypeptide of  claim 1  in an amount sufficient to treat the autoimmune disease. 
     
     
         7 . The method of  claim 6 , wherein the autoimmune disease is lupus.