METHOD FOR TREATING A DISEASE ASSOCIATED WITH SOLUBLE, OLIGOMERIC SPECIES OF AMYLOID BETA 1-42

1 . A method for treating a disease associated with or resulting from the accumulation of soluble oligomer amyloid beta 1-42 comprising administering to a subject in need thereof

(a) a dose of less than 10 mg/kg body weight of an antibody, or antibody fragment thereof, that has a higher affinity for amyloid beta 1-42 oligomers than for amyloid beta 1-42 monomer, amyloid beta 1-40 monomer, plaques and amyloid beta fibrils; and

(b) a second therapeutic comprising

(i) a beta-secretase or gamma-secretase inhibitor,

(ii) an amyloid beta aggregation inhibitor,

(iii) a tau therapeutic, or

(iv) a combination of (i)-(iii).

so that the disease associated with or resulting from the accumulation of soluble oligomer amyloid beta 1-42 is treated.

2 . The method of claim 1 , wherein the affinity of the antibody for amyloid beta 1-42 oligomers compared to amyloid beta 1-40 monomers in a competitive binding assay is at least 500:1.

3 . The method of claim 1 , wherein the antibody, or antibody fragment thereof, blocks binding of amyloid beta 1-42 oligomers to neurons.

4 . The method of claim 1 , wherein the antibody, or antibody fragment thereof, blocks incorporation of amyloid beta 1-42 oligomers into amyloid plaques.

5 . The method of claim 1 , wherein the antibody, or antibody fragment thereof, reverses acute amyloid beta 1-42 oligomer-mediated impairment of long-term potentiation.

6 . The method of claim 1 , wherein administration of the antibody, or antibody fragment thereof, provides improvement in cognitive testing as compared to a subject not receiving the antibody or antibody fragment.

7 . The method of claim 1 , wherein the antibody, or antibody fragment thereof, has

(a) a light chain variable region comprising,

(i) a CDR1 having the sequence Arg-Ser-Ser-Gln-Ser-Ile-Val-His-Ser-Xaa 1 -Gly-Xaa 2 -Thr-Thy-Leu-Glu (SEQ ID NO:1), wherein Xaa 1 is Asn, Ser, Thr, Ala, Asp or Glu and Xaa 2 is Asn, His, Gln, Ser, Thr, Ala, or Asp,

(ii) a CDR2 having the sequence Lys-Ala-Ser-Xaa 1 -Arg-Phe-Ser (SEQ ID NO:2), wherein Xaa 1 is Asn, Gly, Ser, Thr, or Ala, and

(iii) a CDR3 having the sequence Phe-Gln-Gly-Ser-Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 (SEQ ID NO:3), wherein Xaa 1 is Arg, Lys or Tyr, Xaa 2 is Val, Ala, or Leu, Xaa 3 is Pro, His, or Gly, Xaa 4 is Ala, Pro, or Val, and Xaa 5 is Ser, Gly, Arg 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.

8 . The method of claim 1 , wherein the beta-secretase or gamma-secretase inhibitor comprises CTS-21166, Posiphen, ACI-91, MK-8931, TAK-070, MK-0752, GSK188909, OM99-2, KMI-429, GRL-8234 a statine inhibitor, a phenylnorstatine inhibitor, a hydroxyethylamine inhibitor, a carbinamine inhibitor, an acylguanidine inhibitor, an aminoimidazole inhibitor, an aminohydantoin inhibitor, an aminoquinazoline inhibitor, semagacestat, avagacestat, or EVP-0962.

9 . The method of claim 1 , wherein the amyloid beta aggregation inhibitor comprises PBT2, ELND0005, N-(2-methoxy-phenyl)-2-oxo-2-{N′-[3-oxo-3-thiophen-2-yl-1-trifluoromethyl-prop-(Z)-ylidene]-hydrazino}-acetamide, 2-{[1-(2-hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester, 2-{[1-(2-hydroxynaphthalen-1-yl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester, 2-{[1-(2-hydroxyphenyl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester, 2-(5-hydroxy-3-isobutyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(2-methoxyphenyl)-2-oxoacetamide or (E)-2-hydroxy-N′-((1-hydroxynaphthalen-2-yl)methylene)benzohydrazide.

10 . The method of claim 1 , wherein the tau therapeutic comprises EC-102, davunetide, methylthioninium chloride or tideglusib.

11 . A kit comprising:

(a) an antibody, or antibody fragment thereof, that has a higher affinity for amyloid beta 1-42 oligomers than for amyloid beta 1-42 monomer, amyloid beta 1-40 monomer, plaques and amyloid beta fibrils; and

(b) a second therapeutic comprising

(i) a beta-secretase or gamma-secretase inhibitor,

(ii) an amyloid beta aggregation inhibitor,

(iii) a tau therapeutic, or

(iv) a combination of (i)-(iii).

12 . The kit of claim 11 , wherein the antibody, or antibody fragment thereof, has

(a) a light chain variable region comprising,

(i) a CDR1 having the sequence Arg-Ser-Ser-Gln-Ser-Ile-Val-His-Ser-Xaa 1 -Gly-Xaa 2 -Thr-Thy-Leu-Glu (SEQ ID NO:1), wherein Xaa 1 is Asn, Ser, Thr, Ala, Asp or Glu and Xaa 2 is Asn, His, Gln, Ser, Thr, Ala, or Asp,

(ii) a CDR2 having the sequence Lys-Ala-Ser-Xaa 1 -Arg-Phe-Ser (SEQ ID NO:2), wherein Xaa 1 is Asn, Gly, Ser, Thr, or Ala, and

(iii) a CDR3 having the sequence Phe-Gln-Gly-Ser-Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 (SEQ ID NO:3), wherein Xaa 1 is Arg, Lys or Tyr, Xaa 2 is Val, Ala, or Leu, Xaa 3 is Pro, His, or Gly, Xaa 4 is Ala, Pro, or Val, and Xaa 5 is Ser, Gly, Arg 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.

13 . The kit of claim 11 , wherein the beta-secretase or gamma-secretase inhibitor comprises CTS-21166, Posiphen, ACI-91, MK-8931, TAK-070, MK-0752, GSK188909, OM99-2, KMI-429, GRL-8234 a statine inhibitor, a phenylnorstatine inhibitor, a hydroxyethylamine inhibitor, a carbinamine inhibitor, an acylguanidine inhibitor, an aminoimidazole inhibitor, an aminohydantoin inhibitor, an aminoquinazoline inhibitor, semagacestat, avagacestat, or EVP-0962.

14 . The kit of claim 11 , wherein the amyloid beta aggregation inhibitor comprises PBT2, ELND0005, N-(2-methoxy-phenyl)-2-oxo-2-{N′-[3-oxo-3-thiophen-2-yl-1-trifluoromethyl-prop-(Z)-ylidene]-hydrazino}-acetamide, 2-{[1-(2-hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester, 2-{[1-(2-hydroxynaphthalen-1-yl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester, 2-{[1-(2-hydroxyphenyl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester, 2-(5-hydroxy-3-isobutyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(2-methoxyphenyl)-2-oxoacetamide or (E)-2-hydroxy-N′-((1-hydroxynaphthalen-2-yl)methylene)benzohydrazide.

15 . The kit of claim 11 , wherein the tau therapeutic comprises EC-102, davunetide, methylthioninium chloride or tideglusib.