Naturally occurring autoantibodies against alpha-synuclein that inhibit the aggregation and cytotoxicity of alpha-synuclein

Abstract

The present invention refers to human antibodies which are directed against α-Synuclein (α-Syn) and their use in medicine and diagnosis.

1 . A human antibody which is directed against an epitope between amino acids 60-100, preferably between amino acids 73-82 and/or 91-100, more preferably between amino acids 74-79 and/or 92-97, of human o Synuclein (α-Syn), or a fragment or derivative of said antibody. 
     
     
         2 . The antibody of  claim 1  which is a naturally occurring human autoantibody or a fragment or derivative thereof. 
     
     
         3 . The antibody of  claim 1  which binds monomeric α-Syn, aggregated α-Syn, or both monomeric and aggregated α-Syn. 
     
     
         4 . The antibody of  claim 1 , which comprises a heavy chain complementarity determining region 1 (CDR1) having the consensus sequence GFTX 1 SX 2 X 3 X 4 X 5 X 6  (SEQ ID NO.: 27), preferably having the sequence as shown in any one of SEQ ID NOs.: 28-34. 
     
     
         5 . The antibody of  claim 1 , which comprises a heavy chain complementarity determining region 2 (CDR2) having the sequence as shown in any one of SEQ ID NOs.: 35-43. 
     
     
         6 . The antibody of  claim 1 , which comprises a heavy chain complementarity determining region 3 (CDR3) having the sequence as shown in any one of SEQ ID NOs.: 44-64. 
     
     
         7 . The antibody of  claim 1 , which comprises a heavy chain complementarity determining region 1 (CDR1) having the consensus sequence GGSISSGGYXWS (SEQ ID NO.: 65), preferably having the sequence as shown in any one of SEQ ID NOs.: 66 and 67. 
     
     
         8 . The antibody of  claim 1 , which comprises a heavy chain complementarity determining region 2 (CDR2) having the consensus sequence YIYXSGSTYYNPSLKS (SEQ ID NO.: 68), preferably having the sequence as shown in any one of SEQ ID NOs.: 69 and 70. 
     
     
         9 . The antibody of  claim 1 , which comprises a heavy chain complementarity determining region 3 (CDR3) having the sequence as shown in any one of SEQ ID NOs.: 71-75. 
     
     
         10 . The antibody of  claim 1 , which comprises a heavy chain complementarity determining region 1 (CDR1) having the sequence as shown in any one of SEQ ID NOs.: 76-80. 
     
     
         11 . The antibody of  claim 1 , which comprises a heavy chain complementarity determining region 2 (CDR2) having the consensus sequence X 1  IX 2 PX 3 X 4 GX 5 X 6 X 7 YAQKFQG (SEQ ID NO.: 81), preferably having the sequence as shown in any one of SEQ ID NOs.: 82-85. 
     
     
         12 . The antibody of  claim 1 , which comprises a heavy chain complementarity determining region 3 (CDR3) having the sequence as shown in any one of SEQ ID NOs.: 86-91. 
     
     
         13 . The antibody of  claim 1 , which comprises a light chain complementarity determining region 1 (CDR1) having the sequence as shown in SEQ ID NO.: 92. 
     
     
         14 . The antibody of  claim 1 , which comprises a light chain complementarity determining region 2 (CDR2) having the sequence as shown in SEQ ID NO.: 93. 
     
     
         15 . The antibody of  claim 1 , which comprises a light chain complementarity determining region 3 (CDR3) having the consensus sequence MQALQX 1 X 2 X 3 T (SEQ ID NO.: 94), preferably having the sequence as shown in any one of SEQ ID NOs.: 95-98. 
     
     
         16 . The antibody of  claim 1 , which comprises a light chain complementarity determining region 1 (CDR1) having the consensus sequence RASQSVSSX X 2 LA (SEQ ID NO.: 99), preferably having the sequence as shown in any one of SEQ ID NOs.: 100-102. 
     
