Pharmaceutical Composition of an Antigenic Tau Peptide Reconstituted in a Liposome and Related Antibodies and Cell Lines

Abstract

The present invention is related to methods and pharmaceutical compositions for the therapeutic and diagnostic use in the treatment of diseases and disorders which are caused by or associated with neurofibrillary tangles. In particular, the invention relates to pharmaceutical compositions comprising an antigenic peptide, particularly an antigenic phopho-peptide mimicking a major pathological phosphor-epitope of protein tau, for the therapeutic and diagnostic use in the treatment of tauopathies including Alzheimer's Disease.

1 - 97 . (canceled) 
     
     
         98 . An isolated antibody, including a functionally equivalent antibody or a functional part thereof that binds the pathological protein tau-conformer or those parts of the conformer causing the pathological properties of said conformer with an affinity that is at least 40%, particularly at least 50%, particularly at least 60%, particularly at least 70%, particularly at least 80%, particularly at least 90%, particularly at least 95% and up to 100% higher than the binding affinity for the non-pathological tau conformer. 
     
     
         99 . The antibody of  claim 98 , which binds specifically to neurofibrillar tangles (NFTs) and neuropil threads in human Alzheimer's Disease brains. 
     
     
         100 . The antibody of  claim 98  that binds to an epitope on the tau protein, or to a combination of epitopes specific to a pathological protein tau-conformer as represented by or comprised in a peptide sequence selected from the group of sequences as given in SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9 and variant fragments thereof. 
     
     
         101 . The antibody of  claim 100  obtainable by immunizing a suitable animal with an antigenic peptide having an amino acid sequence as given in SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, including a functional fragment thereof. 
     
     
         102 . The antibody according to  claim 98 , which is a monoclonal, polyclonal, chimeric, single chain, bispecific, simianized, human or humanized antibody. 
     
     
         103 . The antibody according to  claim 102 , which is a polyclonal antibody. 
     
     
         104 . The antibody according to  claim 102 , which is a monoclonal antibody. 
     
     
         105 . The antibody according to  claim 102 , which is a human or humanized antibody having its CDRs derived from the antibody according to any one of the preceding claims. 
     
     
         106 . The antibody according to  claim 102 , which is a chimeric antibody. 
     
     
         107 . The antibody or a functional part thereof according to  claim 98 , which antibody has the characteristic binding properties of the antibody produced by hybridoma cell line
 a. ACI-41-Ab1 deposited on Mar. 3, 2010 as DSM ACC3043;   b. 2B6 deposited on Mar. 10, 2010 as DSM ACC3044;   c. 3A8 deposited on Mar. 10, 2010 as DSM ACC3045;   d. 4C1 deposited on Mar. 10, 2010 as DSM ACC3046;   e. 5D10A3 deposited on Mar. 10, 2010 as DSM ACC3047;   f. 6C10 deposited on Mar. 10, 2010 as DSM ACC3048;   g. 6H1 deposited on Mar. 10, 2010 as DSM ACC3049; or   h. 7C2 deposited on Mar. 10, 2010 as DSM ACC3050.   
     
     
         108 . The antibody or a functional part thereof according to  claim 98 , produced by hybridoma cell line
 a. ACI-41-Ab1 deposited on Mar. 3, 2010 as DSM ACC3043;   b. 2B6 deposited on Mar. 10, 2010 as DSM ACC3044;   c. 3A8 deposited on Mar. 10, 2010 as DSM ACC3045;   d. 4C1 deposited on Mar. 10, 2010 as DSM ACC3046;   e. 5D10A3 deposited on Mar. 10, 2010 as DSM ACC3047;   f. 6C10 deposited on Mar. 10, 2010 as DSM ACC3048;   g. 6H1 deposited on Mar. 10, 2010 as DSM ACC3049; or   h. 7C2 deposited on Mar. 10, 2010 as DSM ACC3050.   
     
     
         109 . A pharmaceutical composition comprising an antibody of  claim 98  together with a pharmaceutically acceptable carrier. 
     
     
         110 . The pharmaceutical composition of  claim 109  for the treatment of diseases and disorders which are caused by or associated with the formation of neurofibrillary lesions, the predominant brain pathology in tauopathy comprising a heterogenous group of neurodegenerative diseases or disorders including diseases or disorders which show co-existence of tau and amyloid pathologies including, but not limited to, Alzheimer's Disease, Creutzfeld-Jacob disease, Dementia pugilistica, Down's Syndrome, Gerstmann-Sträussler-Scheinker disease, inclusion-body myositis, and prion protein cerebral amyloid angiopathy, traumatic brain injury and further diseases or disorders which do not show a distinct amyloid pathology including, but not limited to, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, Non-Guamanian motor neuron disease with neurofibrillary tangles x, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, Subacute sclerosing panencephalitis Tangle only dementia, Postencephalitic Parkinsonism, Myotonic dystrophy. 
     
