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 . (canceled) 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . A binding molecule that binds beta-amyloid, wherein the binding molecule comprises a heavy chain variable region (V H ) and a light chain variable region (V L ), wherein the V H  and V L  comprise the V H  and V L  complementarity determining regions (CDRs) of an antibody selected from the group consisting of NI-101.10, NI-101.12, NI-101.13, NI-101.13A, and NI-101.13B. 
     
     
         15 . (canceled) 
     
     
         16 . The binding molecule of  claim 14 , which is an antibody or an antigen binding fragment thereof. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The binding molecule of  claim 14 , capable of binding beta-amyloid plaques, cerebrovascular amyloid, diffuse Abeta deposits, neurofibrillary tangles, hyperphosphorylated tau, alpha-synuclein positive Lewy-bodies or protein aggregates associated with dystrophic neurites. 
     
     
         22 . (canceled) 
     
     
         23 . The binding molecule of  claim 14 , which is selected from the group consisting of a single chain Fv fragment (scFv), a F(ab′) fragment, a F(ab) fragment, and an F(ab′) 2  fragment. 
     
     
         24 . (canceled) 
     
     
         25 . The binding molecule of  claim 16  comprising an amino acid sequence of the V H  and/or V L  region as depicted in Tables 2 and 3. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . A polynucleotide or polynucleotides encoding the binding molecule of  claim 14 . 
     
     
         29 . (canceled) 
     
     
         30 . A vector or vectors comprising the polynucleotide or polynucleotides of  claim 28 . 
     
     
         31 . A host cell comprising the polynucleotide or polynucleotides of  claim 28 . 
     
     
         32 . A method for preparing a disorder-associated protein specific binding molecule, said method comprising
 (a) culturing the cell of  claim 31 ; and   (b) isolating said binding molecule from the culture.   
     
     
         33 . A binding molecule obtainable by the method of  claim 32 . 
     
     
         34 . The binding molecule of  claim 14 , which is detectably labeled. 
     
     
         35 . The binding molecule, antibody or binding fragment of  claim 34 , wherein the detectable label is selected from the group consisting of an enzyme, a radioisotope, a fluorophore and a heavy metal. 
     
     
         36 . The binding molecule  claim 14 , which is attached to a drug. 
     
     
         37 . A pharmaceutical composition comprising the binding molecule, antibody or binding fragment of  claim 14 , and a pharmaceutically acceptable carrier. 
     
     
         38 . (canceled) 
     
     
         39 . The pharmaceutical composition of  claim 38  further comprising an additional agent useful for treating Alzheimer's disease, selected from the group consisting of small organic molecules, anti-Abeta antibodies, and combinations thereof. 
     
     
         40 . The composition of  claim 37 , which is a diagnostic composition and further comprises reagents conventionally used in immuno or nucleic acid based diagnostic methods. 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . A method of treating a neurological disorder characterized by abnormal accumulation and/or deposition of a protein in the central nervous system, which method comprises administering to a human subject in need thereof a therapeutically effective amount of the binding molecule of  claim 14 . 
     
     
         44 . The method of  claim 43 , wherein said disorder is selected from the group consisting of Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, multi-infarct dementia, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, cystic fibrosis, and Gaucher's disease. 
     
     
         45 . The method of  claim 43 , wherein administration is performed intravenously, intramuscularly, subcutaneously, intraperitoneally, intranasally, parenterally or as an aerosol. 
     
     
         46 . A method of diagnosing a disorder related to Alzheimer's disease and Abeta deposition, comprising administering to a human subject the binding molecule of  claim 14 . 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . (canceled)