Humanized antibodies that sequester amyloid beta peptide

• US 8,591,894 B2
• Filed: 12/22/2010
• Issued: 11/26/2013
• Est. Priority Date: 02/24/2000
• Status: Expired due to Term

• Current Assignee: Eli Lilly and Company, Washington University In St Louis
• Original Assignee: Eli Lilly and Company, Washington University In St Louis
• Inventors: Holtzman, David M, DeMattos, Ronald, Bales, Kelly R., Paul, Steven M., Tsurushita, Naoya, Vasquez, Maximiliano
• Primary Examiner(s): Emch, Gregory S
• Application Number:
  US12/976,282
• Publication Number:
  US 20110158986A1
• Time in Patent Office: 1,070 Days
• Field of Search: None
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

A method to treat conditions characterized by formation of amyloid plaques both prophylactically and therapeutically is described. The method employs humanized antibodies which sequester soluble Aβ peptide from human biological fluids or which preferably specifically bind an epitope contained within position 13-28 of the amyloid beta peptide Aβ.

Claims

1. A humanized antibody, or fragment thereof, comprising:

a. a light chain comprising three light chain complementarity determining regions (CDRs) having the following amino acid sequences;

2. The humanized antibody or fragment of claim 1, wherein the antibody or fragment is an IgG₁ immunoglobulin isotype.

3. The humanized antibody fragment of claim 1, wherein the fragment is a F_ab, F_ab′

, or F(_ab′

)² fragment.

4. The humanized antibody or fragment of claim 1, wherein the antibody or fragment is produced in a host cell selected from the group consisting of a myeloma cell, a chinese hamster ovary cell, a syrian hamster ovary cell, and a human embryonic kidney cell.

5. A polynucleic acid comprising a sequence coding for the light chain of the humanized antibody or fragment of claim 1.

6. A polynucleic acid comprising a sequence coding for the heavy chain of the humanized antibody or fragment of claim 1.

7. An expression vector comprising either a polynucleotide sequence encoding the light chain of the antibody or fragment of claim 1 or a polynucleotide sequence encoding the heavy chain of the antibody or fragment of claim 1.

8. A host cell line transfected with the expression vector of claim 7.

9. A host cell line transfected with two expression vectors of claim 7, wherein a first vector comprises the polynucleotide sequence coding for the light chain and a second vector comprises the sequence coding for the heavy chain.

10. A recombinant host cell line that expresses the humanized antibody or fragment of claim 1.

11. A pharmaceutical composition that comprises the humanized antibody or fragment of claim 1, and a pharmaceutically acceptable excipient.

12. A method to inhibit the formation of amyloid plaques or to inhibit the formation of toxic soluble Aβ

species in a human, comprising administering to a human subject in need of such inhibition an effective amount of a humanized antibody or fragment of claim 1.

13. A method to reduce the formation of amyloid plaques or to reduce the formation of toxic soluble Aβ

species in a human, comprising administering to a human subject in need of such reduction an effective amount of a humanized antibody or fragment of claim 1.

14. A method of treating, preventing, or reversing cognitive decline in a subject having clinical or pre-clinical Alzheimer'"'"'s disease, Down'"'"'s syndrome, or clinical or pre-clinical cerebral amyloid angiopathy comprising administering to the subject an effective amount of a humanized antibody or fragment of claim 1.

15. A method of improving cognition in a human subject having clinical or pre-clinical Alzheimer'"'"'s disease, Down'"'"'s syndrome, or clinical or pre-clinical cerebral amyloid angiopathy, comprising administering to the subject an effective amount of a humanized antibody or fragment of claim 1.

16. A method of therapeutically treating Alzheimer'"'"'s disease, comprising administering to a patient in need thereof an effective amount of a humanized antibody or fragment of claim 1.

17. The method of claim 16 wherein said Alzheimer'"'"'s disease is pre-clinical Alzheimer'"'"'s disease.

18. The method of claim 16 wherein said Alzheimer'"'"'s disease is clinical Alzheimer'"'"'s disease.