Apoe immunotherapy

Abstract

The present invention provides antibodies that preferentially bind to an ApoE(1-272) fragment relative to ApoE(1-299). These antibodies serve to reduce the toxicity of this fragment and find use in treatment and prophylaxis of a variety of neurological diseases.

1 - 86 . (canceled) 
     
     
         87 . A method of treating or effecting prophylaxis of Alzheimer's disease comprising administering an effective regime of an antibody that preferentially binds to ApoE(1-272) relative to ApoE(1-299) or an agent that induces such an antibody to a patient having or at risk of Alzheimer's disease and thereby treating or effecting prophylaxis of the disease. 
     
     
         88 . The method of  claim 87 , wherein the antibody is as defined in any of claims  1 - 10 . 
     
     
         89 . The method of  claim 87 , wherein the agent is a fragment of 3-10 contiguous amino acids of ApoE with a C-terminus at residue 272. 
     
     
         90 - 91 . (canceled) 
     
     
         92 . A method of treating or effecting prophylaxis of a disease associated with ApoE4 comprising administering an effective regime of an antibody that preferentially binds to ApoE(1-272) relative to ApoE(1-299) or an agent that induces such an antibody to a patient having or at risk of the disease and thereby treating or effecting prophylaxis of the disease. 
     
     
         93 - 94 . (canceled) 
     
     
         95 . The method of  claim 87 , wherein the antibody comprises a mature heavy chain variable region comprising the three Kabat CDRs of SEQ ID NO:9, and having at least 90% sequence identity to SEQ ID NO:9, and a mature light chain variable region comprising the three Kabat CDRs of SEQ ID NO:10, and having at least 90% sequence identity to SEQ ID NO:10. 
     
     
         96 - 98 . (canceled) 
     
     
         99 . The method of  claim 87 , wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence of SEQ ID NO:17 and a mature light chain variable region having an amino acid sequence of SEQ ID NO:18 provided that position L3 (Kabat numbering) can be occupied by V or L, position L36 (Kabat numbering) can be occupied by F or Y, position L46 (Kabat numbering) can be occupied by R or L, position H1 (Kabat numbering) can be occupied by Q or E, position H3 (Kabat numbering) can be occupied by Q or K, position H5 (Kabat numbering) can be occupied by Q or V, position H42 (Kabat numbering) can be occupied by D or E, and position H83 (Kabat numbering) can be occupied by K or R. 
     
     
         100 - 101 . (canceled) 
     
     
         102 . The method of  claim 87 , wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence of SEQ ID NO:11 and a mature light chain variable region having an amino acid sequence of SEQ ID NO:14. 
     
     
         103 . The method of  claim 87 , wherein the antibody comprises a mature heavy chain variable region having the amino acid sequence of SEQ ID NO:11, a heavy chain constant region having the amino acid sequence of SEQ ID NO:39, a mature light chain variable region having the amino acid sequence of SEQ ID NO:14 and a light chain constant region having the amino acid sequence of SEQ ID NO:35. 
     
     
         104 . A method of screening an agent for activity against Alzheimer's disease, comprising administering the agent to a transgenic animal expressing ApoE and APP transgenes, and determining whether the agent inhibits or delays at least one sign or symptom of Alzheimer's disease, wherein the agent is an antibody that preferentially binds to ApoE(1-272) relative to Apo E(1-299) or an agent that induces such an antibody. 
     
     
         105 . A method of generating an antibody that preferentially binds to ApoE(1-272) relative to binding to ApoE(1-299), comprising immunizing an animal with an immunogen comprising a fragment of ApoE consisting of SEQ ID NO:41 linked to a carrier on the N-terminus of the fragment. 
     
     
         106 . The method of  claim 105 , wherein the immunogen comprises SEQ ID NO:5. 
     
     
         107 - 109 . (canceled) 
     
     
         110 . The antibody of claim  5 , wherein the antibody competes for specific binding to ApoE with 15G8, and wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain constant region is fused to a light chain constant region. 
     
     
         111 . The antibody of claim  5 , wherein the antibody binds to the same epitope on ApoE as 15G8, and wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain constant region is fused to a light chain constant region. 
     
     
         112 . The antibody of claim  56 , wherein the heavy chain constant region is of human IgG1m3 allotype. 
     
     
         113 . The antibody of any of claims  1 - 11 , wherein the antibody competes for specific binding to ApoE with 15G8 and the heavy chain constant region is of human IgG1m1 or IgG1m3 allotype. 
     
     
         114 . The antibody of any of claims  1 - 11 , wherein the antibody binds to the same epitope on ApoE as 15G8 and the heavy chain constant region is of human IgG1m1 or IgG1m3 allotype. 
     
     
         115 . The antibody of claim  56 , wherein the mature heavy chain variable region is fused to a heavy chain constant region having the amino acid sequence of SEQ ID NO:39 provided the C-terminal lysine residue may be omitted and the mature light chain constant region is fused to a light chain constant region having the amino acid sequence of SEQ ID NO:35. 
     
     
         116 . The antibody of claim  56  comprising a mature heavy chain variable region having the amino acid sequence of SEQ ID NO:17, a heavy chain constant region having the amino acid sequence of SEQ ID NO:39, a mature light chain variable region having the amino acid sequence of SEQ ID NO:18 and a light chain constant region having the amino acid sequence of SEQ ID NO:35. 
     
     
         117 . The pharmaceutical composition of claim  82 , wherein the antibody comprises three light chain Kabat CDRs and three heavy chain Kabat CDRs, wherein each light chain CDR has at least 90% sequence identity to a corresponding CDR designated as SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:24, and each heavy chain CDR has at least 90% sequence identity to a corresponding CDR designated as SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21. 
     
     
         118 . The method of  claim 87 , wherein the disease is a neurological disease. 
     
     
         119 . The method of  claim 87 , wherein the neurological disease is Alzheimer's disease.