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 . A recombinantly produced binding molecule, which can selectively recognize a neoepitope of a disorder-associated protein, and which does not substantially recognize the protein in its non-disorder-associated form. 
     
     
         2 . The binding molecule of  claim 1 , which is an antibody or antigen-binding fragment thereof. 
     
     
         3 . The antibody or antigen-binding fragment thereof of  claim 2 , which is a human antibody. 
     
     
         4 . The binding molecule of  claim 1 , which can bind to beta-amyloid plaques, cerebrovascular amyloid, diffuse Abeta deposits, neurofibrillary tangles, hyperphosphorylated tau, alpha-synuclein positive Lewy-bodies or protein aggregates associated with dystrophic neurites. 
     
     
         5 . The binding molecule of  claim 1 , which is an antibody or antigen-binding fragment thereof comprising in its variable region at least one complementarity determining region (CDR) selected from the group consisting of: the heavy chain CDR1 of SEQ ID NO 17, SEQ ID NO 20, SEQ ID NO: 26, or SEQ ID NO: 32, the heavy chain CDR2 of SEQ ID NO: 18, SEQ ID NO: 21, SEQ ID NO: 27 or SEQ ID NO: 33, and the heavy chain CDR3 of SEQ ID NO: 19, SEQ ID NO: 22, SEQ ID NO: 28 or SEQ ID NO: 34, the light chain CDR1 of SEQ ID NO: 23, SEQ ID NO: 29, SEQ ID NO: 35, SEQ ID NO: 46, or SEQ ID NO: 49, the light chain CDR2 of SEQ ID NO: 24, SEQ ID NO: 30, SEQ ID NO: 36, SEQ ID NO: 47, or SEQ ID NO: 50, and the light chain CDR3 of SEQ ID NO: 25, SEQ ID NO: 31, SEQ ID NO: 37, SEQ ID NO: 48, or SEQ ID NO: 51. 
     
     
         6 . The antibody or binding fragment of  claim 5  comprising the amino acid sequence of a heavy chain variable region (VH) selected from the group consisting of: SEQ ID NO: 4; SEQ ID NO: 6; SEQ ID NO: 10; SEQ ID NO: 14; SEQ ID NO: 39; SEQ ID NO: 42; and SEQ ID NO: 43 and/or a light chain variable region (VL) selected from the group consisting of: SEQ ID NO: 8; SEQ ID NO: 12; SEQ ID NO: 16; SEQ ID NO: 41; SEQ ID NO: 44; and SEQ ID NO: 45. 
     
     
         7 . A composition comprising the binding molecule of  claim 1 . 
     
     
         8 . The composition of  claim 7 , further comprising an additional agent useful for treating Alzheimer's disease, selected from the group consisting of small organic molecules, anti-Abeta antibodies, or any combination thereof. 
     
     
         9 . A kit for the diagnosis of a disorder which is characterized by abnormal accumulation and/or deposition of a disorder-associated protein in the brain comprising the binding, molecule of  claim 1 , the composition of  claim 7 , or any combination thereof. 
     
     
         10 . A method for in vivo detection of or targeting a therapeutic and/or diagnostic agent to a disorder-associated protein in the brain, detecting, suppressing formation of or reducing pathological protein aggregates or conformations in a subject, for improving cognition or slowing or reversing cognitive decline associated with diseases, or for extra-corporal extraction of pathological compounds or their precursors from body fluids comprising administering the binding molecule of  claim 1 . 
     
     
         11 . A recombinantly produced antibody or antigen-binding fragment thereof which specifically binds: the same neoepitope of a disorder-associated protein as a reference antibody selected from the group consisting of NI-101.10, NI-101.11, NI-101.12, NI-101.13, NI-101.12F6A, NI-101.13A, and NI-101.13B. 
     
     
         12 . A recombinantly produced antibody or antigen-binding fragment thereof, wherein the antibody competitively inhibits a reference antibody selected from the group consisting of NI-101.10, NI-101.11, NI-101.12, NI-101.13, NI-101.12F6A, NI-101.13A, and NI-101.13B from binding to the neoepitope of a disorder-associated protein. 
     
     
         13 . A recombinantly produced antibody or antigen-binding fragment thereof wherein the antibody comprises an antigen binding domain identical to that of an antibody selected from the group consisting of NI-101.10, NI-101.11, NI-101.12, NI-101.13, NI-101.12F6A, NI-101.13A, and NI-101.13B. 
     
     
         14 . The binding molecule of  claim 1 , which is encoded by a cDNA, or fragment, variant, or derivative thereof, wherein the cDNA is derived from B-cells or memory B-cells obtained from a human patient who is symptom-free but affected with or at risk of developing a disorder, or a human patient with an unusually stable disease course.