Methods for preventing and treating A-beta oligomer-associated and/or -induced diseases and conditions

Abstract

The disclosure pertains to methods of treating or preventing a disease or condition associated with and/or induced by soluble A-beta oligomer such as Alzheimer's disease by administering to a subject in need thereof conformation specific and/or selective antibodies or binding fragments thereof and related products.

1 . A method of treating or preventing a disease or condition associated with and/or induced by soluble A-beta oligomer comprising administering to a subject in need thereof: an isolated conformation specific and/or selective antibody or binding fragment thereof that specifically and/or selectively binds to a cyclic compound comprising an A-beta peptide having a sequence of QKL, HQK, KLV, HHQK (SEQ ID NO: 1), QKLV (SEQ ID NO: 5) or HDSG (SEQ ID NO: 9), they cyclic compound optionally having a sequence of SEQ ID NO: 2, 3, 4, 6, 7, 8, 10, 11 or 12; an immunogen comprising a cyclic compound comprising an A-beta peptide having a sequence of QKL, HQK, KLV, HHQK (SEQ ID NO: 1), QKLV (SEQ ID NO: 5) or HDSG (SEQ ID NO: 9); a cell expressing said antibody or binding fragment thereof; or a nucleic acid encoding said antibody or binding fragment thereof. 
     
     
         2 . The method of  claim 1 , wherein the cyclic compound that is specifically and/or selectively bound has a sequence of SEQ ID NO: 2, 6 or 10. 
     
     
         3 . The method of  claim 1 , wherein the antibody or binding fragment selectively binds to the cyclic compound cover a corresponding linear peptide and/or selectively binds A-beta oligomer over A-beta monomer and/or A-beta fibril, wherein the antibody is at least 2 fold, 3 fold, at least 5 fold, at least 10 fold, at least 20 fold, at least 30 fold, at least 40 fold, at least 50 fold, at least 100 fold, at least 500 fold, at least 1000 fold more selective for the cyclic compound over the corresponding linear compound. 
     
     
         4 . The method of  claim 1  wherein the antibody or binding fragment thereof is a monoclonal antibody, a chimeric antibody, a humanized antibody or a polyclonal antibody or a binding fragment of any of the foregoing. 
     
     
         5 . The method of  claim 1 , wherein the binding fragment is an antibody binding fragment selected from Fab, Fab′, F(ab′)2, scFv, dsFv, ds-scFv, dimers, nanobodies, minibodies, diabodies, and multimers thereof. 
     
     
         6 . The method of  claim 1 , wherein the antibody comprises a light chain variable region and a heavy chain variable region, optionally fused, the heavy chain variable region comprising complementarity determining regions CDR-H1, CDR-H2 and CDR-H3, the light chain variable region comprising complementarity determining region CDR-L1, CDR-L2 and CDR-L3 and with the amino acid sequences of said CDRs comprising the sequences in Table 9 A to I. 
     
     
         7 . The method of  claim 1 ,
 wherein the antibody or binding fragment comprises a heavy chain variable region comprising: i) an amino acid sequence of a heavy chain variable sequence as set forth in Table 10, 12 or 13; ii) an amino acid sequence with at least 50%, at least 60%, at least 70%, at least 80% or at least 90% sequence identity to said heavy chain variable sequence set out in Table 10, 12 or 13, wherein the CDR sequences are the corresponding CDRs as set forth in Table 9, or iii) a conservatively substituted amino acid sequence i) wherein the CDR sequences are the corresponding CDRs as set forth in Table 9; and   wherein the antibody comprises a light chain variable region comprising i) an amino acid sequence of a light chain variable sequence as set forth in Table 10, 12 or 13, ii) an amino acid sequence with at least 50%, at least 60%, at least 70%, at least 80%, at least 90% sequence identity to said light chain variable sequence as set out in Table 10, 12 or 13, wherein the CDR sequences are the corresponding CDRs as set forth in Table 9, or iii) a conservatively substituted amino acid sequence i) wherein the CDR sequences a are the corresponding CDRs as set forth in Table 9.   
     
     
         8 . The method of  claim 1 , wherein the antibody or binding fragment competes for binding to human A-beta with an antibody comprising the CDR sequences as recited in Table 9 and/or antibody produced by the hybridoma cell line deposited under the provisions of the Budapest Treaty with the American Type Culture Collection (ATCC®) 10801 University Blvd., Manassas, Va., 20110-2209, USA on Jul. 19, 2017 and given the Accession number PTA-12431. 
     
     
         9 . The method of  claim 1 , wherein the antibody is comprised in an immunoconjugate comprising the antibody and a cytotoxic agent. 
     
     
         10 . The method of  claim 1  wherein the cell expressing the antibody or binding fragment thereof or the nucleic acid molecule encoding the antibody of or binding fragment thereof is administered, optionally wherein the nucleic acid molecule is comprised in a vector. 
     
