Anti-addl monoclonal antibody and uses thereof

Abstract

Disclosed are antibodies that bind amyloid beta-derived diffusible ligands, also known as ADDLs. The antibodies are selective for ADDLs, can penetrate the brain, and are useful in methods of detecting ADDLs and diagnosing Alzheimer's disease. The antibodies also block binding of ADDLs to neurons, assembly of ADDLS, and tau phosphorylation and are there useful in methods for the preventing and treating diseases associated with ADDLs.

What is claimed: 
     
         1 . An isolated antibody, or an antigen binding fragment thereof, that binds amyloid β-derived diffusible ligands comprising:
 (a) a light chain variable region comprising, 
 (i) a CDR1 of SEQ ID NO: 1, 
 (ii) a CDR2 of SEQ ID NO: 2, and 
 (iii) a CDR3 having the sequence Phe-Gln-Gly-Ser-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5 (SEQ ID NO: 3), wherein Xaa1 is Arg, Lys or Tyr, Xaa2 is Val, Ala, or Leu, Xaa3 is Pro, His, or Gly, Xaa4 is Ala, Pro, or Val, and Xaa5 is Ser, Gly, or Phe; and 
 (b) a heavy chain variable region comprising, 
 (i) a CDR1 of SEQ ID NO: 4, 
 (ii) a CDR2 of SEQ ID NO: 5, and 
 (iii) a CDR3 of SEQ ID NO: 6. 
 
     
     
         2 . The isolated antibody or antigen-binding fragment of  claim 1  wherein the light chain variable region CDR3 is selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13. 
     
     
         3 . The isolated antibody or antigen-binding fragment of  claim 1  wherein the light chain variable region CDR3 is SEQ ID NO: 10. 
     
     
         4 . The isolated antibody of  claim 1  wherein the light chain variable region of said antibody comprises SEQ ID NO: 15 and the heavy chain variable region of said antibody comprises SEQ ID NO: 17. 
     
     
         5 . The isolated antibody of  claim 1  further comprising a heavy chain constant region of SEQ ID NO: 21. 
     
     
         6 . The isolated antibody or antigen-binding fragment of  claim 1  further comprising a light chain variable region CDR1 having the sequence Arg-Ser-Ser-Gln-Ser-Ile-Val-His-Ser-Xaa1-Gly-Xaa2-Thr-Thy-Leu-Glu (SEQ ID NO: 53), wherein Xaa1 is Asn, Ser, Thr, Ala, Asp or Glu and Xaa2 is Asn, His, Gln, Ser, Thr, Ala, or Asp. 
     
     
         7 . The isolated antibody or antigen-binding fragment of  claim 1  further comprising a light chain variable region CDR2 having the sequence Lys-Ala-Ser-Xaa1-Arg-Phe-Ser (SEQ ID NO: 54), wherein Xaa1 is Asn, Gly, Ser, Thr, or Ala. 
     
     
         8 . The isolated antibody of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         9 . A pharmaceutical composition comprising the antibody or antigen binding fragment of  claim 1  in admixture with a pharmaceutically acceptable carrier. 
     
     
         10 . A method for attenuating binding of amyloid β-derived diffusible ligands to a neuron comprising contacting the neuron with the antibody or antigen binding fragment of  claim 1  so that binding of Aβ-derived diffusible ligands to the neuron is attenuated. 
     
     
         11 . A method for inhibiting assembly of amyloid β-derived diffusible ligands comprising contacting a sample containing amyloid β1-42 peptides with the antibody or antigen binding fragment of  claim 1  thereby inhibiting assembly of Aβ-derived diffusible ligands. 
     
     
         12 . A method for inhibiting the phosphorylation of tau protein at Ser202/Thr205 comprising contacting a sample containing a tau protein with the antibody or antigen binding fragment of  claim 1  thereby inhibiting the phosphorylation of tau protein at Ser202/Thr205. 
     
     
         13 . A method for attenuating the symptoms of a disease associated with amyloid β-derived diffusible ligands comprising administering an effective amount of the pharmaceutical composition of  claim 9 . 
     
     
         14 . A method for identifying a putative therapeutic agent that attenuates the binding of amyloid β-derived diffusible ligands to neurons comprising
 (a) contacting a composition comprising a neuron with amyloid β-derived diffusible ligands in the presence of an agent; 
 (b) contacting the composition with the antibody or antigen binding fragment of  claim 1 ; and 
 (c) detecting the amount of antibody or antigen binding fragment bound in the presence of the agent, 
 wherein a decrease in the amount of antibody or antigen binding fragment bound in the presence of the agent as compared to the amount of antibody bound in the absence of the agent indicates that the agent is a putative therapeutic agent for attenuating binding of amyloid β-derived diffusible ligands to neurons. 
 
     
     
         15 . A method for detecting amyloid β-derived diffusible ligands in a sample comprising contacting a sample with the antibody or antigen binding fragment of  claim 1  and determining the presence of a complex comprising the amyloid β-derived diffusible ligands and said antibody or antigen binding fragment. 
     
     
         16 . A method for diagnosing a disease associated with amyloid β-derived diffusible ligands comprising contacting a sample with the antibody or antigen binding fragment of  claim 1  and determining the presence of a complex comprising the amyloid β-derived diffusible ligands and said antibody or antigen binding fragment, wherein the complex is diagnostic of a disease associated with amyloid β-derived diffusible ligands. 
     
     
         17 . A kit for detecting amyloid β-derived diffusible ligands comprising the antibody or antigen binding fragment of  claim 1 .