Immunological control of β-amyloid levels in vivo
Disclosed are antibodies which catalyze hydrolysis of β-amyloid. Antibodies generated are characterized by the amide linkage which they hydrolyze. Methods of generating the antibodies by using β-amyloid peptides which incorporate transition state analogs are also provided. Also disclosed is a vectorized antibody which is characterized by the ability to cross the blood brain barrier, and is further characterized by the ability to catalyze the hydrolysis of β-amyloid. The vectorized antibody can take the form of bispecific antibody, which has a first specificity for the transferrin receptor and a second specificity for a taransition state adopted by β-amyloid hydrolysis.
1. A vectorized antibody which is characterized by the ability to catalyze the hydrolysis of β-amyloid at Val39-Val40, Phe19-Phe20 or Phe20-Ala21 of SEQ ID NO: 1, the vectorized antibody being produced by a method comprising immunizing an animal with a transition state analog which mimics the transition state that β-amyloid adopts during hydrolysis, the transition state analog being selected from a group consisting of statine and phenylalanine-statine.
2. The vectorized antibody of claim 1 which is a bispecific antibody.
3. The vectorized antibody of claim 2 which has a first specificity for the transferrin receptor and a second specificity for a transition state adopted by β-amyloid during hydrolysis and which is characterized by the ability to cross the blood brain barrier.
4. A method for generating antibodies which of catalyze the hydrolysis of β-amyloid at Val39-Val40, Phe19-Phe20 or Phe20-Ala21 of SEQ ID NO: 1, the method comprising the steps:
a) providing an antigen, the antigen being comprised of an epitope which mimics the conformation of a predetermined hydrolysis transition state of β-amyloid and selected from a group consisting of statine and phenylalanine-statine, and
b) immunizing an animal with the antigen under conditions appropriate for the generation of antibodies to the hydrolysis transition state.
5. A vectorized antibody which is characterized by the ability to catalyze the hydrolysis of β-amyloid at Val39-Val39-Val40, Phe19-Phe20 or Phe20-Ala21 of SEQ ID NO: 1, and the ability to bind specifically to a transition state analog which mimics the transition state that δ-amyloid adopts during hydrolysis, the transition state analog being selected from a group consisting of statine and phenylalanine-statine.
6. The vectorized antibody of claim 5 which is a bispecific antibody.
7. The vectorized antibody of claim 6 which has a first specificity for the transferrin receptor and a second specificity for a transition state adopted by β-amyloid during hydrolysis.
8. An antibody which catalyzes hydrolysis of β-amyloid at Val39-Val40, Phe19-Phe20 or Phe20-Ala21 of SEQ ID NO: 1, the antibody being produced by a method comprising immunizing an animal with a transition state analog which mimics the transition state that β-amyloid adopts during hydrolysis, the transition state analog being selected from a group consisting of statine and phenylalanine-statine.