VACCINE FOR THE TREATMENT OF ALZHEIMER'S DISEASE
The invention provides a method for the treatment of a patient having a more severe form of Alzheimer's disease (AD), where the severe form of AD is characterized by pathogenic deposits of amyloid beta peptide (Aβ), comprising the administration of an immunogenic fragment of Aβ capable of inducing an immune response in the form of antibodies to specific to the pathogenic deposits of Aβ and, in particular, to neurotoxic forms of Aβ including N-terminally truncated forms of Aβ. The invention further provides a method for selecting a suitable immunogenic fragment of Aβ for the treatment of a more severe form of AD.
1 . A method of treating patients having a more severe form of Alzheimer's disease (AD) comprising (i) determining that the patient has a more severe form of AD and (ii) administering an immunogenic fragment of Aβ in an amount effective to induce an immune response.
2 . The method of claim 1 where a patient having a more severe form of AD is selected from the group consisting of an individual with an Mini-Mental State Exam (MMSE) score of 20 or less, an individual with an Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score of 35 or higher, an individual with a Global Deterioration Scale (GDS) score of stage 5 or higher, an individual with a Clinical Dementia Rating-Sum of Boxes (CDR-SB) score of 2 or higher, an individual who is under 60-64 years of age and presents with symptoms of AD, or an individual diagnosed after genetic screening to have early onset Alzheimer's disease (EOAD) or a familial form of AD.
3 . The method of claim 2 wherein the immunogenic fragment of Aβ comprises a multivalent vaccine comprising multiple, non-contiguous immunogenic fragments of Aβ, each lacking a T-cell epitope.
4 . The method of claim 3 wherein the multivalent vaccine comprises Aβ3-10 and Aβ21-28 connected via a lysine scaffold.
5 . The method of claim 4 wherein the multivalent vaccine further comprises a carrier conjugated to the Aβ immunogenic fragments.
6 . The method of claim 5 wherein the multivalent vaccine is administered with an adjuvant.
7 . A method of selecting an immunogenic fragment of Aβ for use as a vaccine construct suitable for the treatment of patients having a more severe form of Alzheimer's disease (AD) comprising:
(i) administering a test immunogenic fragment of Aβ to an animal in an amount effective to induce an immune response; and
(ii) evaluating anti-sera from the immunized animal for cross-reactivity to N-terminally truncated forms of Aβ;
where a suitable vaccine construct would be selected as one capable of inducing an immune response in the form of antibodies specific to one or more N-terminally truncated forms of Aβ.
8 . The method of claim 7 wherein the N-terminal truncated form of Aβ is selected from the group consisting of Aβx-42, pGlu-Aβ3-40, pGlu-Aβ 3-42, pGlu-Aβ11-40, and pGlu-Aβ11-42, where x corresponds to residue 2 to 17 of naturally occurring Aβ.