     
         111 . A method for the treatment of a neurodegenerative disease or disorder such as tauopathy comprising administering to an animal, particularly to a mammal, but especially to human, suffering from such a disease or disorder an antibody of  claim 98  or a pharmaceutical composition thereof. 
     
     
         112 . A method of diagnosing a tau-protein-associated disease, disorder or condition in a patient comprising detecting the immunospecific binding of an antibody or an active fragment thereof to an epitope of the tau protein in a sample or in situ which includes the steps of
 (a) bringing the sample or a specific body part or body area suspected to contain the tau protein into contact with an antibody according to  claim 98 , which antibody binds an epitope of the tau protein;   (b) allowing the antibody to bind to the tau protein to form an immunological complex;   (c) detecting the formation of the immunological complex; and   (d) correlating the presence or absence of the immunological complex with the presence or absence of tau protein in the sample or specific body part or area.   
     
     
         113 . A method for diagnosing a predisposition to tau-protein-associated disease, disorder or condition in a patient comprising detecting the immunospecific binding of an antibody or an active fragment thereof to an epitope of the tau protein in a sample or in situ which includes the steps of
 (a) bringing the sample or a specific body part or body area suspected to contain the tau protein into contact with an antibody according to  claim 98 . which antibody binds an epitope of the tau protein;   (b) allowing the antibody to bind to the tau protein to form an immunological complex;   (c) detecting the formation of the immunological complex; and   (d) correlating the presence or absence of the immunological complex with the presence or absence of tau protein in the sample or specific body part or area,   (e) comparing the amount of said immunological complex to a normal control value,   wherein an increase in the amount of said aggregate compared to a normal control value indicates that said patient is suffering from or is at risk of developing an tau protein-associated disease or condition.   
     
     
         114 . A method for monitoring minimal residual disease in a patient following treatment with an antibody or a pharmaceutical composition according to any one of the preceding claims, wherein said method comprises:
 (a) bringing the sample or a specific body part or body area suspected to contain the tau protein into contact with an antibody according to  claim 98 , which antibody binds an epitope of the tau protein;   (b) allowing the antibody to bind to the tau protein to form an immunological complex;   (c) detecting the formation of the immunological complex; and   (d) correlating the presence or absence of the immunological complex with the presence or absence of tau protein in the sample or specific body part or area,   (e) comparing the amount of said immunological complex to a normal control value,   wherein an increase in the amount of said aggregate compared to a normal control value indicates that said patient still suffers from a minimal residual disease.   
     
     
         115 . A method for predicting responsiveness of a patient being treated with an antibody or a pharmaceutical composition according to any one of the preceding claims comprising
 (a) bringing the sample or a specific body part or body area suspected to contain the tau protein into contact with an antibody according to  claim 98 , which antibody binds an epitope of the tau protein;   (b) allowing the antibody to bind to the tau protein to form an immunological complex;   (c) detecting the formation of the immunological complex; and   (d) correlating the presence or absence of the immunological complex with the presence or absence of tau protein in the sample or specific body part or area,   (e) comparing the amount of said immunological complex before and after onset of the treatment,   wherein an decrease in the amount of said aggregate indicates that said patient has a high potential of being responsive to the treatment.   
     
     
         116 . A test kit for detection and diagnosis of tau protein-associated diseases, disorders or conditions comprising an antibody according to  claim 98 . 
     
     
         117 . A test kit according to  claim 116  comprising a container holding one or more antibodies according to the present invention and instructions for using the antibodies for the purpose of binding to tau protein to form an immunological complex and detecting the formation of the immunological complex such that presence or absence of the immunological complex correlates with presence or absence of tau protein. 
     
     
         118 . A cell line producing an antibody according to  claim 98 . 
     
     
         119 . A cell line according to  claim 118 , which is hybridoma cell line ACI-41-Ab1 deposited on Mar. 3, 2010 as DSM ACC3043. 
     
     
         120 . A cell line according to  claim 118 , which is hybridoma cell line 2B6 deposited on Mar. 10, 2010 as DSM ACC3044. 
     
     
         121 . A cell line according to  claim 118 , which is hybridoma cell line 3A8 deposited on Mar. 10, 2010 as DSM ACC3045. 
     
     
         122 . A cell line according to  claim 118 , which is hybridoma cell line 4C1 deposited on Mar. 10, 2010 as DSM ACC3046. 
     
     
         123 . A cell line according to  claim 118 , which is hybridoma cell line 5D10A3 deposited on Mar. 10, 2010 as DSM ACC3047. 
     
     
         124 . A cell line according to  claim 118 , which is hybridoma cell line 6C10 deposited on Mar. 10, 2010 as DSM ACC3048. 
     
     
         125 . A cell line according to  claim 118 , which is hybridoma cell line 6H1 deposited on Mar. 10, 2010 as DSM ACC3049. 
     
     
         126 . A cell line according to  claim 118 , which is hybridoma cell line 7C2 deposited on Mar. 10, 2010 as DSM ACC3050. 
     
     
         127 . The antibody of  claim 98 , wherein the Tau protein is a human Tau protein.