Antibodies and fragments thereof which bind the carboxyl-terminus of an amino-terminal fragment of .beta.APP

• US 5,721,130 A
• Filed: 05/12/1995
• Issued: 02/24/1998
• Est. Priority Date: 04/15/1992
• Status: Expired due to Term

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Eli Lilly and Company, Athena Neurosciences Incorporated (Perrigo Company PLC)
• Inventors: Schenk, Dale B., Seubert, Peter A., Fritz, Lawrence C.
• Primary Examiner(s): Allen, Marianne P.
• Assistant Examiner(s): DUFFY, PATRICIA ANN
• Application Number:
  US08/440,423
• Time in Patent Office: 1,019 Days
• Field of Search: 530/387.1, 530/387.9, 530/388.1, 530/389.1, 530/391.1, 530/391.3, 435/70.21, 435/240.27, 436/547, 436/548
• US Class Current: 435/332
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 2267/0312 Animal model for Alzheimer's disease
• CPC Class Codes: A01K 2267/0318 Animal model for neurodegenerative disease, e.g. non- Alzheimer's
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: G01N 2333/4709 Amyloid plaque core protein
• CPC Class Codes: G01N 2800/2821 Alzheimer
• CPC Class Codes: G01N 33/5008 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/502 for testing non-proliferative effects
• CPC Class Codes: G01N 33/5058 Neurological cells
• CPC Class Codes: G01N 33/5091 for testing the pathological state of an organism
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease
• CPC Class Codes: Y10S 436/811 Test for named disease, body condition or organ function

Abstract

Processing of β-amyloid precursor protein (βAPP) is monitored by detecting the secretion of a soluble βAPP fragment resulting from cleavage of βAPP at the amino-terminus of β-amyloid peptide. In vivo monitoring of secretion of the βAPP fragment may be monitored for diagnosis and prognosis of Alzheimer'"'"'s disease and other β-amyloid-related diseases, while in vitro monitoring of such secretion from cultured cells may be monitored to identify inhibitors of β-amyloid production. The βAPP fragment may be detected using antibodies and other specific binding substances which recognize a carboxy-terminal residue on the fragment.

Claims

1. An antibody composition comprising antibody molecules that specifically recognize an amino-terminal fragment of β

APP which is cleaved at the amino-terminus of β

-amyloid peptide, but which antibody molecules do not specifically recognize a secreted fragment of β

APP whose sequence extends into the sequence of β

-amyloid peptide.

2. The antibody composition of claim 1, wherein the antibody molecules comprise intact immunoglobulins.

3. The antibody composition of claim 1, wherein the antibody molecules comprise immunoglobulin fragments which specifically recognize the amino-terminal fragment of β

APP which is cleaved at the amino-terminus of β

-amyloid peptide, but which do not specifically recognize a secreted fragment of β

APP whose sequence extends into the sequence of β

-amyloid peptide.

4. The antibody composition of claim 3 wherein the immunoglobulin fragment is an F(ab) fragment, and Fv fragment, a V_L fragment or a V_H fragment.

5. The antibody composition of claim 1, wherein the antibody molecules have been raised against a peptide comprising at least residues 591-596 of β

APP.

6. The antibody composition of claim 5, comprising antisera raised against said peptide.

7. The antibody composition of claim 1, wherein the amino-terminal fragment of β

APP has a carboxy-terminal residue that corresponds to methionine⁵⁹⁶ or leucine⁵⁹⁶ .

8. The antibody composition of claim 1 wherein the antibody molecules are labelled.

9. The antibody composition of claim 1 comprising monoclonal antibodies.

10. The antibody composition of claim 9 wherein the antibody molecules are labelled.

11. The antibody composition of claim 1 wherein the antibody molecules are mouse antibody molecules, rabbit antibody molecules, sheep antibody molecules or goat antibody molecules.

12. The antibody composition of claim 1 wherein the antibody molecules are recombinantly produced.

13. A hybridoma that produces antibody molecules that specifically recognize an amino-terminal fragment of β

APP which is cleaved at the amino-terminus of β

-amyloid peptide, but which antibody molecules do not specifically recognize a secreted fragment of β

APP whose sequence extends into the sequence of β

-amyloid peptide.

14. The hybridoma of claim 13 wherein the amino-terminal fragment of β

APP has a carboxy-terminal residue that corresponds to methionine⁵⁹⁶ or leucine⁵⁹⁶.