Method of providing disease-specific binding molecules and targets

Abstract

Provided are novel specific binding molecules, particularly human antibodies as well as fragments, derivatives and variants thereof that recognize neoepitopes of disease-associated proteins which derive from native endogenous proteins but are prevalent in the body of a patient in a variant form and/or out of their normal physiological context. In addition, pharmaceutical compositions comprising such binding molecules, antibodies and mimics thereof and methods of screening for novel binding molecules, which may or may not be antibodies as well as targets in the treatment of neurological disorders such as Alzheimer's disease are described.

1 .- 51 . (canceled) 
     
     
         52 . A polynucleotide encoding:
 (i) a heavy chain variable (VH) region operably linked to a human IgG1 constant region or fragment thereof, wherein the VH region comprises a heavy chain complementarity determining region 1 (VHCDR1) having an amino acid sequence according to SEQ ID NO:20, a heavy chain complementarity determining region 2 (VHCDR2) having an amino acid sequence according to SEQ ID NO:21, and a heavy chain complementarity determining region (VHCDR3) having an amino acid sequence according to SEQ ID NO:22, or   (ii) a light chain variable (VL) region comprising a light chain complementarity determining region 1 (VLCDR1) having an amino acid sequence according to SEQ ID NO:23, a light chain complementarity determining region 2 (VLCDR2) having an amino acid sequence according to SEQ ID NO:24, and a light chain complementarity determining region 3 (VLCDR3) having an amino acid sequence according to SEQ ID NO:25.   
     
     
         53 . The polynucleotide of  claim 52 , wherein:
 (i) the VH region encoded by the polynucleotide comprises an amino acid sequence according to SEQ ID NO: 39, or   (ii) the VL region encoded by the polynucleotide comprises an amino acid sequence according to SEQ ID NO: 41.   
     
     
         54 . The polynucleotide of  claim 53 , wherein the VH region encoded by the polynucleotide has a nucleotide sequence according to SEQ ID NO: 38. 
     
     
         55 . The polynucleotide of  claim 53 , wherein the VL region encoded by the polynucleotide has a nucleotide sequence according to SEQ ID NO: 40. 
     
     
         56 . The polynucleotide of  claim 52 , wherein the polynucleotide is a polyribonucleotide. 
     
     
         57 . The polynucleotide of  claim 53 , wherein the polynucleotide is a polyribonucleotide. 
     
     
         58 . A vector comprising the polynucleotide of  claim 52 . 
     
     
         59 . A vector comprising the polynucleotide of  claim 53 . 
     
     
         60 . A vector comprising the polynucleotide of  claim 54 . 
     
     
         61 . A vector comprising the polynucleotide of  claim 55 . 
     
     
         62 . A vector comprising the polynucleotide of  claim 56 . 
     
     
         63 . A vector comprising the polynucleotide of  claim 57 . 
     
     
         64 . A composition comprising:
 (i) a first polynucleotide encoding a heavy chain variable (VH) region operably linked to a human IgG1 constant region or fragment thereof, wherein the VH region comprises a heavy chain complementarity determining region 1 (VHCDR1) having an amino acid sequence according to SEQ ID NO:20, a heavy chain complementarity determining region 2 (VHCDR2) having an amino acid sequence according to SEQ ID NO:21, and a heavy chain complementarity determining region (VHCDR3) having an amino acid sequence according to SEQ ID NO:22, and   (ii) a second polynucleotide encoding a light chain variable (VL) region comprising a light chain complementarity determining region 1 (VLCDR1) having an amino acid sequence according to SEQ ID NO:23, a light chain complementarity determining region 2 (VLCDR2) having an amino acid sequence according to SEQ ID NO:24, and a light chain complementarity determining region 3 (VLCDR3) having an amino acid sequence according to SEQ ID NO:25.   
     
     
         65 . The composition of  claim 60 , wherein:
 (i) the VH region encoded by the first polynucleotide comprises an amino acid sequence according to SEQ ID NO: 39, and   (ii) the VL region encoded by the second polynucleotide comprises an amino acid sequence according to SEQ ID NO: 41.   
     
     
         66 . A construct comprising:
 (i) one or more regulatory elements, and   (ii) the polynucleotide of  claim 52 ,   wherein the one or more regulatory elements are operatively linked to the polynucleotide of  claim 52 .   
     
     
         67 . The construct of  claim 66 , wherein the one or more regulatory elements are selected from a group consisting of a promoter, enhancer, operator, repressor, transcription termination signal, transcription control regions, ribosome binding sites, translation initiation and termination codons, and internal ribosome entry site. 
     
     
         68 . A construct comprising:
 (i) one or more regulatory elements, and   (ii) the polynucleotide of  claim 53 ,   wherein the one or more regulatory elements are operatively linked to the polynucleotide of  claim 53 .   
     
     
         69 . The DNA construct of  claim 68 , wherein the one or more regulatory elements are selected from the group consisting of a promoter, enhancer, operator, repressor, transcription termination signal, transcription control regions, ribosome binding sites, translation initiation and termination codons, and internal ribosome entry site.