     
         11 . The method of  claim 1 , wherein the disease or condition associated with and/or induced by soluble A-beta oligomer is Alzheimer's disease (AD). 
     
     
         12 . The method of  claim 1 , wherein a combination of antibodies or binding fragments is administered. 
     
     
         13 . A composition comprising two or more antibodies or binding fragments thereof comprising a CDR set listed in Table 9, a variable heavy and light domain region combination listed in Table 10 or Table 12 or 13 or two or more nucleic acid molecules encoding one of the foregoing. 
     
     
         14 . A method of inhibiting A-beta oligomer propagation, the method comprising contacting a cell or tissue expressing A-beta with or administering to a subject in need thereof an effective amount of an isolated A-beta oligomer specific or selective antibody or binding fragment thereof that specifically and/or selectively binds to a cyclic compound comprising an A-beta peptide having a sequence of QKL, HQK, KLV, HHQK (SEQ ID NO: 1), QKLV (SEQ ID NO: 5) or HDSG (SEQ ID NO: 9), they cyclic compound optionally having a sequence of SEQ ID NO: 2, 3, 4, 6, 7, 8, 10, 11 or 12; an immunogen comprising a cyclic compound comprising an A-beta peptide having a sequence of QKL, HQK, KLV, HHQK (SEQ ID NO: 1), QKLV (SEQ ID NO: 5) or HDSG (SEQ ID NO: 9); a cell expressing said antibody or binding fragment thereof; or a nucleic acid encoding said antibody or binding fragment thereof or immunoconjugate thereof, to inhibit A-beta aggregation and/or oligomer propagation. 
     
     
         15 . The method of  claim 14 , wherein a biological sample from the subject to be treated is assessed for the presence or levels of A-beta using an antibody described herein. 
     
     
         16 . The method of  claim 14 , wherein more than one antibody or immunoconjugate is administered. 
     
     
         17 . The method of  claim 14 , wherein the antibody or binding fragment thereof, immunoconjugate, cell or nucleic acid is administered directly to the brain or other portion of the CNS. 
     
     
         18 . A hybrdioma cell line deposited under the provisions of the Budapest Treaty with the American Type Culture Collection (ATCC®) 10801 University Blvd., Manassas, Va., 20110-2209, USA on Jul. 19, 2017 and given the Accession number PTA-124318. 
     
     
         19 . An antibody or binding fragment thereof comprising a light chain variable region and a heavy chain variable region, optionally fused, the heavy chain variable region comprising complementarity determining regions CDR-H1, CDR-H2 and CDR-H3, the light chain variable region comprising complementarity determining region CDR-L1, CDR-L2 and CDR-L3 and with the amino acid sequences of said CDRs comprising the sequences in Table 9B, 9C, 9G, 9H or 9I; or an antibody that competes for binding with said antibody comprising a light chain variable region and a heavy chain variable region, optionally fused, the heavy chain variable region comprising complementarity determining regions CDR-H1, CDR-H2 and CDR-H3, the light chain variable region comprising complementarity determining region CDR-L1, CDR-L2 and CDR-L3 and with the amino acid sequences of said CDRs comprising the sequences in Tables 9B, 9C, 9G, 9H or 9I, optionally wherein the antibody or binding fragment is a monoclonal antibody, a chimeric antibody, a humanized antibody or a polyclonal antibody or a binding fragment of any of the foregoing optionally wherein the binding fragment is an antibody binding fragment selected from Fab, Fab′, F(ab′)2, scFv, dsFv, ds-scFv, dimers, nanobodies, minibodies, diabodies, and multimers thereof. 
     
     
         20 . An immunoconjugate comprising the antibody or binding fragment of  claim 19  and a detectable label or cytotoxic agent, optionally, wherein the detectable label comprises a positron emitting radionuclide, optionally for use in subject imaging such as PET imaging. 
     
     
         21 . A composition or kit comprising the antibody or binding fragment of  claim 19 , an immunoconjugate comprising said antibody, or a nucleic acid encoding said antibody. 
     
     
         22 . A nucleic acid molecule encoding the antibody of  claim 19 , optionally comprised in a vector, or a cell expressing said antibody or binding fragment. 
     
     
         23 . A method, the method comprising contacting a biological sample, optionally a brain tissue sample or an extract thereof, whole blood, plasma, serum and/or CSF, from a subject with the antibody or binding fragment of  claim 17  or an immunoconjugate comprising said antibody or binding fragment under conditions permissive for forming an antibody: A-beta oligomer complex; and detecting the presence of any antibody: A-beta oligomer complex. 
     
     
         24 . The method of  claim 23 , wherein the level of A-beta is detected by SPR.