Method of treatment of neurodementing diseases using isolated, monoclonal, human, anti-B-amyloid antibody
Isolated, monoclonal, human, anti-β-amyloid antibodies are provided which bind to dimeric forms of Ab with higher affinity than to monomeric forms of Ab and when bound to an Aβ polypeptide comprising Aβ(21-37) shield Aβ(21-37) from proteolytic digestion. The antibodies were shown to inhibit fibril formulation and reduce plaque size in vivo and to not bind brain vessel walls. Accordingly, the antibodies are useful in human and veterinary medicine for the treatment and prophylaxis of Alzheimer's disease and other neurodementing diseases. Methods of detecting or measuring the progression of a neurodementing disease also are provided.
1. A method of treating a neurodementing disease in a patient comprising administering to said patient a therapeutically acceptable amount of an antibody, wherein the antibody comprises:
a full set of six CDRs, three from the variable heavy chain region (VH) (SEQ ID NOs: 15, 23 and 29) and three from the variable light chain region (VL) (SEQ ID NOs: 33, 41 and 45); or
a full set of six CDRs, three from the variable heavy chain region (VH) (SEQ ID NOs: 13, 21 and 28) and three from the variable light chain region (VL) (SEQ ID NOs: 34, 38 and 44); or
a full set of six CDRs, three from the variable heavy chain region (VH) (SEQ ID NOs: 14, 27 and 30) and three from the variable light chain region (VL) (SEQ ID NOs: 33, 42 and 44); or
the three CDRs from the VL and the three CDRs from the VH amino acid sequence pairs of SEQ ID NO: 53 and SEQ ID NO: 60, SEQ ID NO: 47 and SEQ ID NO: 56, SEQ ID NO: 48 and SEQ ID NO: 57, SEQ ID NO: 145 and SEQ ID NO: 60, SEQ ID NO: 51 and SEQ ID NO: 60, SEQ ID NO: 52 and SEQ ID NO: 60, SEQ ID NO: 146 and SEQ ID NO: 60, SEQ ID NO: 53 and SEQ ID NO: 148, SEQ ID NO: 55 and SEQ ID NO: 61, SEQ ID NO: 145 and SEQ ID NO: 62, SEQ ID NO: 54 and SEQ ID NO: 60, SEQ ID NO: 54 and SEQ ID NO: 61, SEQ ID NO: 54 and SEQ ID NO: 148, SEQ ID NO: 145 and SEQ ID NO: 148, or SEQ ID NO: 146 and SEQ ID NO: 61;
wherein said antibody binds to dimeric forms of Aβ with higher affinity than to monomeric forms of Aβ;
and wherein the neurodementing disease is selected from the group consisting of Alzheimer's disease, Down's syndrome, dementia with Lewy bodies, fronto-temporal dementia and cerebral amyloid angiopathy.
2. The method of claim 1 , wherein the antibody binds to a peptide comprising Aβ(21-37) (SEQ ID NO: 2).
3. The method of claim 1 , wherein the antibody shields residues of Aβ(21-37) from proteolytic digestion when being bound to an Aβ polypeptide comprising Aβ(21-37).
4. The method of claim 1 , wherein the antibody binds specifically to Aβ partial polypeptides Aβ(12-40) or Aβ(20-37) when said antibody is coupled to NHS-activated 6-aminohexanoic acid-coupled sepharose, but does not bind specifically to Aβ(17-28), Aβ(25-35) or Aβ(31-40).
5. The method of claim 1 , wherein the antibody shields residues of Aβ(21-37) from proteolytic digestion when being bound to an Aβ polypeptide comprising Aβ(21-37).
6. The method of claim 1 wherein the antibody is administered intravenously at a dose between 0.01 mg/kg to 100 mg/kg.
7. The method of claim 1 , wherein the antibody is administered to the brain.