Methods and Compositions for Inhibiting the Effects of Amyloid Beta Oligomers

Patent metadata

Field	Value
Publication number	US-2016009782-A1
Application number	US-201414772357-A
Country	US
Kind code	A1
Filing date	Mar 10, 2014
Priority date	Mar 12, 2013
Publication date	Jan 14, 2016
Grant date	—

Abstract

Methods and compositions are provided for reducing the effects of amyloid beta (Aβ) oligomers on a cell. Aspects of the methods generally include providing an agent that prevents Aβ oligomer activation of PirB/LILRB2 protein on cells, or providing a PirB/LILRB2 polypeptide composition to cells to prevent the Aβ oligomer activation of cells mediated by non-PirB/LILRB2 receptors. These methods find many uses, for example, in treating the decline in CNS function in individuals suffering from an Aβ-associated disease or disorder, and for screening candidate agents to identify new therapeutics that interfere with these toxic effects of Aβ in individuals having an Aβ-associated disease or disorder.

First claim

That which is claimed is:

1 . A method of treating an Aβ oligomer-associated nervous system disease or disorder in an individual, treating cognitive decline associated with the presence of Aβ oligomers in an individual, or inhibiting synapse loss in the presence of Aβ oligomers in an individual, the method comprising:
administering to the individual an effective amount of an agent that inhibits Aβ oligomer activation of PirB/LILRB2.

2 . The method according to claim 1 , wherein the agent inhibits Aβ oligomer binding to PirB/LILRB2.

3 . The method according to claim 2 , wherein the agent comprises a PirB/LILRB2 polypeptide.

4 . The method according to claim 3 , wherein the PirB/LILRB2 polypeptide comprises the first two Ig-like domains of PirB or LILRB2.

5 . The method according to claim 3 , wherein the PirB/LILRB2 polypeptide consists essentially of the first two Ig-like domains of PirB or LILRB2.

6 . The method according to claim 3 , wherein the agent comprises a dimer of PirB/LILRB2 polypeptides.

7 . The method according to claim 6 , wherein each PirB/LILRB2 polypeptide of the dimer is fused to an Fc domain.

8 . The method according to claim 6 , wherein each PirB/LILRB2 polypeptide of the dimer comprises the first two Ig-like domains of PirB or LILRB2.

9 . The method according to claim 6 , wherein each PirB/LILRB2 polypeptide of the dimer consists essentially of the first two Ig-like domains of PirB or LILRB2.

10 . The method according to claim 2 , wherein the agent is an antibody that binds to amino acid residues within the first or second Ig-like domain of PirB or LILRB2.

11 . The method according to claim 1 , wherein the agent inhibits Aβ oligomer-induced PirB/LILRB2 activation of downstream proteins.

12 . The method according to claim 11 , wherein the agent inhibits PirB/LILRB2 activation of cofilin, PP2A, PP2B or PP2C.

13 . The method according to claim 1 , wherein the disease or disorder is Alzheimer's Disease or Down syndrome.

14 . The method according to claim 13 , wherein the method further comprises measuring cognition in the subject.

15 . The method according to claim 1 , wherein the disease or disorder is glaucoma.

16 . The method according to claims 15 , wherein the method further comprises measuring visual acuity in the subject.

17 . A method of treating an Aβ oligomer-associated nervous system disease or disorder in an individual, treating cognitive decline associated with the presence of Aβ oligomers in an individual, or inhibiting synapse loss in the presence of Aβ oligomers in an individual, the method comprising:
administering to the subject an effective amount of a PirB/LILRB2 polypeptide to treat the Aβ oligomer-associated nervous system disease or disorder in the individual, treat the cognitive decline associated with the presence of Aβ oligomers in the individual, or inhibit synapse loss in the presence of Aβ oligomers in the individual.

18 . The method according to claim 17 , wherein the PirB/LILRB2 polypeptide comprises the first two Ig-like domains of PirB or LILRB2.

19 . The method according to claim 17 , wherein the PirB/LILRB2 polypeptide consists essentially of the first two Ig-like domains of PirB or LILRB2.

20 . The method according to claim 17 , wherein the agent comprises a dimer of PirB/LILRB2 polypeptides.

21 . The method according to claim 17 , wherein each PirB/LILRB2 polypeptide of the dimer is fused to an Fc domain.

22 . The method according to claim 17 , wherein each PirB/LILRB2 polypeptide of the dimer comprises the first two Ig-like domains of PirB or LILRB2.

23 . A composition comprising:
a PirB/LILRB2 polypeptide consisting essentially of the first two Ig-like domains of PirB or LilRB2.

24 . A composition comprising a polypeptide dimer, the dimer comprising:
a first polypeptide comprises a dimerizing Fc domain fused to a PirB/LILRB2 polypeptide consisting essentially of the first two Ig-like domains of PirB or LILRB2, and a second polypeptide comprises a dimerizing Fc domain fused to a PirB/LILRB2 polypeptide consisting essentially of the first two Ig-like domains of PirB or LILRB2.

25 . The composition according to claim 23 or 24 , wherein the dimerizing Fc domain is human IgG1-Fc.

Assignees

• Univ Leland Stanford Junior

Inventors

• Shatz Carla J
• Kim Taeho

Classifications

• A61K38/1774

  Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules) · CPC title

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title

• C07K14/70503 Primary

  Immunoglobulin superfamily · CPC title

• C07K2319/70

  containing domain for protein-protein interaction · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title