     
         17 . The antibody of  claim 1 , which comprises a light chain complementarity determining region 2 (CDR2) having the consensus sequence X 1 ASX 2 RAT (SEQ ID NO.: 103), preferably having the sequence as shown in any one of SEQ ID NOs.: 104-106. 
     
     
         18 . The antibody of  claim 1 , which comprises a light chain complementarity determining region 3 (CDR3) having the sequence as shown in any one of SEQ ID NOs.: 107-114, 145, 146, and 147. 
     
     
         19 . The antibody of  claim 1 , which comprises a light chain complementarity determining region 1 (CDR1) having the consensus sequence RX 1 SQX 2 IX 3 X 4 X 5 LX 6  (SEQ ID NO.: 115), preferably having the sequence as shown in any one of SEQ ID NOs.: 116-122. 
     
     
         20 . The antibody of  claim 1 , which comprises a light chain complementarity determining region 2 (CDR2) having the sequence as shown in any one of SEQ ID NOs.: 123-127. 
     
     
         21 . The antibody of  claim 1 , which comprises a light chain complementarity determining region 3 (CDR3) having the sequence as shown in any one of SEQ ID NOs.: 128-144. 
     
     
         22 . The antibody of  claim 1 , which comprises a heavy chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1 is selected from the sequences shown in SEQ ID NOs.: 28-34, CDR2 is selected from the sequences shown in SEQ ID NOs.: 35-43, and CDR3 is selected from the sequences shown in SEQ ID NOs.: 44-64. 
     
     
         23 . The antibody of  claim 1 , which comprises a heavy chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1 is selected from the sequences shown in SEQ ID NOs.: 66-67, CDR2 is selected from the sequences shown in SEQ ID NOs.: 69-70, and CDR3 is selected from the sequences shown in SEQ ID NOs.: 71-75. 
     
     
         24 . The antibody of  claim 1 , which comprises a heavy chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1 is selected from the sequences shown in SEQ ID NOs.: 76-80, CDR2 is selected from the sequences shown in SEQ ID NOs.: 82-85, and CDR3 is selected from the sequences shown in SEQ ID NOs.: 86-91. 
     
     
         25 . The antibody of  claim 1 , which comprises a light chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1 has the sequence shown in SEQ ID NO.: 92, CDR2 has the sequence shown in SEQ ID NO.: 93, and CDR3 is selected from the sequences shown in SEQ ID NOs.: 95-98. 
     
     
         26 . The antibody of  claim 1 , which comprises a light chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1 is selected from the sequences shown in SEQ ID NOs.: 100-102, CDR2 is selected from the sequences shown in SEQ ID NOs.: 104-106, and CDR3 is selected from the sequences shown in SEQ ID NOs.: 107-114, 145, 146, and 147. 
     
     
         27 . The antibody of  claim 1 , which comprises a light chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1 is selected from the sequences shown in SEQ ID NOs.: 116-122, CDR2 is selected from the sequences shown in SEQ ID NOs.: 123-127, and CDR3 is selected from the sequences shown in SEQ ID NOs.: 128-144. 
     
     
         28 . The antibody of  claim 1 , wherein the complementarity determining regions (CDRs) of the heavy chain are flanked by framework regions consisting of a consensus sequence as shown in:
 (i) SEQ ID NOs.: 3-6, or   (ii) SEQ ID NOs.: 7-10, or   (iii) SEQ ID NOs.: 11-14; or variants thereof.   
     
     
         29 . The antibody of  claim 1 , wherein the complementarity determining regions (CDRs) of the light chain are flanked by framework regions consisting of a consensus sequence as shown in:
 (i) SEQ ID NOs.: 15-18, or   (ii) SEQ ID NOs.: 19-22, or   (iii) SEQ ID NOs.: 23-26; or variants thereof.   
     
     
         30 . The antibody of  claim 1 , which comprises a heavy chain comprising framework regions consisting of a consensus sequence as shown in SEQ ID NOs.: 3-6 or variants thereof, further comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1 is selected from the sequences shown in SEQ ID NOs.: 28-34, CDR2 is selected from the sequences shown in SEQ ID NOs.: 35-43, and CDR3 is selected from the sequences shown in SEQ ID NOs.: 44-64. 
     
