Transgenic mouse assay to determine the effect of Aβ antibodies and Aβ Fragments on alzheimer's disease characteristics

• US 6,710,226 B1
• Filed: 11/27/2000
• Issued: 03/23/2004
• Est. Priority Date: 12/02/1997
• Status: Expired due to Term

• Current Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson)
• Original Assignee: Neuralab Ltd. (Perrigo Company PLC)
• Inventors: Schenk, Dale B.
• Primary Examiner(s): Crouch, Deborah
• Application Number:
  US09/723,384
• Time in Patent Office: 1,212 Days
• Field of Search: 800/8, 800/12, 800/13, 800/14, 800/18, 800/3
• US Class Current: 800/12
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/53 DNA (RNA) vaccination
• CPC Class Codes: A61K 2039/55505 Inorganic adjuvants
• CPC Class Codes: A61K 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• CPC Class Codes: A61K 2039/55566 Emulsions, e.g. Freund's adjuvant, MF59
• CPC Class Codes: A61K 2039/55572 Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
• CPC Class Codes: A61K 2039/55577 Saponins; Quil A; QS21; ISCOMS
• CPC Class Codes: A61K 2039/6037 Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
• CPC Class Codes: A61K 2039/605 MHC molecules or ligands thereof
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/0007 Nervous system antigens; Prions
• CPC Class Codes: C07K 14/4711 Alzheimer's disease; Amyloid plaque core protein
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: G01N 2800/2821 Alzheimer

Abstract

The invention provides compositions and methods for treatment of amyloidogenic diseases. Such methods entail administering an agent that induces a beneficial immune response against an amyloid deposit in the patient. The methods are particularly useful for prophylactic and therapeutic treatment of Alzheimer'"'"'s disease. In such methods, a suitable agent is Aβ peptide, active fragments thereof or an antibody thereto.

Claims

1. A method of screening an antibody to Aβ

for use in treatment of Alzheimer'"'"'s disease, comprising;

administering an antibody that specifically binds to Aβ

to a transgenic mouse whose genome comprising a DNA sequence expressing an APP, wherein the mouse is disposed to develop characteristics of Alzheimer'"'"'s disease;

detecting a reduction in the extent or rate of development of at least one of the characteristic of Alzheimer'"'"'s disease relative to a control mouse.

2. The method of claim 1, wherein the antibody is a polyclonal antibody.

3. The method of claim 1, wherein the antibody is a monoclonal antibody.

4. The method of claim 3, further comprising screening a population of antibodies to identify an antibody that binds to an epitope within amino acids 1-28 of Aβ

.

5. The method of claim 3, wherein the antibody that is administered binds to an epitope within residues 1-10 of Aβ

.

6. The method of claim 3, wherein the antibody that is administered binds to an epitope within residues 1-16 of Aβ

.

7. The method of claim 3, wherein the antibody that is administered binds to an epitope within residues 1-5 of Aβ

.

8. The method of claim 3, wherein the antibody that is administered is a human antibody and binds to an epitope within residues 1-10 of Aβ

.

9. The method of claim 3, wherein the antibody is a humanized antibody and binds to an epitope within residues 1-10 of Aβ

.

10. The method of claim 3, wherein the antibody is a chimeric antibody and binds to an epitope within residues 1-10 of Aβ

.

11. The method of claim 3, wherein the antibody administered specifically binds to Aβ

in dissociated form with a binding affinity of at least 10⁷ M<sup>−

1</sup>.

12. The method of claim 3, wherein the antibody administered specifically binds to Aβ

42.

13. The method of claim 3, wherein the antibody administered has human IgG1 isotype.

14. The method of claim 3, wherein the antibody is administered intraperitoneally, subcutaneously, intramuscularly, or intravenously.

15. The method of claim 3, wherein the antibody is administered at a site separated by the blood-brain barrier from the brain of the transgenic mouse.

16. The method of claim 3, wherein the at least one detected characteristic is a level of Aβ

in the brain of the mouse.

17. The method of claim 3, further comprising monitoring the transgenic mouse for the level of antibodies to Aβ

in the blood.

18. A method of screening an immunogenic fragment of Aβ

for use in treatment of Alzheimer'"'"'s disease, comprising;

administering an immunogenic fragment of Aβ

to a transgenic mouse whose genome comprises a DNA sequence expressing an APP, wherein the mouse is disposed to develop characteristics of Alzheimer'"'"'s disease;

detecting a reduction in the extent or rate of development of at least one of the characteristics relative to a control mouse.

19. The method of claim 18, wherein the immunogenic fragment of Aβ

is administered with an adjuvant that enhances the antibody response to the immunogenic fragment of Aβ

.

20. The method of claim 19, wherein the adjuvant is alum.

21. The method of claim 19, wherein the adjuvant is MPL.

22. The method of claim 19, wherein the adjuvant is QS21.

23. The method of claim 18, wherein the immunogenic fragment of Aβ

is administered at a dosage greater than 20 μ

g.

24. The method of claim 18, wherein the immunogenic fragment of Aβ

is administered at a dosage greater than 50 μ

g.

25. The method of claim 18, wherein the immunogenic fragment of Aβ

is administered at a dosage greater than 100 μ

g.

26. The method of claim 18, wherein the immunogenic fragment of Aβ

comprises an epitope within amino acids 1-12 of Aβ

.

27. The method of claim 26, wherein the immunogenic fragment of Aβ

comprises up to 20 contiguous amino acids of Aβ

.

28. The method of claim 18, wherein a longer polypeptide comprising the immunogenic fragment of Aβ

and other amino acid is administered.

29. The method of claim 18, wherein the immunogenic fragment of Aβ

is administered intraperitoneally, subcutaneously, intramuscularly, or intravenously.

30. The method of claim 18, wherein the antibody is administered at a site separated by the blood-brain barrier from the brain of the transgenic mouse.

31. The method of claim 18, wherein the at least one detected characteristic is a level of Aβ

in the brain of the mouse.

32. The method of claim 18, further comprising monitoring the transgenic mouse for the level of antibodies to Aβ

in the blood.