     
         31 . The antibody of  claim 1 , which comprises a heavy chain comprising framework regions consisting of a consensus sequence as shown in SEQ ID NOs.: 7-10 or variants thereof, further comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1 is selected from the sequences shown in SEQ ID NOs.: 66-67, CDR2 is selected from the sequences shown in SEQ ID NOs.: 69-70, and CDR3 is selected from the sequences shown in SEQ ID NOs.: 71-75. 
     
     
         32 . The antibody of  claim 1 , which comprises a heavy chain comprising framework regions consisting of a consensus sequence as shown in SEQ ID NOs.: 11-14 or variants thereof, further comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1 is selected from the sequences shown in SEQ ID NOs.: 76-80, CDR2 is selected from the sequences shown in SEQ ID NOs.: 82-85, and CDR3 is selected from the sequences shown in SEQ ID NOs.: 86-91. 
     
     
         33 . The antibody of  claim 1 , which comprises a light chain comprising framework regions consisting of a consensus sequence as shown in SEQ ID NOs.: 15-18 or variants thereof, further comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1 has the sequence shown in SEQ ID NO.: 92, CDR2 has the sequence shown in SEQ ID NO.: 93, and CDR3 is selected from the sequences shown in SEQ ID NOs.: 95-98. 
     
     
         34 . The antibody of  claim 1 , which comprises a light chain comprising framework regions consisting of a consensus sequence as shown in SEQ ID NOs.: 19-22 or variants thereof, further comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1 is selected from the sequences shown in SEQ ID NOs.: 100-102, CDR2 is selected from the sequences shown in SEQ ID NOs.: 104-106, and CDR3 is selected from the sequences shown in SEQ ID NOs.: 107-114, 145, 146 and 147. 
     
     
         35 . The antibody of  claim 1 , which comprises a light chain comprising framework regions consisting of a consensus sequence as shown in SEQ ID NOs.: 23-26 or variants thereof, further comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1 is selected from the sequences shown in SEQ ID NOs.: 116-122, CDR2 is selected from the sequences shown in SEQ ID NOs.: 123-127, and CDR3 is selected from the sequences shown in SEQ ID NOs.: 128-144. 
     
     
         36 . The antibody of  claim 1  for use in medicine, particularly in human medicine. 
     
     
         37 . The antibody of  claim 1  for use in the treatment of a neurodegenerative disorder, particularly Parkinson's disease or Dementia with Lewy bodies. 
     
     
         38 . The antibody of  claim 1  for use in passive immune therapy. 
     
     
         39 . The antibody of  claim 1  for use as a diagnostic agent. 
     
     
         40 . A nucleic acid molecule encoding the antibody of  claim 1  optionally in operative linkage to an expression control sequence. 
     
     
         41 . A recombinant cell which comprises the nucleic acid molecule of  claim 40 . 
     
     
         42 . A method of preparing an antibody of  claim 1  comprising the steps: culturing a recombinant cell which comprises a nucleic acid molecule encoding the antibody of  claim 1  optionally in operative linkage to and expression control sequence under conditions which allow expression of the antibody encoding nucleic acid molecule, and collecting the antibody from the cell or the culture supernatant. 
     
     
         43 . A pharmaceutical composition comprising the antibody of  claim 1 , together with a pharmaceutically acceptable carrier. 
     
     
         44 . The composition of  claim 43  for use in passive immune therapy. 
     
     
         45 . A pharmaceutical composition comprising the nucleic acid molecule of  claim 40  with a pharmaceutically acceptable carrier. 
     
     
         46 . A pharmaceutical composition comprising the recombinant cell of  claim 41  together with a pharmaceutically acceptable carrier. 
     
     
         47 . A method of treating a neurodegenerative disease in a patient in need of such treatment, comprising administering an effective amount of an antibody of  claim 1  to said patient.